Biology subjects

Lewis, A.

Publications and source records attributed to Lewis, A..

4 recordsLinked to original sources

bioRxiv2026

INFORME: coupling information-theoretic experimental design with nonlinear mixed-effects modeling for efficient observation scheduling

Mathematical models of treatment response can inform individualized therapy, but their calibration often requires longitudinal measurements that are costly, burdensome, and collected on fixed schedules. Such schedules may be inefficient, over-sampling patients whose response is already well characterized while delaying informative measurements for those whose model parameters remain uncertain. We present INFORME (INFORmation-theoretic design with Mixed Effects), a framework that combines Bayesian information-theoretic experimental design with nonlinear mixed-effects modeling to adaptively select each patients next measurement time. Population and response-subgroup parameter distributions learned from an existing cohort provide informative priors, allowing candidate measurement times to be ranked by their expected reduction in patient-specific parameter uncertainty. As observations accumulate, priors can be updated to reflect the response subgroup most consistent with the patients data. We evaluate INFORME in two radiotherapy datasets: 150 synthetic tumor volume trajectories from a hybrid cellular automaton model of prostate cancer spheroids (HD1) and longitudinal tumor volumes from 39 patients with head-and-neck cancer (HD2). In HD1, population priors allowed omission of both pretreatment scans, while adaptive scheduling reduced the protocol from nine scans to three or four, with the response group identified from a single post-treatment scan on day 27. In HD2, the adaptive schedule used three scans instead of six and improved prediction by delaying the first on-treatment scan from week 1 to week 2, avoiding transient dynamics that produced false-positive and false-negative response projections. Across both datasets, the adaptive schedules used a mean of 2.7 scans in stead of seven and advanced completion of the patient-specific prediction by a mean of 15.5 days (95% CI, 6.7-24.3) relative to the equidistant protocol, while treatment duration remained unchanged. INFORME therefore reduces measurement burden and accelerates patient-specific prediction by concentrating observations at times that are most informative for model calibration.

systems biology↗

bioRxiv2018

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

Alzheimers disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by {beta}-amyloid pathology to induce exaggerated IL-1{beta} responses to acute stimulation with LPS or IL-1{beta}. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1{beta} induction nor NF{kappa}B p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1{beta}, NF{kappa}B-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1{beta} we demonstrate that astrocytes proximal to A{beta}-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1{beta}, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

neuroscience↗

bioRxiv2018

Macrophage Il-1beta protects against mycobacterial infection downstream of Hif-1alpha in zebrafish

Drug resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to TB to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. Here, we use an Il-1{beta} fluorescent transgenic line to show that there is an early innate immune pro-inflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum (Mm) infection. We demonstrate that host-derived hypoxia signalling, mediated by the Hif-1 transcription factor, can prime macrophages with increased levels of Il-1{beta} in the absence of infection, upregulating neutrophil antimicrobial nitric oxide production, leading to greater protection against infection. Our data link Hif-1 to proinflammatory macrophage Il-1{beta} transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial nitric oxide, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.

immunology↗

bioRxiv2017

Mycophenolate mofetil increases susceptibility toopportunistic fungal infection independent of lymphocytes

Anti-proliferative agents that target lymphoid cells are common immunosuppressive agents used in the treatment of diverse autoimmune, graft versus host and inflammatory diseases. Mycophenolate mofetil (MMF) is an anti-proliferative agent that targets lymphoid dependence on inosine monophosphate dehydrogenase for the de novo purine synthesis of deoxyguanosine triphosphate (dGTP) for DNA replication. Here we show that MMF has a distinct and specific in vivo effect on macrophages, in the absence of lymphoid cells. This results in increased macrophage cell death that is dependent on the depletion of cellular GTP, independent of DNA synthesis. Furthermore, the macrophage specific effect of MMF treatment causes an increase in susceptibility to the opportunistic fungal infection Cryptococcus neoformans by reducing phagocytosis and increasing the release of intracellular pathogens via macrophage lysis. Our study demonstrates the need for a better mechanistic understanding of immunosuppressive treatments used in clinical practice and of the specific infection risks associated with certain treatment regimens.

immunology↗