Biology subjects

Woods, E.

Publications and source records attributed to Woods, E..

8 recordsLinked to original sources

bioRxiv2026

Progressive deterioration of adaptive immune repertoires in Down syndrome linked to interferon hyperactivity and lymphoid tissue disorganization

Persons with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display strong dysregulation of adaptive immunity, which underlies high risk of complications from infections, widespread autoimmunity, and poor vaccine responses. However, the mechanisms by which T21 dysregulates adaptive immunity across the lifespan remain poorly understood. We report here a multimodal analysis of adaptive immunity across development and aging in DS, including deep B cell profiling by mass cytometry matched to transcriptome and proteome data, B and T cell receptor sequencing (BCR, TCR), and spatial transcriptomics of tonsil tissue. T21 causes progressive shifts in B cell subsets together with accelerated age-dependent B cell loss linked to hyperactive interferon and JAK/STAT signaling. The peripheral immunoglobulin repertoire shows dysregulated class switching, progressive loss of diversity, differential VDJ usage, and imbalanced rates of somatic hypermutation across immunoglobulin isotypes mirrored by contraction and skewing of the TCR repertoire. In children with DS, tonsil tissues are highly disorganized with smaller germinal centers, fibrotic intrusions, lower rates of cell proliferation, strong inflammatory signaling, and transcriptional programs indicative of dysregulated lymphocyte homing and residence. Together, these results point to hyperactive interferon signaling as a driver of dysregulated adaptive immunity in DS amenable to early therapeutic intervention.

immunology↗

bioRxiv2026

Altered Tonsillar Microbiome in Children with Down Syndrome and Obstructive Sleep Apnea

Background and ObjectivesChildren with Down syndrome (DS) have a high prevalence of obstructive sleep apnea (OSA) due to anatomic, neuromuscular, immunological and metabolic factors, yet the contribution of the tonsillar microbiome to airway obstruction in this population remains unexplored. We hypothesized that DS-associated OSA would be associated with a distinct tonsillar microbiome compared to non-DS OSA. MethodsTonsillar tissue from 22 DS and 18 NDS participants were analyzed by 16S rRNA sequencing. Alpha and beta diversity were assessed using Faiths phylogenetic diversity and UniFrac distances, respectively, and significantly different taxa were identified with ANCOM-BC and Mann-Whitney testing. ResultsAlthough overall microbial richness and community structure were similar between groups, overweight DS participants demonstrated increased phylogenetic diversity compared to normal-weight DS peers. Taxonomic profiling of the entire patient cohort revealed that in DS tonsils there were selective alterations in key genera with selective depletion of Haemophilus and enrichment of Staphylococcus, Rothia, and Lactobacillales. Haemophilus abundance correlated positively with tonsil weight in both cohorts. ConclusionsThese findings suggest that while global diversity is preserved, specific microbial shifts distinguish the DS tonsillar niche, potentially reflecting altered immune and metabolic environments associated with trisomy 21. Understanding these microbial differences may reveal mechanisms underlying the higher incidence and persistence of OSA in DS and inform targeted therapeutic strategies.

microbiology↗

bioRxiv2025

Very low amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in ALS

IntroductionIn many clinical and research settings, transcranial magnetic stimulation (TMS) intensities are standardised based on resting motor threshold (RMT). It is well-established that contraction of the target muscle increases motor evoked potential (MEP) amplitude and correspondingly decreases RMT. As such, when estimating RMT it is crucial to ensure the target muscle is relaxed. Typically trials in which baseline electromyographic (EMG) amplitude exceeds a specified threshold are rejected. The influence of motor activity below typical rejection thresholds on MEP amplitudes has yet to be established. MethodsWe retrospectively analysed TMS-EMG data collected during RMT measurement in 45 healthy controls (1761 datapoints) and 35 people with amyotrophic lateral sclerosis (ALS, 1238 datapoints). Trials where root mean squared (RMS) baseline EMG amplitude exceeded 10{micro}V were rejected. Generalised linear mixed-effects models were used to assess effects of muscle activity below this rejection threshold on probability of evoking an MEP with peak-to-peak amplitude [≥]50{micro}V. ResultsGreater sub-rejection-threshold activity significantly increases MEP probability in controls (p<0.0004) and people with ALS (p=0.0010). Models predicted a 31-38% increase in MEP probability when baseline RMS-EMG amplitude increased from 1{micro}V to 9{micro}V. Sub-rejection- threshold baseline activity was significantly greater in ALS than controls (p=0.0055). DiscussionWe have shown for the first time that higher EMG amplitudes below a typical rejection threshold markedly increase probability of evoking an MEP with peak-to-peak amplitude [≥]50{micro}V. Researchers should take measures to account for effects of sub-rejection-threshold activity on RMT, particularly in populations where baseline activity may be elevated, such as in ALS.

neuroscience↗

bioRxiv2025

Divergence of root system traits in soybean between breeding and diversity lines

Roots are critical for supporting basic plant functions such as anchoring in various substrates, uptake of water and nutrients, and hosting symbiotic relationships. In crops, indirect changes to root system architecture (RSA) have occurred largely as a result of selection for yield or other related aboveground traits. In cultivated soybean (Glycine max), evidence of changes to RSA resulting from breeding for crop performance has been inconsistent, with some studies supporting an overall decrease in performance-related trait values, such as root length and density, and other work showing the opposite. The current study sets out to ask whether there is any systematic differentiation in RSA between a set of elite breeding lines (n=8) of soybean developed for the Midwest United States and a group of biogeographically diverse landraces from the USDA Soybean Germplasm Collection (n=16. Groups are compared across three distinct developmental stages (V2-V6, V7-R2, R3-R7) and two contrasting soil environments. In total, 432 root systems were phenotyped for 12 structural traits derived from 2D images along with root and shoot biomass. A new 3D root modeling approach leveraging photogrammetry-derived pointclouds is additionally tested on a subset of 30 contrasting root systems. Results indicate that the diversity lines had smaller root systems overall but greater phenotypic plasticity in response to soil environment as compared to breeding lines. Additionally, the study finds evidence for trade-offs between above-ground and below-ground trait plasticity. Core ideasO_LIPrevious work suggests crop root system architecture (RSA) has changed as a result of indirect selection C_LIO_LIThis study compares RSA in elite breeding lines with that of diverse landraces in cultivated soybean C_LIO_LIA total of 432 root systems are analyzed across 24 genotypes, two soil environments and three developmental stages C_LIO_LIFindings show diversity lines have smaller root systems but greater plasticity in response to soil environment C_LI

plant biology↗

bioRxiv2024

Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax

Children with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) are at increased risk for treatment-related mortality and relapse, highlighting the need for new therapies. Leukemia cell lines (CLs) have been fundamental to understanding therapeutic responses to pharmacological agents. We generated three DS B-ALL CLs characterized with diverse genomic alterations, including IGH::CRLF2 rearrangement (BCR::ABL1 like), mutations in FLT3 and TP53, and a novel ERG::CEBPD rearrangement. DS CLs had diminished proliferation, metabolism, and mitochondrial function when compared to non-DS (NDS) CLs and interestingly, these findings were similar to NDS Philadelphia chromosome-like (Ph-like) B-ALL CLs. Based on similar mitochondrial defects and prior preclinical data using Venetoclax for Ph-like B-ALL, we hypothesized that Venetoclax would be effective in DS. Intriguingly, Venetoclax was more effective in DS when compared to both NDS and Ph-like CLs. Efficacy was observed in DS patient derived xenografts (PDXs) and diagnostic/relapsed patient samples treated with Venetoclax, which synergized with Trametinib and Vincristine. Mass spectrometry-based multiomics analyses in DS and NDS B-ALL patient samples revealed an enriched metabolite profile in DS, particularly in the hubs of glucose metabolism and polyunsaturated phosphatidylcholines and phosphatidylinositols. Transcriptome analyses in DS B-ALL patients (n=249) supported enhanced glucose and fatty acid metabolism. Glucose regulated B-ALL viability through de novo serine biosynthesis. Targeting serine synergized with Venetoclax in DS B-ALL CLs. In summary, we have generated novel tools for studying DS B-ALL and identify altered metabolism in DS that responds to Venetoclax.

cancer biology↗

bioRxiv2023

Ischaemic Preconditioning attenuates Chronic Renal Damage following Ischaemia Reperfusion Injury

Acute Kidney Injury (AKI) is a common cause of Chronic Kidney Disease (CKD). The leading cause of AKI worldwide is Ischaemia Reperfusion Injury (IRI), seen most commonly in the clinical setting as a result of sepsis-driven hypotension. We are increasingly recognising, however, that AKI and CKD are one closely associated continuum of disease, rather than distinct entities. Ischaemic Preconditioning (IPC) is a strategy aimed at reducing the deleterious effects of IRI. This study demonstrates an efficacious model of kidney IRI, and the protective influence of IPC in attenuating renal injury/fibrosis. A rat model of bilateral kidney IRI was used: Male Lewis rats (n=84) were assigned to IRI, sham or IPC. In IRI, renal pedicles were clamped for 45 minutes. IPC groups underwent pulsatile IPC prior to IRI. Kidneys were retrieved at 24-hours, 48-hours, 7-days, 14-days and 28-days, and assessed histologically. IRI led to marked histological damage and renal fibrosis development by 28 days. Histological injury scores and degree of fibrosis were significantly increased following IRI and attenuated with IPC. IPC resulted in a 66% reduction in renal fibrosis at 28 days (p<0.001). IRI also led to a significant increase in serum creatinine acutely, which was attenuated by IPC (p<0.0001). Interestingly at 14-days, there was limited histological damage and differentiation between IRI and IPC kidneys was difficult. IPC can protect from both acute and chronic kidney damage. 14-days post IRI represents a transitional phase, which maybe a timepoint for commitment to either fibrosis or recovery, and hence offers potential for therapeutic intervention.

pathology↗

bioRxiv2022

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Most patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.

cancer biology↗

bioRxiv2019

TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

Natural Killer (NK) cells provide important protection from cancer and are a key requirement for particular immunotherapies. In activated NK cells, a metabolic response towards increased glycolysis and oxidative phosphorylation is crucial for NK cell effector functions. However, there is accumulating evidence that NK cells become dysfunctional during chronic inflammatory diseases, such as human breast cancer. This dysfunction is apparent in peripheral blood NK cells and can impact on normal NK cell immune responses and their effective targeting during immunotherapy. Herein, we demonstrate that prolonged cytokine stimulation combined with metabolic restriction, through inhibition of mTORC1, is sufficient to induce persistent dysfunction in human NK cells. TGF{beta}, also restricted NK cell metabolism and promoted persistent NK cell dysfunction. NK cells from patients with metastatic breast cancer had profound metabolic defects in glycolysis and mitochondrial function, and clear structural differences in NK cell mitochondrial morphology. Importantly, blocking elevated TGF{beta} improved readouts of metabolism and restored IFN{gamma} production in patient NK cells.

immunology↗