Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2 (FGF2). As markers of angiogenesis, we measured the length and width of intersegmental vessels (ISVs), performed whole-mount in situ hybridization with fli1 and cadh5 vascular markers, and counted the number of interconnecting vessels (ICVs) in sub-intestinal venous plexus (SIVP). In addition, we measured angiogenesis after performing zebrafish yolk membrane (ZFYM) assay with microinjection of fibroblast growth factor 2 (FGF2) and perivitelline tumor xenograft assay with microinjection of tumorigenic FGF2-overexpressing endothelial (FGF2-T-MAE) cells. The results showed that caffeine treatment causes a shortening and thinning of ISVs along with a decreased expression of the vascular marker genes and a decrease in the number of ICVs in the SIVP. Caffeine was also able to block angiogenesis induced by exogenous FGF2 or FGF2-producing cells. Overall, our results are suggestive of the inhibitory effect of caffeine in both direct and indirect angiogenesis.     

Advances in De Novo Drug Design: From Conventional to Machine Learning Methods

De novo drug design is a computational approach that generates novel molecular structures from atomic building blocks with no a priori relationships. Conventional methods include structure-based and ligand-based design, which depend on the properties of the active site of a biological target or its known active binders, respectively. Artificial intelligence, including ma-chine learning, is an emerging field that has positively impacted the drug discovery process. Deep reinforcement learning is a subdivision of machine learning that combines artificial neural networks with reinforcement-learning architectures. This method has successfully been em-ployed to develop novel de novo drug design approaches using a variety of artificial networks including recurrent neural networks, convolutional neural networks, generative adversarial networks, and autoencoders. This review article summarizes advances in de novo drug design, from conventional growth algorithms to advanced machine-learning methodologies and high-lights hot topics for further development.     

Acute poisoning with pesticides in the state of Mato Grosso do Sul, Brazil

Exposure to pesticides has been the source of many acute and chronic health problems in the rural population, mainly in developing countries. The objective of this study was to characterize the poisonings from acute exposure to agricultural pesticides used in the state of Mato Grosso do Sul, Brazil, from 1992 to 2002, which were reported to the Integrated Center of Toxicological Vigilance of the State Health Department. A total of 1355 involuntary (accidental or occupational) and voluntary (intentional self-poisoning) cases were reported during the period of the study. The majority of the poisonings occurred with men ranging in age from 15 to 49 years of age (55.1%). One hundred seventy-six poisonings lead to death, with a case fatality rate (CFR) three times higher than the average Brazilian CFR. The pesticide poisoning rates, per 100,000 inhabitants living in rural areas, ranged from 25 to 65.7 during the period of the study. In 2000, the micro-region of Campo Grande, where the state capital is located, had the highest rate, with 100.5 exposure/100,000 inhabitants, followed by Dourados, the larger agricultural region of the state. Insecticides were involved in 75.7% of the poisoning cases, followed by herbicides, with 12.2% of the cases. The anticholinestherase insecticides methamidophos, carbofuran and monochrotophos were the primary pesticides involved in the poisonings. The insecticide dimethoate was associated with the highest CFR (30.8%). The high rates of pesticide poisoning in the rural populations of certain regions of the state of Mato Grosso do Sul indicate the need for a more detailed study concerning the risk of pesticide poisoning among these populations.     

Crystallization of a Polyamide 6/Montmorillonite Nanocomposite at Rapid Cooling

The crystallization behavior of a polyamide 6/organo‐modified montmorillonite (PA 6/OMMT) nanocomposite has been investigated by scanning chip calorimetry and wide‐angle X‐ray scattering, with emphasis placed on the evaluation of the effect of supercooling/cooling rate on the crystal/mesophase polymorphism of the PA 6 matrix. Presence of OMMT has negligible effect on the kinetics of formation of α‐crystals of PA 6 at low cooling rate while there is observed enhanced nucleation of γ‐mesophase on fast cooling. Furthermore, addition of OMMT leads to a distinct increase of the cooling rate required to completely vitrify the amorphous state. The performed experiments demonstrate that the nucleating effect of OMMT in PA 6/OMMT nanocomposites is of particular importance at cooling conditions relevant in polymer processing.

     

Techno-economic analysis of PEM fuel cells role in photovoltaic-based systems for the remote base stations

Expansion of telecommunication networks even to the most remote areas where connection to the utility grid could never be justified, especially in touristic regions, has led to the increasing need for stand-alone power systems. In Adriatic coastal area employment of hybrid photovoltaic-based systems is straightforward due to high sun potential. Inherent intermittent nature of renewable sources is especially not compatible with telecommunication system who require uninterrupted power supply. This leads to the need of not only energy storage, but also a “back up” solution in the case of primary system failure. Emphasis is put on the system reliability and simplicity while system price is not necessarily top priority. Usual approach of using diesel generators as a “back up” has been challenged by the introduction of PEM fuel cells. Even with hydrogen technologies market development still lagging behind some comparable advantages such as high energy conversion efficiency, silent operation and no emissions make PEM fuel cells a legitimate candidate for replacing traditional oil burning generators. Techno-economic analysis of various stand-alone power systems for the remote base station on an Adriatic island is made. At the moment, levelized cost of electricity point of view still gives slight advantage to the diesel generators. Though, uncertain petroleum market and fast developing hydrogen technology market could reverse this trend in the near future. Long term reliability of PEM fuel cells system still needs to be examined in practice, as this combined with pro-environmental characteristics of fuel cells can make the difference especially in pristine and protected areas.     

Investigation of Flow Distribution in Microchannels Heat Sinks

The thermal efficiency of microchannel-based heat sinks relies on uniform fluid flow distribution between channels. Maldistribution, whether caused by poor manifold design or blockage of individual microchannels, can lead to hotspots and consequent thermal damage. This work considers design of manifolds for even flow distribution and the effect of channel blockage on the flow. An approximate model was used to evaluate the effect of manifold geometry on the flow distribution, and the results were compared with computational fluid dynamics (CFD) simulation. Various parameters, which influence the flow distribution such as the shape of distributing and collecting manifolds and position of inlet and outlet holes, have been studied for different inlet flow rates. The effect of channel blockage on flow distribution and pressure drop has been investigated. It was found that good agreement between results of the approximate model and results of CFD simulations are shown only for low Reynolds numbers. Results obtained by approximate model and CFD simulations were used to assist design of manifolds for uniform flow distribution between microchannels.     

Ligand-based vascular targeting of disease

This review illustrates the basic principles of ligand-based vascular targeting and presents some of the most advanced results obtained in this field, not only in terms of biopharmaceuticals, which are currently being investigated in clinical and preclinical studies, but also in terms of enabling technologies that facilitate target and ligand discovery. Whereas most of the vascular targeting research activities have so far concentrated on tumoral angiogenesis, the development of non-oncological applications has recently gained momentum and is likely to become an important area of modern pharmaceutical research.     

A microfluidic vesicle screening platform: monitoring the lipid membrane permeability of tetracyclines

For many drugs including antibiotics such as tetracyclines it is crucial that the molecule has the ability to quickly and passively permeate lipid membranes. Hence, the understanding of the permeability in relation to the molecular structure is an important aspect to rationally design novel pharmaceutically active compounds with high bioavailability. Here, we present a versatile method to study the kinetics of tetracycline permeation across liposome membranes on a microchip. Liposomes are immobilized onto the glass surface in a stripe pattern via an avidin-biotin bond and covered by microchannels to allow continuous delivery of tetracycline and buffer. The fluid flow provides a constant concentration profile and thereby resembles the drug transport via blood in the human body. Total internal reflection fluorescence (TIRF) microscopy was used to image the formation of a fluorescent drug-europium complex inside the liposomes. The permeation rates of various tetracyclines were investigated and the results compared to a conventional method (water-octanol partitioning). The findings largely confirm the correlation between membrane permeability and lipophilicity of the permeating molecules (Overton's rule). However, slight deviations reveal that lipophilicity is an important but not the exclusive parameter for the prediction of permeation. The method is fast enough to study the permeation of unstable tetracyclines such as rolitetracycline. Additionally, with the use of different cholesterol concentrations, the influence of membrane composition on the permeation rate can be investigated conveniently. The microfluidic approach can be easily applied to investigate the kinetics of other processes such as ligand-membrane receptor association and dissociation, provided that the process can be visualized by means of fluorescence spectroscopy.     

Covariance and time-scale methods for blind separation of delayed sources

An extension of the blind source separation technique based on the second-order blind identification (SOBI) approach is presented to separate mixtures of delayed sources. When the delay is small such that the first-order Taylor approximation holds, the delayed mixture is transformed as the mixture of the original sources and their derivatives. Two algorithms are proposed for the rotation step that recovers the extended source vector (original sources and the corresponding derivatives). The first approach is based on the odd symmetry of the derivative of the autocorrelation function; and the second method identifies the locations of single auto terms in the optimized time-scale plane. A simulation analysis was conducted to evaluate the performance of the proposed algorithms. The results showed that the proposed methods substantially improved the performance of SOBI and its extension in the time-scale plane when the sources presented delays in the mixtures. In addition, the proposed algorithms were applied representatively to experimental multichannel surface electromyographic signals to identify motor unit action potential trains from the interference signal. The performance of the proposed methods was superior to previous methods also in this representative application. In conclusion, extensions of the SOBI approach of source separation have been proposed for the case of sources being delayed in the mixtures. These techniques were proven superior to previous approaches.