Multiscale computational model of aortic remodeling following postnatal disruption of TGFß signaling.

The healthy adult aorta is a remarkably resilient structure, able to resist relentless cardiac-induced and hemodynamic loads under normal conditions. Fundamental to such mechanical homeostasis is the mechano-sensitive cell signaling that controls gene products and thus the structural integrity of the wall. Mouse models have shown that smooth muscle cell-specific disruption of transforming growth factor-beta (TGFß) signaling during postnatal development compromises this resiliency, rendering the aortic wall susceptible to aneurysm and dissection under normal mechanical loading. By contrast, disruption of such signaling in the adult aorta appears to introduce a vulnerability that remains hidden under normal loading, but manifests under increased loading as experienced during hypertension. We present a multiscale (transcript to tissue) computational model to examine possible reasons for compromised mechanical homeostasis in the adult aorta following reduced TGFß signaling in smooth muscle cells.

Corrigendum: Colloidal nanomaterials for water quality improvement and monitoring.

[This corrects the article DOI: 10.3389/fchem.2022.1011186.].

Colloidal nanomaterials for water quality improvement and monitoring.

Water is the most important resource for all kind forms of live. It is a vital resource distributed unequally across different regions of the globe, with populations already living with water scarcity, a situation that is spreading due to the impact of climate change. The reversal of this tendency and the mitigation of its disastrous consequences is a global challenge posed to Humanity, with the scientific community assuming a major obligation for providing solutions based on scientific knowledge. This article reviews literature concerning the development of nanomaterials for water purification technologies, including collaborative scientific research carried out in our laboratory (nanoLAB@UA) framed by the general activities carried out at the CICECO-Aveiro Institute of Materials. Our research carried out in this specific context has been mainly focused on the synthesis and surface chemical modification of nanomaterials, typically of a colloidal nature, as well as on the evaluation of the relevant properties that arise from the envisaged applications of the materials. As such, the research reviewed here has been guided along three thematic lines: 1) magnetic nanosorbents for water treatment technologies, namely by using biocomposites and graphite-like nanoplatelets; 2) nanocomposites for photocatalysis (e.g., TiO2/Fe3O4 and POM supported graphene oxide photocatalysts; photoactive membranes) and 3) nanostructured substrates for contaminant detection using surface enhanced Raman scattering (SERS), namely polymers loaded with Ag/Au colloids and magneto-plasmonic nanostructures. This research is motivated by the firm believe that these nanomaterials have potential for contributing to the solution of environmental problems and, conversely, will not be part of the problem. Therefore, assessment of the impact of nanoengineered materials on eco-systems is important and research in this area has also been developed by collaborative projects involving experts in nanotoxicity. The above topics are reviewed here by presenting a brief conceptual framework together with illustrative case studies, in some cases with original research results, mainly focusing on the chemistry of the nanomaterials investigated for target applications. Finally, near-future developments in this research area are put in perspective, forecasting realistic solutions for the application of colloidal nanoparticles in water cleaning technologies.

Intracellular signaling control of mechanical homeostasis in the aorta.

Mature arteries exhibit a preferred biomechanical state in health evidenced by a narrow range of intramural and wall shear stresses. When stresses are perturbed by changes in blood pressure or flow, homeostatic mechanisms tend to restore target values via altered contractility and/or cell and matrix turnover. In contrast, vascular disease associates with compromised homeostasis, hence we must understand mechanisms underlying mechanical homeostasis and its robustness. Here, we use a multiscale computational model wherein mechanosensitive intracellular signaling pathways drive arterial growth and remodeling. First, we identify an ensemble of cell-level parameterizations where tissue-level responses are well-regulated and adaptive to hemodynamic perturbations. The responsible mechanism is persistent multiscale negative feedback whereby mechanosensitive signaling drives mass turnover until homeostatic target stresses are reached. This demonstrates how robustness emerges despite inevitable cell and individual heterogeneity. Second, we investigate tissue-level effects of signaling node knockdowns (ATIR, ROCK, TGF[Formula: see text]RII, PDGFR, ERK1/2) and find general agreement with experimental reports of fault tolerance. Robustness against structural changes manifests via low engagement of the node under baseline stresses or compensatory multiscale feedback via upregulation of additional pathways. Third, we show how knockdowns affect collagen and smooth muscle turnover at baseline and with perturbed stresses. In several cases, basal production is not remarkably affected, but sensitivities to stress deviations, which influence feedback strength, are reduced. Such reductions can impair adaptive responses, consistent with previously reported aortic vulnerability despite grossly normal appearances. Reduced stress sensitivities thus form a candidate mechanism for how robustness is lost, enabling transitions from health towards disease.

In Vitro Hepatotoxic and Neurotoxic Effects of Titanium and Cerium Dioxide Nanoparticles, Arsenic and Mercury Co-Exposure.

Considering the increasing emergence of new contaminants, such as nanomaterials, mixing with legacy contaminants, including metal(loid)s, it becomes imperative to understand the toxic profile resulting from these interactions. This work aimed at assessing and comparing the individual and combined hepatotoxic and neurotoxic potential of titanium dioxide nanoparticles (TiO2NPs 0.75-75 mg/L), cerium oxide nanoparticles (CeO2NPs 0.075-10 µg/L), arsenic (As 0.01-2.5 mg/L), and mercury (Hg 0.5-100 mg/L) on human hepatoma (HepG2) and neuroblastoma (SH-SY5Y) cells. Viability was assessed through WST-1 (24 h) and clonogenic (7 days) assays and it was affected in a dose-, time- and cell-dependent manner. Higher concentrations caused greater toxicity, while prolonged exposure caused inhibition of cell proliferation, even at low concentrations, for both cell lines. Cell cycle progression, explored by flow cytometry 24 h post-exposure, revealed that TiO2NPs, As and Hg but not CeO2NPs, changed the profiles of SH-SY5Y and HepG2 cells in a dose-dependent manner, and that the cell cycle was, overall, more affected by exposure to mixtures. Exposure to binary mixtures revealed either potentiation or antagonistic effects depending on the composition, cell type and time of exposure. These findings prove that joint toxicity of contaminants cannot be disregarded and must be further explored.

Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.

Thoracic aortopathy-aneurysm, dissection, and rupture-is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.

A multiscale model of cardiac concentric hypertrophy incorporating both mechanical and hormonal drivers of growth.

Growth and remodeling in the heart is driven by a combination of mechanical and hormonal signals that produce different patterns of growth in response to exercise, pregnancy, and various pathologies. In particular, increases in afterload lead to concentric hypertrophy, a thickening of the walls that increases the contractile ability of the heart while reducing wall stress. In the current study, we constructed a multiscale model of cardiac hypertrophy that connects a finite-element model representing the mechanics of the growing left ventricle to a cell-level network model of hypertrophic signaling pathways that accounts for changes in both mechanics and hormones. We first tuned our model to capture published in vivo growth trends for isoproterenol infusion, which stimulates ß-adrenergic signaling pathways without altering mechanics, and for transverse aortic constriction (TAC), which involves both elevated mechanics and altered hormone levels. We then predicted the attenuation of TAC-induced hypertrophy by two distinct genetic interventions (transgenic Gq-coupled receptor inhibitor overexpression and norepinephrine knock-out) and by two pharmacologic interventions (angiotensin receptor blocker losartan and ß-blocker propranolol) and compared our predictions to published in vivo data for each intervention. Our multiscale model captured the experimental data trends reasonably well for all conditions simulated. We also found that when prescribing realistic changes in mechanics and hormones associated with TAC, the hormonal inputs were responsible for the majority of the growth predicted by the multiscale model and were necessary in order to capture the effect of the interventions for TAC.

Unravelling the Potential Cytotoxic Effects of Metal Oxide Nanoparticles and Metal(Loid) Mixtures on A549 Human Cell Line.

Humans are typically exposed to environmental contaminants' mixtures that result in different toxicity than exposure to the individual counterparts. Yet, the toxicology of chemical mixtures has been overlooked. This work aims at assessing and comparing viability and cell cycle of A549 cells after exposure to single and binary mixtures of: titanium dioxide nanoparticles (TiO2NP) 0.75-75 mg/L; cerium oxide nanoparticles (CeO2NP) 0.0.75-10 µg/L; arsenic (As) 0.75-2.5 mg/L; and mercury (Hg) 5-100 mg/L. Viability was assessed through water-soluble tetrazolium (WST-1) and thiazolyl blue tetrazolium bromide (MTT) (24 h exposure) and clonogenic (seven-day exposure) assays. Cell cycle alterations were explored by flow cytometry. Viability was affected in a dose- and time-dependent manner. Prolonged exposure caused inhibition of cell proliferation even at low concentrations. Cell-cycle progression was affected by TiO2NP 75 mg/L, and As 0.75 and 2.5 µg/L, increasing the cell proportion at G0/G1 phase. Combined exposure of TiO2NP or CeO2NP mitigated As adverse effects, increasing the cell surviving factor, but cell cycle alterations were still observed. Only CeO2NP co-exposure reduced Hg toxicity, translated in a decrease of cells in Sub-G1. Toxicity was diminished for both NPs co-exposure compared to its toxicity alone, but a marked toxicity for the highest concentrations was observed for longer exposures. These findings prove that joint toxicity of contaminants must not be disregarded.

White bean (Phaseolus vulgaris L.) as a sorbent for the removal of zinc from rainwater.

The present work aimed to assess the sorption capacity of the common white bean (Phaseolus vulgaris L.) to remove Zn(II) from rainwater, rendering it suitable for use in buildings, and the efficiency of the process was evaluated for two initial Zn(II) concentrations, representing high (100 µg L-1) and very high (500 µg L-1) levels of Zn(II) in rainwater. The effects of the amount of beans (1, 5 and 10 beans per 50 mL), as well as the initial pH values of the zinc solution [acid (4), neutral (5.6) and basic (7) for atmospheric waters] were also assessed. The removal of Zn from water was affected by the change in pH values. When 5 and 10 beans were used, after 4 h and 2 h of contact time, respectively, the accumulated Zn(II) on the beans was released back into the solution, and this release occurred first for the highest tested pH value. The sorption rate of Zn(II) from the solution increased with the increasing amount of beans, but for 5 and 10 beans this only took place up to 4 h and 2 h, respectively. Furthermore, the removal percentages of Zn(II) increased with the increase of the initial concentrations of the metal in water. Kinetic studies revealed that a pseudo-first-order model provided the best fitting for the experimentally obtained values. Fourier transform infrared spectroscopy coupled with attenuated total reflectance (FTIR-ATR) analyses of the bean shells and cores indicated that contact with a Zn(II) solution did not cause notable alterations to the chemical structures of these bean components. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) analyses suggested that the process of sorption occurred at the surface of the beans (shells). The results obtained in this study also suggest that the matrix of rainwater samples did not interfere with the removal of metal, and that the process of the removal of Zn(II) by the white beans can be applied to real samples. On the whole, results indicate that for the removal of Zn(II) from rainwater, 1 bean up to 6 h, or 5 and 10 beans up to 2 h can be used per 50 mL for the removal of up to 60% of Zn(II) present in water, thus constituting a viable solution for the effective reduction of this metal in rainwater.

Variable outcomes of human heart attack recapitulated in genetically diverse mice.

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction.

A General Route for Growing Metal Sulfides onto Graphene Oxide and Exfoliated Graphite Oxide.

Graphene-based materials are elective materials for a number of technologies due to their unique properties. Also, semiconductor nanocrystals have been extensively explored due to their size-dependent properties that make them useful for several applications. By coupling both types of materials, new applications are envisaged that explore the synergistic properties in such hybrid nanostructures. This research reports a general wet chemistry method to prepare graphene oxide (GO) sheets decorated with nanophases of semiconductor metal sulfides. This method allows the in situ growth of metal sulfides onto GO by using metal dialkyldithiocarbamate complexes as single-molecule precursors. In particular, the role of GO as heterogeneous substrate for the growth of semiconductor nanocrystals was investigated by using Raman spectroscopic and imaging methods. The method was further extended to other graphene-based materials, which are easily prepared in a larger scale, such as exfoliated graphite oxide (EGO).

Multilayer three-dimensional filter paper constructs for the culture and analysis of aortic valvular interstitial cells.

Culturing aortic valvular interstitial cells in an environment that models the aortic valve is an essential step towards understanding the progression of calcific aortic valve disease. Here the adaption of a three-dimensional (3-D) stacked paper-based culture system is presented for analyzing valve cells in a thick collagen gel matrix. Filter paper layers, modeled after a 96-well plate design, were printed with a wax well-plate template and then seeded with valve cell and collagen mixtures that quickly gelled into 3-D cultures. Stacking these layers permitted extensive customization of culture thickness and cell density profiles to model the full thickness of native valve tissue. Aortic valvular interstitial cells seeded into the paper-based constructs consistently demonstrated high survival up to 14 days of culture with significant increases in cell number through the first 3 days of culture. After 4 days following seeding, valve cells in single layer cultures showed reduced smooth muscle α-actin expression with a stabilized cell density, suggesting a transition from an activated phenotype to a more quiescent state. Valve cells in multilayer cultures demonstrated the ability to migrate from layer to layer and had the highest smooth muscle α-actin expression in areas with predicted low oxygen tensions. These results establish the filter-paper-based method as a viable culture system for analyzing valve cells in an in vitro 3-D model of the aortic valve.

Impact of magnetic nanofillers in the swelling and release properties of κ-carrageenan hydrogel nanocomposites.

Natural polysaccharides such as κ-carrageenan are an important class of biomaterials for drug delivery. The incorporation of magnetic nanoparticles in polysaccharide hydrogels is currently being explored as a strategy to confer to the hydrogels novel functionalities valuable for specific bio-applications. Within this context, κ-carrageenan magnetic hydrogel nanocomposites have been prepared and the effect of magnetic (Fe3O4) nanofillers in the swelling of the hydrogels and in the release kinetics and mechanism of a model drug (methylene blue) has been investigated. In vitro release studies demonstrated the applicability of the composites in sustained drug release. The mechanism controlling the release seems to be determined by the strength of the gel network and the extent of gel swelling, both being affected by the incorporation of nanofillers. Furthermore, it was demonstrated that the release rate and profile could be tailored using variable Fe3O4 nanoparticles load. Thus, this seems to be a promising strategy for the development of drug delivery systems with tailored released behavior.