Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks

Many biological processes are controlled by both deterministic and stochastic influences. However, efforts to model these systems often rely on either purely stochastic or purely rule-based methods. To better understand the balance between stochasticity and determinism in biological processes a computational approach that incorporates both influences may afford additional insight into underlying biological mechanisms that give rise to emergent system properties. We apply a combined approach to the simulation and study of angiogenesis, the growth of new blood vessels from existing networks. This complex multicellular process begins with selection of an initiating endothelial cell, or tip cell, which sprouts from the parent vessels in response to stimulation by exogenous cues. We have constructed an agent-based model of sprouting angiogenesis to evaluate endothelial cell sprout initiation frequency and location, and we have experimentally validated it using high-resolution time-lapse confocal microscopy. ABM simulations were then compared to a Monte Carlo model, revealing that purely stochastic simulations could not generate sprout locations as accurately as the rule-informed agent-based model. These findings support the use of rule-based approaches for modeling the complex mechanisms underlying sprouting angiogenesis over purely stochastic methods

Effect of biological variables and capture period on the proximate composition and fatty acid composition of the dorsal muscle tissue of Hypophthalmus edentatus (Spix, 1829)

This study analyzed the chemical composition of the dorsal muscle tissue of Hypophthalmus edentatus, in particular, fatty acids of the lipidic fraction, and its relationship with the biological variables and the capture period. The average values for moisture, ash, protein and total lipids were 63.15, 1.11, 14.27 and 17.24%, respectively. In the lipidic fraction, 35 fatty acids were identified, the most abundant being: 16:0, 18:1omega9, 18:0, 16:1omega7, 18:3omega3, DHA and EPA. The totals of respectively saturated, monounsaturated and polyunsaturated fatty acids were 41.15, 35.30 and 23.88%. The PUFA/SFA ratio was equal to 0.68 and the omega3/ omega6 ratio equal to 1.98. The PCA demonstrated that the long chain PUFAs contributed positively to the formation of the first axis. The CCA showed some effects of the biological factors (weight, reproductive cycle, sex) and the capture period on the variation of total lipids and some fatty acids.<br>Este trabalho teve como objetivo estudar a composição química da musculatura dorsal de Hypophthalmus edentatus,em particular, a composição dos ácidos graxos da fração lipídica, e relacionar esta composição com variáveis biológicas e o período de coleta. Os valores de mediana para umidade, cinzas, proteína e lipídio total foram 63,15%, 1,11%, 14,27% e 17,24%, respectivamente. Na fração lipídica foram identificados 35 ácidos graxos sendo os mais abundantes: 16:0, 18:1ômega 9, 18:0, 16:1ômega 7, 18:3ômega 3, DHA e EPA. Os totais de ácidos graxos saturados, monoinsaturados e poliinsaturados foram, respectivamente, 41,15%, 35,30% e 23,88%. A razão AGPI/AGS foi igual a 0,68 e a razão w 3/w 6 igual a 1,98. Na ACP contribuíram positivamente para formação do primeiro eixo AGPIs de cadeia longa e, negativamente, alguns AGSs e AGMIs de 14 a 18 carbonos. A análise de variáveis canônica sugere a existência de algum efeito de fatores biológicos (peso, estádio, sexo) e do período de coleta sobre a variação de alguns dos componentes químicos do tecido muscular dorsal de H. edentatus,principalmente, lipídios totais e alguns ácidos graxos

Clinical efficacy and safety of angiogenesis inhibitors: sex differences and current challenges

Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signaling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signaling pathway inhibition include an increase in arterial pressure, left ventricular (LV) dysfunction ultimately causing heart failure, and thromboembolic events, including pulmonary embolism, stroke, and myocardial infarction. Sex steroids such as androgens, progestins, and estrogen and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor treatments, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target and cell-type selectivity likely will open the way personalized medicine in men and women requiring antiangiogenic therapy and result in reduced adverse effects and improved therapeutic efficacy