Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC₅₀ value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC₅₀ value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.     

Feasibility of glioblastoma tissue response mapping with physiologic BOLD imaging using precise oxygen and carbon dioxide challenge

Magnetic Resonance Materials in Physics, Biology and Medicine - Innovative physiologic MRI development focuses on depiction of heterogenous vascular and metabolic features in glioblastoma. For this...     

Double emulsions (W/O/W): physical characteristics and perceived intensity of salty taste

This study addressed the correlation between physical characteristics of double emulsions and sensory perception, as the microstructure of these systems may provide the mechanism to understanding the initial cause of the altered salty taste. Thus, double emulsions (W/O/W) were prepared using different volumes of the internal aqueous phase while maintaining the same fat and sodium contents in the evaluated systems. Polyglycerol polyricinoleate (PGPR) and tween 80 were used as hydrophobic and hydrophilic emulsifiers, respectively. After preparation, the samples were stored at 25 °C for 4 days and submitted to analysis of optical microscopy, distribution and polydispersity of the oil droplets size, electrical conductivity, rheological behaviour and sensorial analysis. It was found that the use of different emulsifier concentrations (PGPR) did not influence the physical characteristics of the emulsions with the same formulation, but emulsions with different internal aqueous phase concentrations presented different results. These distinct characteristics may have influenced sensorial perception, as the emulsion with higher internal phase concentration was considered saltier. Thus, it can be concluded that structural differences of the double emulsions can be used to decrease the sodium contents without perceivable changes in salty taste.     

LTE‐based satellite communications in LEO mega‐constellations

The integration of satellite and terrestrial networks is a promising solution for extending broadband coverage to areas not connected to a terrestrial infrastructure, as also demonstrated by recent commercial and standardisation endeavours. However, the large delays and Doppler shifts over the satellite channel pose severe technical challenges to traditional terrestrial systems, as long‐term evolution (LTE) or 5G. In this paper, 2 architectures are proposed for a low Earth orbit mega‐constellation realising a satellite‐enabled LTE system, in which the on‐ground LTE entity is either an eNB (Sat‐eNB) or a relay node (Sat‐RN). The impact of satellite channel impairments as large delays and Doppler shifts on LTE PHY/MAC procedures is discussed and assessed. The proposed analysis shows that, while carrier spacings, random access and RN attach procedures do not pose specific issues and hybrid automatic repeat request requires substantial modifications. Moreover, advanced handover procedures will be also required due to the satellites' movement.     

Challenges for a shared European countryside of uncertain future. Towards a modern community-based landscape perspective

This paper addresses current changes in the highly diverse European landscape, and the way these transitions are being treated in policy and landscape management in the fragmented, heterogeneous and dynamic context of today’s Europe. It appears that intersecting driving forces are increasing the complexity of European landscapes and causing polarising developments in agricultural land use, biodiversity conservation and cultural landscape management. On the one hand, multifunctional rural landscapes, especially in peri-urban regions, provide services and functions that serve the citizens in their demand for identity, support their sense of belonging and offer opportunities for recreation and involvement in practical landscape management. On the other hand, industrial agricultural production on increasingly large farms produces food, feed, fibre and energy to serve expanding international markets with rural liveability and accessibility as a minor issue. The intermediate areas of traditionally dominant small and family farms in Europe seem to be gradually declining in profitability. The paper discusses the potential of a governance approach that can cope with the requirement of optimising land-sharing conditions and community-based landscape development, while adapting to global market conditions.     

Practical and theoretical advances in predicting the function of a protein by its phylogenetic distribution.

The gap between the amount of genome information released by genome sequencing projects and our knowledge about the proteins' functions is rapidly increasing. To fill this gap, various 'genomic-context' methods have been proposed that exploit sequenced genomes to predict the functions of the encoded proteins. One class of methods, phylogenetic profiling, predicts protein function by correlating the phylogenetic distribution of genes with that of other genes or phenotypic characteristics. The functions of a number of proteins, including ones of medical relevance, have thus been predicted and subsequently confirmed experimentally. Additionally, various approaches to measure the similarity of phylogenetic profiles and to account for the phylogenetic bias in the data have been proposed. We review the successful applications of phylogenetic profiling and analyse the performance of various profile similarity measures with a set of one microsporidial and 25 fungal genomes. In the fungi, phylogenetic profiling yields high-confidence predictions for the highest and only the highest scoring gene pairs illustrating both the power and the limitations of the approach. Both practical examples and theoretical considerations suggest that in order to get a reliable and specific picture of a protein's function, results from phylogenetic profiling have to be combined with other sources of evidence.     

Role of nitrogen lewis basicity in boronate affinity chromatography of nucleosides

Urinary modified nucleosides have a potential role as cancer biomarkers, and most of the methods used in their study have utilized low-pressure phenylboronate affinity chromatography materials for the purification of the cis-diol-containing nucleosides. In this study, a boronate HPLC column was surprisingly shown not to trap the nucleosides as would be expected from experience with the classic Affigel 601 resin but showed only partial selectivity toward cis-diol groups while other groups exhibited better retention. In aprotic conditions, trapping of nucleosides was possible; however, the selectivity toward cis-diol-containing compounds was lost with the Lewis basicity of available nitrogens being the main determinant of retention. The experimental findings are compared to and confirmed by DFT calculations.     

Pathogenesis of Helicobacter pullorum infections in broilers

Four groups of 23 one-day-old broiler chickens were each inoculated by gavage with a different Helicobacter pullorum strain isolated from humans or poultry. As a control, a fifth group of eight animals was inoculated with phosphate-buffered saline. Faecal samples were collected weekly and tested for the presence of H. pullorum DNA using PCR. At 1, 8, 15, 22 and 42 days postinoculation, birds were euthanized and samples from the liver and intestinal tract were histologically, immunohistochemically and bacteriologically examined. The samples were also tested for the presence of H. pullorum DNA by PCR. All animals remained clinically healthy throughout the experiment although mild lesions in the caeca were present in animals inoculated with H. pullorum. In all H. pullorum-inoculated groups, DNA of this bacterium was detected in faecal samples until 42 days postinoculation. The main site of colonization was the caecum. Immunohistochemical examination revealed that the bacterium was closely associated with the caecal epithelial cells. It was concluded that H. pullorum may colonize the caecum of broilers and is excreted in their faeces until slaughter age. This implies that chicken meat might constitute a source of infection for human beings.     

Synergetic nanowire growth

Interest in nanowires continues to grow because they hold the promise of monolithic integration of high-performance semiconductors with new functionality into existing silicon technology. Most nanowires are grown using vapour-liquid-solid growth, and despite many years of study this growth mechanism remains under lively debate. In particular, the role of the metal particle is unclear. For instance, contradictory results have been reported on the effect of particle size on nanowire growth rate. Additionally, nanowire growth from a patterned array of catalysts has shown that small wire-to-wire spacing leads to materials competition and a reduction in growth rates. Here, we report on a counterintuitive synergetic effect resulting in an increase of the growth rate for decreasing wire-to-wire distance. We show that the growth rate is proportional to the catalyst area fraction. The effect has its origin in the catalytic decomposition of precursors and is applicable to a variety of nanowire materials and growth techniques.     

Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury

Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10–48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.