Fractals in the Neurosciences: A Translational Geographical Approach.

The chapter presents three new fractal indices (fractal fragmentation index, fractal tentacularity index, and fractal anisotropy index) and normalized Kolmogorov complexity with proven applicability in geographic research, developed by the authors, and the possibility of their future use in neuroscience. The research demonstrates the relevance of fractal analysis in different fields and the basic concepts and principles of fractal geometry being sufficient for the development of models relevant to the studied reality. Also, the research highlighted the need to continue interdisciplinary research based on known fractal indicators, as well as the development of new analysis methods with the translational potential between fields.

A New Synthetic Curcuminoid Displays Antitumor Activities in Metastasized Melanoma.

AIM: The semisynthetic derivatives MePip-SF5 and isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis. METHODS AND RESULTS: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than its original substance of curcumin (IC50 MePip-SF5 2.8 vs. 13.8 µM). Similarly, the melanoma cytotoxicity of isogarcinol was increased by 40% compared to garcinol (IC50 3.1 vs. 2.1 µM). The in vivo toxicity of both drugs was assessed in healthy C57BL/6 mice challenged with escalating doses. Isogarcinol induced toxicity above a dose of 15 mg/kg, while MePip-SF5 showed no in vivo toxicity up to 60 mg/kg. Both drugs were tested in murine pulmonary metastatic melanoma. C57BL/6 mice (n = 10) received 500,000 B16F10 melanoma cells intravenously. After intraperitoneal injection of MePip-SF5 (60 mg/kg) or isorgarcinol (15 mg/kg) at days 8, 11 and 14 and sacrifice at day 16, the MePip-SF5-treated mice showed a significantly (p < 0.05) lower pulmonary macroscopic and microscopic tumor load than the vehicle-treated controls, whereas isogarcinol was ineffective. The pulmonary RNA levels of the mitosis marker Bub1 and the inflammatory markers TNFα and Ccl3 were significantly (p < 0.05) reduced in the MePip-SF5-treated mice. Both drugs were well tolerated, as shown by an organ inspection and normal liver- and kidney-related serum parameters. CONCLUSIONS: The novel curcuminoid MePip-SF5 showed a convincing antimetastatic effect and a lack of systemic toxicity in a relevant preclinical model of metastasized melanoma.

ComsystanJ: A collection of Fiji/ImageJ2 plugins for nonlinear and complexity analysis in 1D, 2D and 3D.

Complex systems such as the global climate, biological organisms, civilisation, technical or social networks exhibit diverse behaviours at various temporal and spatial scales, often characterized by nonlinearity, feedback loops, and emergence. These systems can be characterized by physical quantities such as entropy, information, chaoticity or fractality rather than classical quantities such as time, velocity, energy or temperature. The drawback of these complexity quantities is that their definitions are not always mathematically exact and computational algorithms provide estimates rather than exact values. Typically, evaluations can be cumbersome, necessitating specialized tools. We are therefore introducing ComsystanJ, a novel and user-friendly software suite, providing a comprehensive set of plugins for complex systems analysis, without the need for prior programming knowledge. It is platform independent, end-user friendly and extensible. ComsystanJ combines already known algorithms and newer methods for generalizable analysis of 1D signals, 2D images and 3D volume data including the generation of data sets such as signals and images for testing purposes. It is based on the framework of the open-source image processing software Fiji and ImageJ2. ComsystanJ plugins are macro recordable and are maintained as open-source software. ComsystanJ includes effective surrogate analysis in all dimensions to validate the features calculated by the different algorithms. Future enhancements of the project will include the implementation of parallel computing for image stacks and volumes and the integration of artificial intelligence methods to improve feature recognition and parameter calculation.

Fractal algorithms and RGB image processing in scribal and ink identification on an 1819 secret initiation manuscript to the "Philike Hetaereia".

Historical texts incorporate important characteristics that need to be assessed including genre, text structure and content. Often overlooked are characteristics of handwritten manuscripts commonly divided into legibility, readability and aesthetics. To determine the scientific feasibility of classification of handwritten texts an objective approach is developed to describe twenty handwritten pages of an 1819 Greek manuscript, that refers to the initiation to the Greek secret "friendly society" (Philike Hetaereia) organization, established as part of the Greek independence against the Ottoman Turks. It is investigated through a fractal and RGB image analysis approach. Fractal Minkowski Dimension was applied on the handwritten text and the RGB color analysis on the ink and paper and both were used as a non-invasive manner and revealed interesting results. The novel RGB image analysis and the fractal analysis of the manuscript identified respectively, five iron gall inks and four scribes from the ink content and handwritten styles, of the compact five lines text and whole text pages. The novel approach was verified with another old manuscript of known ink pigments, as well as with thirteen known handwritten texts of that period and four prints representing modern and similar period texts substantiating the findings of the novel methods.

Kolmogorov compression complexity may differentiate different schools of Orthodox iconography.

The complexity in the styles of 1200 Byzantine icons painted between 13th and 16th from Greece, Russia and Romania was investigated through the Kolmogorov algorithmic information theory. The aim was to identify specific quantitative patterns which define the key characteristics of the three different painting schools. Our novel approach using the artificial surface images generated with Inverse FFT and the Midpoint Displacement (MD) algorithms, was validated by comparison of results with eight fractal and non-fractal indices. From the analyzes performed, normalized Kolmogorov compression complexity (KC) proved to be the best solution because it had the best complexity pattern differentiations, is not sensitive to the image size and the least affected by noise. We conclude that normalized KC methodology does offer capability to differentiate the icons within a School and amongst the three Schools.

Synthesis and bioevaluation of new vascular-targeting and anti-angiogenic thieno[2,3-d]pyrimidin-4(3H)-ones.

A series of forty-six 5,6-annulated 2-arylthieno [2,3-d]pyrimidin-4(3H)-ones were prepared as potentially pleiotropic anticancer drugs with variance in the tubulin-binding trimethoxyphenyl motif at C-2 of a thieno [2,3-d]pyrimidine fragment, enlarged by additional rings of different size and substitution. By assessing their cytotoxicity against various cancer cells, their influence on the polymerization of neat tubulin and the dynamics of microtubule and F-actin cytoskeletons, and their vascular-disrupting and anti-angiogenic activities in vitro and in vivo, structure-activity relations were identified which suggest the 3-iodo-4,5-dimethoxyphenyl substituted thienopyrimidine 2e as a promising anticancer drug candidate for further research. 2020 Elsevier Ltd. All rights reserved.

Dynamics of Forest Fragmentation and Connectivity Using Particle and Fractal Analysis.

The ever decreasing area of forests has lead to environmental and economical challenges and has brought with it a renewed interest in developing methodologies that quantify the extent of deforestation and reforestation. In this study we analyzed the deforested areas of the Apuseni Mountains, which has been under economic pressure in recent years and resulted in widespread deforestation as a means of income. Deforested surface dynamics modeling was based on images contained in the Global Forest Database, provided by the Department of Geographical Sciences at Maryland University between 2000 and 2014. The results of the image particle analysis and modelling were based on Total Area (ha), Count of patches and Average Size whereas deforested area distribution was based on the Local Connected Fractal Dimension, Fractal Fragmentation Index and Tug-of-War Lacunarity as indicators of forest fragmentation or heterogeneity. The major findings of the study indicated a reduction of the tree cover area by 3.8%, an increase in fragmentation of 17.7% and an increase in heterogeneity by 29%, while fractal connectivity decreased only by 0.1%. The fractal and particle analysis showed a clustering of forest loss areas with an average increase from 1.1 to 3.0 ha per loss site per year. In conclusion, the fractal and particle analysis provide a relevant methodological framework to further our understanding of the spatial effects of economic pressure on forestry.

New naphthopyran analogues of LY290181 as potential tumor vascular-disrupting agents.

A series of 19 analogues of the antiproliferative naphthopyran LY290181 were prepared for structure-activity relationship studies. We found the best activities for test compounds bearing small substituents at the meta position of the phenyl ring. The mode of action of LY290181 and eight new analogues was studied in detail. The compounds were highly anti-proliferative with IC50 values in the sub-nanomolar to triple-digit nanomolar range. The new analogues led to G2/M arrest due to interruption of the microtubule dynamics. In 518A2 melanoma cells they caused a mitotic catastrophe which eventually led to apoptosis. The naphthopyrans also induced a disruption of the vasculature in the chorioallantoic membrane (CAM) of fertilized chicken eggs as well as in xenograft tumors in mice. In a preliminary therapy trial, the difluoro derivative 2b retarded the growth of resistant xenograft tumors in mice.

Fluoro and pentafluorothio analogs of the antitumoral curcuminoid EF24 with superior antiangiogenic and vascular-disruptive effects.

A series of 14 analogs of the curcuminoid EF24, (3E,5E)-3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone, bearing fluorine or pentafluorothio substituents, were prepared and tested for antiproliferative, vascular-disruptive, and antiangiogenic activity, as well as for their influence on other cancer-relevant targets. They proved antiproliferative against eight cancer cell lines with IC50 values in the low single-digit micromolar to triple-digit nanomolar range. Like EF24, the hexafluoro 3c and 3d and bis(pentafluorothio) 4f derivatives arrested HT-29 colon carcinoma cells in G2/M phase of the cell cycle, yet inhibited angiogenesis, e.g. in zebrafish larvae, to a much greater extent. The antimigratory effects in 518A2 melanoma cells of 3c, its regioisomer 3d, and of 4f, originate from an inhibition of NF-κB translocation. Moreover, 3c and 3d showed potential as vascular-disruptive agents in chorioallantoic/vitelline membrane (CA/VM) assays.

Ferrocenyl-Coupled N-Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs.

Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2-ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC50 (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F-actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.

Gold(I) biscarbene complexes derived from vascular-disrupting combretastatin A-4 address different targets and show antimetastatic potential.

Gold N-heterocyclic carbene (NHC) complexes are an emerging class of anticancer drugs. We present a series of gold(I) biscarbene complexes with NHC ligands derived from the plant metabolite combretastatin A-4 (CA-4) that retain its vascular-disrupting effect, yet address different cellular and protein targets. Unlike CA-4, these complexes did not interfere with tubulin, but with the actin cytoskeleton of endothelial and cancer cells. For the highly metastatic 518A2 melanoma cell line this effect was accompanied by a marked accumulation of cells in the G1 phase of the cell cycle and a suppression of active prometastatic matrix metalloproteinase-2. Despite these mechanistic differences the complexes were as strongly antivascular as CA-4 both in vitro in tube formation assays with human umbilical vein endothelial cells, and in vivo as to blood vessel disruption in the chorioallantoic membrane of chicken eggs. The antiproliferative effect of the new gold biscarbene complexes in a panel of six human cancer cell lines was impressive, with low sub-micromolar IC50 values (72 h) even against CA-4-refractory HT-29 colon and multidrug-resistant MCF-7 breast carcinoma cells. In preliminary studies with a mouse melanoma xenograft model the complexes led to significant decreases in tumor volume while being very well tolerated.