Biology subjects

Araujo, R.

Publications and source records attributed to Araujo, R..

9 recordsLinked to original sources

bioRxiv2026

Hypothalamic CYP46A1 cholesterol metabolism regulates diet-induced obesity

Obesity is a growing global health challenge which affects over 38% of the population and increases the risk of developing metabolic disorders. Effective long-term treatment options remain limited and often lead to significant side effects. The hypothalamus plays a central role in metabolic regulation by integrating peripheral and central signals to maintain energy homeostasis. While the hypothalamus regulates peripheral lipid metabolism, the role of lipid metabolic pathways within the hypothalamus itself remains unclear. Therefore, the molecular mechanisms linking hypothalamic activity to the development of obesity remain poorly understood. Given that cholesterol is the most abundant brain lipid, we investigated molecular players involved in its local regulation. Here, we identify the rate-limiting enzyme for brain cholesterol degradation, Cyp46a1, as a critical regulator of diet-induced obesity. We show that Cyp46a1 expression is significantly reduced in the hypothalamus of C57BL/6J mice exposed to a high-fat diet, suggesting a role in metabolic dysregulation. We used recombinant Adeno-Associated Viruses (AAV) to modulate Cyp46a1 expression in the arcuate nucleus, a key hypothalamic region regulating energy balance. We evaluated longitudinal changes in body weight, adipocyte size, PPAR-{gamma} expression, and hepatic lipid accumulation and pancreatic histopathology in mice undergoing chow or high fat diets. These experiments demonstrated that hypothalamic Cyp46a1 regulates body weight, adipocyte size, and hepatic and pancreatic histopathology. Conversely, CYP46A1 overexpression protects against high-fat diet-induced obesity and improves glucose homeostasis and insulin sensitivity, likely via crosstalk with hepatic and pancreatic function. Moreover, we found that hypothalamic CYP46A1 expression selectively modulates gut microbiota composition, linking this enzyme to the microbiota-gut-brain axis. Finally, we found that Cyp46a1 levels influence cognitive and motor performance, suggesting broader physiological relevance. Collectively, our findings reveal a previously unrecognized role of hypothalamic Cyp46a1 and cholesterol pathway control in obesity pathophysiology and metabolic homeostasis. These findings identify hypothalamic Cyp46a1 as a promising therapeutic target for obesity and its related comorbidities.

neuroscience↗

bioRxiv2025

Cell division during Xenopus gastrulation influences neuroectoderm patterning

Oriented cell division is essential for establishing the anterior-posterior body (A-P) axis in diverse species. However, in Xenopus laevis, blocking cell division during gastrulation does not impair the development of the neural tube and body elongation. Here, we demonstrate that neither neurulation nor dorsal mesoderm formation is dependent on cell division. On the other hand, neural plate elongation and A-P patterning are impacted in the absence of cell division, resulting in trunk defects and anterior defects that appear during tailbud stages. We also show that cell division is abundant around the ectoderm of the gastrulating embryo. Still, it is more intense in the dorsal ectoderm (presumptive neural plate), where there is a clear preference for A-P oriented cell divisions. Taken together, our results highlight a conserved mechanism of A-P oriented cell division that is present during neural plate elongation and patterning.

developmental biology↗

bioRxiv2025

Swiftly squeaky clean: lessons learned from eradicating an overpopulation of rats on an island of constraints

Invasive rats threaten island biodiversity, disrupting ecosystems and endangering native species. While rat eradication has succeeded on many islands, tropical islands present unique management challenges. Strict regulations and financial constraints on some tropical islands further limit proven eradication methods, complicating rodent management. This study addresses these challenges by demonstrating a real-time active adaptive management (RAM) approach, providing a cautious, cost-efficient, scientifically grounded, and adaptive pathway to eradication, while adhering to strict environmental regulations. We implemented RAM on a Brazilian island at USD 3,300 per hectare, integrating rodenticide (brodifacoum) application, population monitoring, and iterative management adjustments. This approach eradicated a rat overpopulation within five months, with early population increases observed in the threatened masked booby and the endemic Noronha elaenia and Noronha skink. Despite logistical constraints, RAM proved effective and cost-efficient, marking its first application in a biological system. Our findings highlight the value of innovation, interdisciplinary collaboration, and adaptive decision-making when the application of best-practice methods is constrained.

ecology↗

bioRxiv2024

Automated Analysis of Bird Head Motion from Videos in Unconstrained Settings

This study introduces a framework applicable to videos of habitual behaviors of multiple bird species to automatically assess head angular velocities and frequencies during various behaviors in natural habitats. The process involves detecting birds, identifying key points on their heads, and tracking changes in their positions over time. Bird detection and key point extraction were trained on publicly available datasets, including Animal Kingdom, NABirds, Birdsnap, CUB-200-2011, and eBird, featuring videos and images of diverse bird species in uncontrolled settings. Initial challenges arose due to the complexity of video backgrounds, leading to misidentifications and inaccurate key point estimates. These issues were addressed through validation, refinement, filtering, and smoothing steps. Head angular velocities and rotation frequencies were computed from the refined key points. The algorithm performed well at moderate speeds but was limited by the 30 Hz frame rate of most eBird videos, which constrained measurable angular velocities and frequencies and caused motion blur, affecting key point detection. Our findings suggest that the framework may provide plausible estimates of head motion but also emphasize the importance of high frame rate videos in future research, including extensive comparisons against ground truth data, to fully characterize bird head movements.

evolutionary biology↗

bioRxiv2023

Robust Homeostasis of Cellular Cholesterol via Antithetic Integral Control

Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances, and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.

biochemistry↗

bioRxiv2022

Protein-protein complexes can undermine ultrasensitivity-dependent biological adaptation

Robust Perfect Adaptation (RPA) is a ubiquitously-observed signalling response across all scales of biological organisation. A major class of network architectures that drive RPA in complex networks is the Opposer module - a feedback-regulated network into which specialised integral-computing opposer node(s) are embedded. Although ultrasensitivity-generating chemical reactions have long been considered a possible mechanism for such adaptation-conferring opposer nodes, this hypothesis has relied on simplified Michaelian models, which neglect the presence of protein-protein complexes, and which are now widely acknowledged to make inaccurate predictions of signalling responses. Here we develop complex-complete models of interlinked covalent-modification cycles with embedded ultrasensitivity: explicitly capturing all molecular interactions and protein complexes. Strikingly, we demonstrate that the presence of protein-protein complexes thwarts the networks capacity for RPA in any free active protein form, conferring RPA capacity instead on the concentration of a larger protein pool consisting of two distinct forms of a single protein. Furthermore, compared to predictions by simplified models, the parametric requirements for RPA in this protein pool are much more severe, and RPA generally obtains over a narrower range of input stimuli. These surprising results raise fundamental new questions as to the biochemical requirements for adaptation-conferring Opposer modules within complex cellular networks.

biochemistry↗

bioRxiv2022

Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model

The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients has not significantly improved in the past 3 decades, highlighting the need for more effective treatment approaches. Poor patient outcomes and lack of response to therapy can be attributed, in part, to the dense, fibrotic nature of PDAC tumours, which impedes the uptake of systemically administered drugs. Wet-spun alginate fibres loaded with the chemotherapeutic agent gemcitabine have been developed as a potential tool for overcoming the physical and biological barriers presented by the PDAC tumour microenvironment and deliver high concentrations of drug to the tumour directly over an extended period of time. While exciting, the practicality, safety, and effectiveness of these devices in a clinical setting requires further investigation. Furthermore, an in-depth assessment of the drug-release rate from these devices needs to be undertaken to determine whether an optimal release profile exists. Using a hybrid computational model (agent-based model and partial differential equation system), we developed a simulation of pancreatic tumour growth and response to treatment with gemcitabine loaded alginate fibres. The model was calibrated using in vitro and in vivo data and simulated using a finite volume method discretization. We then used the model to compare different intratumoural implantation protocols and gemcitabine-release rates. In our model, the primary driver of pancreatic tumour growth was the rate of tumour cell division and degree of extracellular matrix deposition. We were able to demonstrate that intratumoural placement of gemcitabine loaded fibres was more effective than peritumoural placement. Additionally, we found that an exponential gemcitabine release rate would improve the tumour response to fibres placed peritumourally. Altogether, the model developed here is a tool that can be used to investigate other drug delivery devices to improve the arsenal of treatments available for PDAC and other difficult-to-treat cancers in the future. Author SummaryPancreatic cancer has a dismal prognosis with a median survival of 3-5 months for untreated disease. The treatment of pancreatic cancer is challenging due to the dense nature of pancreatic tumours which impedes retention of drug at the tumour site. As such, systemic administration of chemotherapies, such as gemcitabine, has a limited efficacy. To overcome this, sustained-release devices have been proposed. These devices are injected locally and release drug slowly over time, providing a concentrated local, sustained drug concentration. To investigate the possible efficacy of these devices, we developed a mathematical model that would allow us to probe treatment perturbations in silico. We modelled the individual cancer cells and their growth and death from gemcitabine loaded into the sustained delivery devices. Our platform allows future investigations for these devices to be run in silico so that we may better understand the forms of the drug release-profile that are necessary for optimal treatment.

cancer biology↗

bioRxiv2020

Ultrasensitivity and bistability in covalent modification cycles with positive autoregulation

Switch-like behaviours in biochemical networks are of fundamental significance in biological signal processing, and exist as two distinct types: ultra-sensitivity and bistability. Here we propose two new models of a reversible covalent-modification cycle with positive autoregulation (PAR) - a motif structure that is thought to be capable of both ultrasensitivity and bistability in different parameter regimes. These new models appeal to a modelling framework that we call complex complete, which accounts fully for the molecular complexities of the underlying signalling mechanisms. Each of the two new models encodes a specific molecular mechanism for PAR. We demonstrate that the modelling simplifications for PAR models that have been used in previous work, which rely on a Michaelian approximation for the enzyme-mediated reactions, are unable to accurately recapitulate the qualitative signalling responses supported by our full complex-complete models. Strikingly, we show that the parameter regimes in which ultrasensitivity and bistability obtain in the complex-complete framework contradict the predictions made by the Michaelian simplification. Our results highlight the critical importance of accurately representing the molecular details of biochemical signalling mechanisms, and strongly suggest that the Michaelian approximation may be inadequate for predictive models of enzyme-mediated chemical reactions with added regulations.

systems biology↗

bioRxiv2020

Soft ticks perform evaporative cooling during blood-feeding

Feeding on the blood of warm-blooded vertebrates is associated to thermal stress in haematophagous arthropods. It has been demonstrated that blood-sucking insects protect their physiological integrity either by synthesising heat-shock proteins or by means of thermoregulatory mechanisms. In this work, we describe the first thermoregulatory mechanism in a tick species, Ornithodoros rostratus. By performing real-time infrared thermography during feeding on mice we found that this acarian eliminates big amounts of fluid (urine) through their coxal glands; this fluid quickly spreads over the cuticular surface and its evaporation cools-down the body of the tick. The spread of the fluid is possible thanks to capillary diffusion through the sculptured exoskeleton of Ornithodoros. We discuss our findings in the frame of the adaptive strategies to cope with the thermal stress experienced by blood-sucking arthropods at each feeding event warm-blooded hosts.

zoology↗