Biology subjects

Williams, C. A.

Publications and source records attributed to Williams, C. A..

15 recordsLinked to original sources

bioRxiv2026

A global analysis of climate-driven reversal risks in forests

The integrity of forest-based climate solutions and carbon credits requires persistent carbon storage, but climate change is increasing the risk of natural disturbances that release carbon back into the atmosphere. Using global satellite data, disturbance modeling, and machine learning, we provide the first spatially explicit and scenario-based maps of long-term probability of carbon loss in global forests under different disturbance severities and climate scenarios. We find that North American conifer forests, tropical rainforests, and Asian (sub)tropical dry forests face the greatest risks, and that Eurasian temperate forests, African (sub)tropical dry forests face the lowest. Globally, the likelihood of reversals over 100 years is 31%-42% across all scenarios. Our work helps to maximize the benefits of forest-based climate solutions by informing more strategic project placement and more robust reversal-risk compensation mechanisms, such as buffer pools, and highlights critical additional science to better understand and manage risks of these essential climate solutions. Plain Language SummaryForests can help slow and lessen climate impacts. However, in places this benefit is becoming less reliable as climate change increases natural disturbances such as wildfires, drought, storms, and insect outbreaks, which can release stored carbon back into the atmosphere. In this study, we created the first scenario-based global maps of risks and found that the risk of carbon loss is widespread and highly variable across regions, with especially high vulnerability in North American conifer forests, tropical rainforests, and Asian tropical and subtropical dry forests. Our study highlights the importance of considering disturbance risks when siting forest projects for climate mitigation, and developing protocols for carbon markets, such as in voluntary programs and under the UNFCCC Paris Agreement. Key PointsO_LIA demographic model framework estimates the reversal risk from natural disturbances over 100 years in global forests C_LIO_LISpatially explicit maps under different severity scenarios show variation in the integrated 100-year risk of carbon reversal C_LIO_LISpatially explicit maps estimate the required buffer pool needed to compensate for disturbance-driven reversals in global forests C_LI

ecology↗

bioRxiv2026

Atomic layer deposition for core-shell microparticle vaccines enabling programmable antigen delivery to lymph nodes enhance humoral immune responses

Technologies that simplify complex dosing regimens as single-shot immunizations may be important for vaccines against difficult to neutralize pathogens. Here we characterized delivery mechanisms of core-shell microparticles comprising clinically-relevant HIV immunogen formulations spray-dried to form solid spherical microparticles and subsequently coated with a nanoscopic alumina shell using atomic layer deposition (ALD). ALD particles exhibited a time delay in antigen release programmed by the alumina shell followed by prolonged antigen release, which steadily accumulated in antigen-presenting cells at the injection site and draining lymph nodes and accumulated on follicular dendritic cells in B cell follicles. ALD vaccines elicited continuous expansion of antigen-specific germinal center B cells over 8 weeks, serum antibody responses with >10-fold slower antigen-binding off-rates, and 2-fold more long-lived plasma cells compared to traditional bolus vaccination with potent adjuvants. Single administration ALD technology thus promotes key events in the primary immune response important for vaccines against HIV and other challenging pathogens.

immunology↗

bioRxiv2026

RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease

The interaction of the endosomal sorting protein SORL1 with the retromer complex at endosomal membranes controls a recycling pathway whose dysfunction is pathogenic in Alzheimers disease (AD) and is linked to other neurodegenerative disorders. To search for novel therapeutic targets, we hypothesize that endosomal SORL1-retromer might be regulated by SORL1s cytoplasmic tail. We begin by completing an in vitro analysis of the tail and show that its phosphorylation by ROCK2 (Rho-associated kinase 2) reduces SORL1s affinity to retromer. Since RhoGEF12 (Rho guanine nucleotide exchange factor 12) is an upstream activator of ROCK2 that is upregulated in AD, we used a RhoGEF12 pharmacological inhibitor to mechanistically and therapeutically validate the findings in neuronal cultures. First, in mouse neurons we confirm that the inhibitor increases endosomal SORL1-retromer. Next, we turned to human iPSC-derived neurons to show that the inhibitor reduces A{beta}40 and A{beta}42, an indicator of pathway upregulation, in a SORL1-dependent manner. Finally, we validate its therapeutic potential by applying the RhoGEF12 inhibitor to human iPSC-derived neurons expressing AD-associated mutations in either APP or SORL1. Collectively, our results identify a novel and therapeutically amenable mechanism that regulates endosomal SORL1-retromer and preclinically validate RhoGEF12 as a therapeutic target for AD and potentially other neurodegenerative disorders. One sentence summaryPharmacological inhibition of RhoGEF12 increases endosomal SORL1-retromer recycling and reduces pathogenic amyloid secretion in human neuronal models, identifying a novel, targetable pathway for treating Alzheimers disease.

neuroscience↗

bioRxiv2025

Evaluating Microglial Contributions to the Neurovascular Unit in Health and Neurodegeneration Using Human In Vitro Models

BackgroundMicroglia are emerging as critical regulators of neurovascular function in health and Alzheimers disease (AD), yet their interactions with the human neurovascular unit (NVU), particularly brain endothelial cells, remain incompletely understood. Current in vitro NVU platforms typically exclude microglia and lack perfusable vascular networks with physiologically relevant architecture. Here, we established complementary two-dimensional (2D) and three-dimensional (3D) NVU models to investigate microglia-endothelial and microglia-neurovascular interactions. MethodsHuman induced pluripotent stem cell derived-neurons (iNs), astrocytes (iAs), and microglia-like cells (iMGLs) were incorporated into a soft-lithography based engineered microvessel system to establish a multicellular neuroimmune-vascular model. To specifically evaluate iMGL-endothelial cell (EC) interactions, iMGL were co-cultured with primary human brain microvascular endothelial cells (HBMECs) and junctional protein localization was evaluated using immunofluorescence. The barrier integrity of engineered microvessels containing iMGL was evaluated using dextran permeability. Our 2D and 3D systems were stimulated with tumor necrosis factor- (TNF) to evaluate whether iMGL would promote or attenuate EC inflammation and barrier breakdown. ResultsIncorporation of iNs, iAs, and iMGLs into a perfusable vascular model enabled a more complete representation of NVU cellular diversity and promoted neuronal health. In monolayer co-culture with iMGL, HBMECs enhanced the junctional localization of tight and adherens junction proteins through both contact-dependent and paracrine mechanisms. Following an inflammatory challenge, iMGLs reduced endothelial inflammatory activation, suggesting a protective role in response to AD-relevant inflammatory conditions. Finally, when embedded in 3D collagen matrices surrounding perfusable endothelialized lumen networks, iMGLs reduced dextran permeability and preserved endothelial barrier integrity following TNF challenge. ConclusionsTogether, these findings establish a 3D perfusable neuroimmune-vascular model that enables the dissection of microglial contributions to neurovascular function in health and disease.

cell biology↗

bioRxiv2025

The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function

BackgroundSynaptic dysfunction is an early feature of Alzheimers disease (AD) and a significant contributor to cognitive decline and neurodegeneration. Proper localization of proteins involved in pre-and post-synaptic composition is dependent on endosomal recycling and trafficking. Alterations in trafficking complexes, such as retromer, have been shown to impair neuronal synaptic function. The SORL1 gene has been strongly implicated in AD pathogenesis and its protein product, SORLA, is an endosomal receptor that works in conjunction with retromer to regulate endosomal recycling. MethodsWe utilized our established human induced pluripotent stem cell (hiPSC) derived excitatory cortical neuron model to examine SORL1s role in synaptic protein composition and neuronal function. We used Quantitative Multiplex co-Immunoprecipitation (QMI), a mesoscale proteomics assay to measure synaptic protein interactions, immunocytochemistry to assay synapses and AMPA receptor subunits, and multi-electrode arrays (MEAs) to measure neuronal function of SORL1 KO and isogenic control hiPSC derived neurons. ResultsWe show that loss of SORL1 expression significantly changes many synaptic protein-protein interactions and patterns of expression. We demonstrate that SORL1 deficient neurons are hyperactive and that the increased activity is driven by glutamatergic neurotransmission. Hyperexcitability has been seen in other models of AD with familial AD variants in amyloid precursor protein and presenilin genes, due to the increases in amyloid beta (A{beta}) peptides. In the case of SORL1 deficiency, the hyperexcitability we observe is primarily due to mis-trafficking of synaptic proteins, rather than an overall increase in A{beta}. Finally, we find that SORL1 deficient neurons have impaired synaptic plasticity. ConclusionsThese findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis. Furthermore, our work supports further emphasis on exploring the SORL1-retromer pathway for therapeutic development in AD.

neuroscience↗

bioRxiv2025

Designed NGF mimetics with reduced nociceptive signatures in neurons

The clinical use of Nerve Growth Factor (NGF) for neuronal regeneration has been hampered by pain sensitization side effects. NGF signals through the receptor tyrosine kinase TrkA and the co-receptor p75NTR; pain sensitization is thought to involve p75NTR. We sought to overcome this limitation by de novo design of a TrkA agonist that does not bind p75NTR. We designed homodimeric TrkA engaging constructs that dimerize TrkA subunits in a variety of geometries, and identified those eliciting the strongest signaling. The resulting designed agonists are able to stimulate transdifferentiated neurons and neuroblastoma cell lines, leading to neurite outgrowth and neuronal differentiation, with considerably reduced transcription of inflammation and pain related genes. These agonists are promising candidates for promoting neuronal regeneration without adverse side effects. HighlightsO_LIDe novo designed TrkA agonists activate MAPK and PI3K-AKT signaling C_LIO_LIRigid fusions allow for highly tunable signaling signatures C_LIO_LITrkA agonists lead to neurite outgrowth in neuroblastoma cells comparable to retinoic acid C_LIO_LIModulation of the TrkA pathway without co-stimulating p75NTR leads to a downregulation of inflammatory and nociceptive signature in neurons. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/648806v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@c48066org.highwire.dtl.DTLVardef@c9c5a7org.highwire.dtl.DTLVardef@cf8ebdorg.highwire.dtl.DTLVardef@a4345a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

A human cytomegalovirus prefusion-like glycoprotein B subunit vaccine elicits similar humoral immunity to that of postfusion gB in mice

Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects. Despite the global disease burden, there is no FDA-approved HCMV vaccine. The most efficacious HCMV vaccine candidates to date have used glycoprotein B (gB), a class III viral fusion protein, in its postfusion form. While some viral fusion proteins have been shown to elicit stronger neutralizing responses in their prefusion conformation, HCMV prefusion-like and postfusion gB were recently shown to elicit antibodies with similar fibroblast neutralization titers in mice. We aimed to define and compare the specificity and functionality of plasma IgG elicited by distinct prefusion-like and postfusion gB constructs. Prefusion-like and postfusion gB elicited comparable IgG responses that predominantly mapped to AD-5 antigenic domain known to elicit neutralizing antibodies. Interestingly, postfusion gB elicited significantly higher plasma IgG binding to cell-associated gB and antibody dependent cellular phagocytosis than that of prefusion-like gB. The vaccines elicited comparable neutralization titers of heterologous HCMV strain AD169r in fibroblasts, yet neither elicited neutralizing titers against the vaccine-matched strain Towne in fibroblasts. Our data indicate that gB in this prefusion-like conformation elicits similar specificity and functional humoral immunity to that of postfusion gB, unlike certain class I viral fusion proteins which have been used as vaccine antigens. These findings deepen our understanding of the immune response elicited by class III fusion proteins and may inform further design and testing of conformationally-dependent herpesvirus glycoprotein vaccine candidates.

immunology↗

bioRxiv2024

The ERK5 MAP kinase regulates annexin complexes and membrane dynamics in embryonic stem cells

The ERK5 MAP kinase signalling pathway controls key processes in mouse Embryonic Stem Cells (mESCs) maintenance, including expression of naive pluripotency genes and a transcriptional programme for stem cell rejuvenation. However, quantitative proteomics suggests that ERK5 signalling controls levels of proteins implicated in diverse biological processes. Here, we show that Annexin A2 (ANXA2) and its accessory protein S100A10, which are implicated in regulation of membrane dynamics, are major targets of the ERK5 signalling pathway in mESCs. ERK5 activation promotes expression of the ANXA2/S100A10 protein complex via transcriptional induction of the KLF2 pluripotency factor. Furthermore, either ERK5 signalling or ectopic expression of the ANXA2/S100A10 complex promotes formation of membrane protrusions in mESCs. Our data therefore identify a new function for the ERK5 pathway in regulation of an Annexin complex and membrane dynamics, which may have implications for development and disease.

developmental biology↗

bioRxiv2023

TEMPORAL PATTERN OF SYNAPTIC ACTIVATION DIFFERENTIALLY AFFECTS PLASTICITY IN NORMAL AND INJURED BRAIN

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction, however little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials (PSPs) in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naive), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naive or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.

neuroscience↗

bioRxiv2022

Perpendicular Shear Stresses Drive Transmural Helical Remodeling in Engineered Human Ventricular Models

Tissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture.

bioengineering↗

bioRxiv2021

An ERK5-KLF2 signalling module regulates early embryonic gene expression dynamics and stem cell rejuvenation

The ERK5 MAP kinase signalling pathway drives transcription of naive pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5-dependent ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative-feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern dynamic 2C gene transcription and mESC rejuvenation.

developmental biology↗

bioRxiv2020

CoVaccine HT™ adjuvant potentiates robust immune responses to recombinant SARS-CoV-2 Spike S1 immunisation

The current COVID-19 pandemic has claimed hundreds of thousands of lives and its causative agent, SARS-CoV-2, has infected millions, globally. The highly contagious nature of this respiratory virus has spurred massive global efforts to develop vaccines at record speeds. In addition to enhanced immunogen delivery, adjuvants may greatly impact protective efficacy of a SARS-CoV-2 vaccine. To investigate adjuvant suitability, we formulated protein subunit vaccines consisting of the recombinant S1 domain of SARS-CoV-2 Spike protein alone or in combination with either CoVaccine HT or Alhydrogel. CoVaccine HT induced high titres of antigen-binding IgG after a single dose, facilitated affinity maturation and class switching to a greater extent than Alhydrogel and elicited potent cell-mediated immunity as well as virus neutralising antibody titres. Data presented here suggests that adjuvantation with CoVaccine HT can rapidly induce a comprehensive and protective immune response to SARS-CoV-2.

immunology↗

bioRxiv2020

Genomics of Ocular Chlamydia trachomatis after 5 years of SAFE interventions for trachoma in Amhara, Ethiopia

BackgroundTo eliminate trachoma as a public health problem, the WHO recommends the SAFE strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed over 124 million doses of antibiotic between 2007 and 2015. Despite these interventions, trachoma remained hyperendemic in many districts and a considerable level of Chlamydia trachomatis (Ct) infection was evident. MethodsWe utilised residual material from Abbott m2000 Ct diagnostic tests to sequence 99 ocular Ct samples from Amhara and investigated the role of Ct genomic variation in the continued transmission of Ct following 5 years of SAFE. FindingsSequences were typical of ocular Ct, at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide-resistance in this Ct population. Polymorphism in a region around ompA gene was associated with village-level TF prevalence. Additionally, greater ompA diversity at the district-level was associated with increased Ct infection prevalence. InterpretationWe found no evidence for Ct genomic variation contributing to continued transmission of Ct after treatment, adding to previous evidence that azithromycin does not drive acquisition of macrolide resistance alleles in Ct. Increased Ct infection in villages and in districts with more ompA variants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity. FundingEuropean Commission; Neglected Tropical Disease Support Center; International Trachoma Initiative

genomics↗

bioRxiv2019

Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70% of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis patients and from skin swabs of epidermal vesicles on non-encephalopathic patients. Phylogenetic analysis revealed high inter-host diversity and little population structure. By contrast, samples from different lesions in the same patient clustered with similar patterns of allelic variants. Comparison of consensus genome sequences shows HSV-1 has been freely recombining, except for distinct islands of linkage disequilibrium (LD). This suggests functional constraints prevent recombination between certain genes, notably those encoding pairs of interacting proteins. Distinct LD patterns characterised subsets of viruses recovered from CSF and skin lesions, which may reflect different evolutionary constraints in different body compartments. Functions of genes under differential constraint related to immunity or tropism and provide new hypotheses on tissue-specific mechanisms of viral infection and latency.

evolutionary biology↗

bioRxiv2017

Modelling of the cardiopulmonary responses to maximal aerobic exercise in patients with cystic fibrosis

Cystic fibrosis (CF) is a debilitating chronic condition, which requires complex and expensive disease management. Exercise has now been recognised as a critical factor in improving health and quality of life in patients with CF. Hence, cardiopulmonary exercise testing (CPET) is used to determine aerobic fitness of young patients as part of the clinical management of CF. However, at present there is a lack of conclusive evidence for one limiting system of aerobic fitness for CF patients at an individual patient level.\n\nHere, we perform detailed data analysis that allows us to identify important systems-level factors that affect aerobic fitness. We use patients data and principal component analysis to confirm the dependence of CPET performance on variables associated with ventilation and metabolic rates of oxygen consumption. We find that the time at which participants cross the anaerobic threshold (AT) is well correlated with their overall performance. Furthermore, we propose a predictive modelling framework that captures the relationship between ventilatory dynamics, lung capacity and function and performance in CPET within a group of children and adolescents with CF. Specifically, we show that using Gaussian processes (GP) we can predict AT at the individual patient level with reasonable accuracy given the small sample size of the available group of patients. We conclude by presenting future perspectives for improving and extending the proposed framework.\n\nOur modelling and analysis have the potential to pave the way to designing personalised exercise programmes that are tailored to specific individual needs relative to patients treatment therapies.

physiology↗