Biology subjects

Abrahams, D.

Publications and source records attributed to Abrahams, D..

6 recordsLinked to original sources

bioRxiv2026

The effect of atmospheric pollution caused by pheasant Phasianus colchicus releases on the epiphytic flora on trees in sensitive woodlands

The release and management of pheasants (Phasianus colchicus) in the UK for recreational shooting exerts a range of effects on the ecosystem into which they are released. We studied possible effect of nutrient deposition on epiphytic tree flora at 20 pheasant release sites distributed through England (18) and Wales (2) during winter and spring 2023/24. Sites were all Ancient Semi-natural Woodlands (ASNWs) and had substantial (600-8000 pheasants) in a single release pen. We measured N-sensitive and N-tolerant indicator bryophyte and lichen species on tree trunks near to the pen and then in plots along a transect 100m, 250m, 500m and 1km+ away from the pen. To achieve a gradient of pheasant use, the transects were located in the opposite direction to the game managed / shooting area. We recorded 1.9 times more coverage of N-tolerant lichens and bryophytes combined on selected tree species at the pen-edge compared to the control plots. The relationship showed a decline from the pen edge to 250m away but then stabilised. We also detected higher levels of coverage of N-sensitive tree flora at 100m and 250 m compared to the penedge plot. These measures were also higher at these mid distances compared to the 500m and 1000m plots. We suggest far plots were nearer wood edges and were affected by ambient inputs of aerial N from farmland and other external sources. The overall interpretation is that concentrations of pheasants in and around release pens for several months from late summer until early winter in ASNWs does affect the balance of N-sensitive and tolerant tree flora up to potentially 250m and this is a consideration when locating release pens in and near to sensitive woods.

ecology↗

bioRxiv2025

A simple, anesthesia-free infusion technique for in vivo metabolic tracing

Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.

biochemistry↗

bioRxiv2024

Nanoparticles use magnetoelectricity to target and eradicate cancer cells

This study presents the first in vivo and in vitro evidence of an externally controlled, predictive, MRI-based nanotheranostic agent capable of cancer cell specific targeting and killing via irreversible electroporation (IRE) in solid tumors. The rectangular-prism-shaped magnetoelectric nanoparticle is a smart nanoparticle that produces a local electric field in response to an externally applied magnetic field. When externally activated, MENPs are preferentially attracted to the highly conductive cancer cell membranes, which occurs in cancer cells because of dysregulated ion flux across their membranes. In a pancreatic adenocarcinoma murine model, MENPs activated by external magnetic fields during magnetic resonance imaging (MRI) resulted in a mean three-fold tumor volume reduction (62.3% vs 188.7%; P < .001) from a single treatment. In a longitudinal confirmatory study, 35% of mice treated with activated MENPs achieved a durable complete response for 14 weeks after one treatment. The degree of tumor volume reduction correlated with a decrease in MRI T2* relaxation time (r = .351; P = .039) which suggests that MENPs have a potential to serve as a predictive nanotheranostic agent at time of treatment. There were no discernable toxicities associated with MENPs at any timepoint or on histopathological analysis of major organs. MENPs are a noninvasive alternative modality for the treatment of cancer. SummaryWe investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, [≥]300 {micro}g of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory studys experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

bioengineering↗

bioRxiv2023

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

cancer biology↗

bioRxiv2021

Proton export drives the Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect". It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

cancer biology↗

bioRxiv2019

Lymph Nodes Inhibit T-cell Effector Functions Locally by Establishing Acidic Niches

Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical T-zones of lymph nodes are highly acidic. We further show that T-cells can be activated by dendritic cells at low pH, and their effector functions are restored rapidly upon increasing pH. Thus, we describe a novel physiological mechanism whereby activated T-cells are kept in stasis by acidosis whilst resident in lymph nodes.

physiology↗