Abstract Redox cycling is an understated mechanism of toxicity associated with a plethora xenobiotics, responsible for preventing the effective treatment serious conditions such as malaria and cardiomyopathy. Quinone compounds are notorious redox cyclers, present in drugs doxorubicin, which used to treat host human cancers. However, therapeutic index doxorubicin undermined by dose-dependent cardiotoxicity, may be function futile cycling. In this study, doxorubicin-specific silico quinone...

In early preclinical drug development, potential candidates are tested in the laboratory using isolated cells. These vitro experiments traditionally involve cells cultured a two-dimensional monolayer environment. However, three-dimensional spheroid systems have been shown to more closely resemble functionality and morphology of vivo . While increasing usage hepatic cultures allows for relevant experimentation realistic biological environment, underlying physical processes transport, uptake...

Many in vitro liver cell models, such as 2D systems, that are used to assess the hepatotoxic potential of xenobiotics suffer major limitations arising from a lack preservation physiological phenotype and metabolic competence. To circumvent some these there has been increased focus on producing more representative 3D models. Here we have novel approach construct size-controllable hepatic spheroid model using freshly isolated primary rat hepatocytes (PRH) utilising liquid-overlay technique...

The effect of climate change on the spatiotemporal dynamics malaria transmission is studied using an unprecedented ensemble projections, employing three diverse bias correction and downscaling techniques, in order to partially account for uncertainty climate- driven projections. These large ensembles drive two dynamical spatially explicit epidemiological models provide future hazard projections focus region eastern Africa. While produce very distinct patterns recent climate, their response...

Outbreaks of Rift Valley fever (RVF), a relatively recently emerged zoonosis endemic to large parts sub-Saharan Africa that has the potential spread beyond continent, have profound health and socio-economic impacts, particularly in communities where resilience is already low. Here output from new, dynamic disease model [the Liverpool RVF (LRVF) model], driven by downscaled, bias-corrected climate change data an ensemble global circulation models Inter-Sectoral Impact Model Intercomparison...

Outbreaks of Rift Valley fever (RVF) in eastern Africa have previously occurred following specific rainfall dynamics and flooding events that appear to support the emergence large numbers mosquito vectors. As such, transmission virus is considered be sensitive environmental conditions therefore changes climate can impact spatiotemporal epizootic vulnerability. Epidemiological information describing methods parameters RVF its dependence on climatic factors are used develop a new...

A major bottleneck in the study of human liver physiology is provision stable tissue sufficient quantity. As a result, current approaches to modelling drug efficacy and toxicity rely heavily on immortalized animal cell lines. These models are informative but do possess significant drawbacks. To address issues presented by those models, researchers have turned pluripotent stem cells (PSCs). PSCs can be generated from defined genetic backgrounds, scalable, capable differentiation all types...

Read-across refers to the process by which information from one (source) chemical is used infer about another similar (target) chemical. This method can be fill data gaps and so inform safety assessment where are lacking for chemicals of interest. As cannot considered as absolutely another, only with respect a given property, it essential justify selection (analogues) purposes read-across. A previously created dataset available physiologically-based kinetic (PBK) models (referred PBK...

Cancer cells depend on glucose metabolism via glycolysis as a primary energy source, despite the presence of oxygen and fully functioning mitochondria, in order to promote growth, proliferation longevity. Glycolysis relies upon NAD+ accept electrons glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction, linking redox state cytosolic pool glycolytic rate. The free NAD+/NADH ratio is involved over 700 oxidoreductive enzymatic reactions such, regarded metabolic readout overall cellular...

Herein, we describe a protocol for the preparation and analysis of primary isolated rat hepatocytes in 3D cell culture format described as spheroids. The hepatocyte cells spontaneously self-aggregate into spheroids without need synthetic extracellular matrices or hydrogels. Primary (PRHs) are readily available source differentiated liver therefore conserve many required liver-specific functional markers, elicit natural vivo phenotype when compared with common hepatic lines. We liquid-overlay...

Many xenobiotics can bind to off-target receptors and cause toxicity via the dysregulation of downstream transcription factors. Identification subsequent in these chemicals has often required extensive chemical testing animal models. An alternative, integrated vitro/in silico approach for predicting toxic functional responses is presented refine vitro receptor identification reduce burden on vivo testing. As part methodology, mathematical modeling used mechanistically describe processes that...

Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in United Kingdom and States. However, exceeding maximum recommended dose can cause serious liver injury even death. Promising APAP toxicity biomarkers are thought to add value those currently clarification functional relationships between these would aid clinical implementation an improved identification framework. The framework define overdose highly dependent upon time since ingestion initial dose; information...

Read-across, wherein information from a data-rich chemical is used to make prediction for similar that lacks the relevant data, increasingly being accepted as an alternative animal testing. Identifying chemicals can be considered (analogues) crucial process. Two resources have been developed previously address issue of analogue selection and facilitate physiologically-based kinetic (PBK) model development, using read-across. Chemical-specific PBK models, available in literature, were...

Nanoparticles have the potential to increase efficacy of anticancer drugs whilst reducing off-target side effects. However, there remain uncertainties regarding cellular uptake kinetics nanoparticles which could implications for nanoparticle design and delivery. Polymersomes are candidates cancer therapy encapsulate chemotherapy drugs. Here we develop a mathematical model simulate polymersomes via endocytosis, process by bind cell surface before becoming internalised where they then break...

In pharmaceutical therapeutic design or toxicology, accurately predicting the permeation of chemicals through human epithelial tissues is crucial, where significantly influenced by tissue's cellular architecture. Current mathematical models for multi-layered epithelium such as oral mucosa only use simplistic 'bricks and mortar' geometries therefore do not account complex architecture these at microscale level, extensive plasma membrane convolutions that define extracellular spaces between...

HIF (Hypoxia Inducible Factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There increasing evidence cell signaling pathways encode temporal information, and thus fate may be determined by dynamics of protein levels. We have developed a mathematical model describe transient HIF-1{\alpha} measured single cells subjected hypoxic shock. The essential characteristics these data are modeled with system differential equations...