Biology subjects

Cox, P.

Publications and source records attributed to Cox, P..

4 recordsLinked to original sources

bioRxiv2026

PINN-ing the Balloon: A Physically Informed Neural Network Modelling the Nonlinear Haemodynamic Response Function in MRI

Accurate characterisation of the haemodynamic response function (HRF) is central to interpreting blood-oxygen-level-dependent (BOLD) signals in functional magnetic resonance imaging, yet standard estimation approaches remain centred around phenomenological formulations lacking biophysical grounding. We present a proof-of-concept methodological study: a physics-informed neural network (PINN) framework that bridges these paradigms by embedding the Balloon-Windkessel model directly into the training objective of a multi-headed neural network. Our approach simultaneously estimates probable latent neurovascular state variables such as cerebral blood inflow, metabolic rate of oxygen consumption, blood volume, and deoxyhaemoglobin content, through an indirect optimisation scheme in which the predicted BOLD signal is obtained via convolution of the estimated HRF with experimental stimuli. Training is governed by a composite loss, balancing differential-equation residuals, hard physics regularisation term, physiological initial conditions and data fidelity. In simulations with temporal signal-to-noise ratios representative of clinical acquisitions, the framework recovered ground-truth state variables with coefficients of determination exceeding 0.95 and mean squared errors below 10-3, at a physics-to-data weighting of 0.40:0.60. Application to 1.5 T block-design clinical data from an ischaemic stroke patient provides feasibility testing, yielding physiologically plausible, subject-specific HRF estimates, establishing feasibility of single-subject, physics-constrained HRF inference without reliance on fixed gamma basis assumptions. To our knowledge, this constitutes the first deployment of a single PINN incorporating the full Balloon-Windkessel model within an indirect training objective, reconstructing full BOLD observations, thereby positioning PINN-based haemodynamic modelling as a principled and personalised route towards more interpretable and patient-specific biomarkers.

neuroscience↗

bioRxiv2024

ENTPD3-specific CAR Regulatory T cells for Local Immune Control in T1D

Despite advances in Type 1 Diabetes (T1D) management such as hybrid closed loop systems, patients still face significant morbidity, reduced life expectancy, and impaired glucose regulation compared to healthy individuals or those with pancreas transplants. Here we developed beta cell-specific Chimeric Antigen Receptors (CAR) targeting the antigen ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) using a novel cell-based phage display methodology. ENTPD3 is highly expressed on beta cells of both early and progressed T1D patients. ENTPD3 CAR regulatory T cells (Tregs) homed, expanded and persisted in pancreatic islets in a T1D mouse model (NOD) and completely prevented disease progression. Human ENTPD3 CAR Tregs displayed a stable regulatory phenotype, strong activation, and suppression. Importantly, ENTPD3 CAR T cells recognised and were fully activated by human islets. This approach holds great promise as a durable treatment option for patients with prediabetes, new-onset diabetes, or those undergoing beta cell replacement therapy.

immunology↗

bioRxiv2024

OpenExo: An Open-Source Modular Exoskeleton to Augment Human Function

While the field of wearable robotic exoskeletons is rapidly expanding, there are several barriers to entry that discourage many from pursuing research in this area, ultimately hindering growth. Chief among these are the lengthy and costly development time to get an exoskeleton from conception to implementation and the necessity for a broad set of expertise. Additionally, many exoskeletons are designed for a specific utility (e.g., ankle plantarflexor assistance) and are confined to the laboratory environment, limiting the flexibility of the designed system to adapt to answer new questions and explore new domains. To address these barriers, we present OpenExo, an open-source modular untethered exoskeleton framework that provides access to all aspects of the design process including (1) software, (2) electronics, (3) hardware, and (4) control schemes. To demonstrate the utility of this exoskeleton framework, we performed benchtop and experimental validation testing with the system across multiple configurations including (1) hip-only incline assistance, (2) ankle-only indoor and outdoor assistance, (3) hip-and-ankle load-carriage assistance, and (4) elbow-only weightlifting assistance. All aspects of the software architecture, electrical components, hip and Bowden-cable transmission designs, and control schemes are freely available for other researchers to access, use, and modify when looking to address research questions in the field of wearable exoskeletons. Our hope is that OpenExo will rapidly accelerate the development and testing of new exoskeleton designs and control schemes, while simultaneously encouraging others, including those who would have been turned away from entering the field, to explore new and unique research questions. One-Sentence SummaryWe present an open-source, open-hardware exoskeleton to aid in accelerating the growth of robotic exoskeleton research.

bioengineering↗

bioRxiv2018

ITPase Deficiency Causes Martsolf Syndrome With a Lethal Infantile Dilated Cardiomyopathy

Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Through genetic analysis of 85 unrelated \"mutation negative\" probands referred with Martsolf syndrome we identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). The probands reported here each presented with a lethal and highly distinctive disorder; Martsolf syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rl/dl) into RNA and DNA. In Itpa-null cells, dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA but this was not associated with detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in lymphoblastoid RNA from an affected individual. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA - and by implication rI production - correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.\n\nAuthor SummaryNucleotide triphosphate bases containing inosine, ITP and dITP, are continually produced within the cell as a consequence of various essential biosynthetic reactions. The enzyme inosine triphosphate pyrophosphatase (ITPase) scavenges ITP and dITP to prevent their incorporation into RNA and DNA. Here we describe two unrelated families with complete loss of ITPase function as a consequence of disruptive mutations affecting both alleles of ITPA, the gene that encodes this protein. Both of the families have a very distinctive and severe combination of clinical problems, most notably a failure of heart muscle that was lethal in infancy or early childhood. They also have features of another rare genetic disorder affecting the brain and the eyes called Martsolf syndrome. We could not detect any evidence of dITP accumulation in genomic DNA from the affected individuals. A low but detectable level of inosine was present in the mitochondrial DNA but this did not have any obvious detrimental effect. The inosine accumulation in RNA was detectable in the patient cells. We made both cellular and animal models that were completely deficient in ITPase. Using these reagents we could show that the highest level of inosine accumulation into RNA was seen in the embryonic mouse heart. In this tissue more than 1 in 400 bases in all RNA in the cell was inosine. In normal tissues inosine is almost undetectable using very sensitive assays. The inosine accumulation did not seem to be having a global effect on the balance of RNA molecules or proteins.

genetics↗