Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity.

Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC50s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC50s of 67.2082 ± 0.9731 and >100 µM, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.

Powerful, transferable representations for molecules through intelligent task selection in deep multitask networks.

Chemical representations derived from deep learning are emerging as a powerful tool in areas such as drug discovery and materials innovation. Currently, this methodology has three major limitations - the cost of representation generation, risk of inherited bias, and the requirement for large amounts of data. We propose the use of multi-task learning in tandem with transfer learning to address these limitations directly. In order to avoid introducing unknown bias into multi-task learning through the task selection itself, we calculate task similarity through pairwise task affinity, and use this measure to programmatically select tasks. We test this methodology on several real-world data sets to demonstrate its potential for execution in complex and low-data environments. Finally, we utilise the task similarity to further probe the expressiveness of the learned representation through a comparison to a commonly used cheminformatics fingerprint, and show that the deep representation is able to capture more expressive task-based information.

Ethical issues in the development and implementation of nutrition-related public health policies and interventions: A scoping review.

BACKGROUND: The limited integration of ethics in nutrition-related public health policies and interventions is one major concern for those who have the task of implementing them. Ethical challenges that are overlooked during the development of such interventions could raise serious ethical issues during their implementation and even after. As a result, these decision makers need technical support and ethical guidance for adaptation of interventions to local (cultural, social, economic, etc.) contexts. AIM: The goal of this scoping review is to delineate and "map" the range of ethical issues in nutrition-related public health interventions, as well as the range of the various fields in which they may arise. METHODS: A scoping review of empirical research and conceptual literature was conducted following the framework of Arksey and O'Malley. Searches using PubMed with Medical Subject Headings (MeSH) categories and Advanced Search Builder as well as in the Global Health Library were performed. The final sample consists of 169 publications. RESULTS: The ethics of public health prevention or treatment of obesity and non-communicable diseases is the most explicitly and frequently discussed subject. In comparison, ethical issues raised by public health interventions in the fields of undernutrition, breastfeeding, vitamin/mineral supplementation and food fortification, food security, food sustainability and food safety are addressed in a lower proportion of the sample. The results illustrate the various natures, types, and scopes of existing public health nutrition-related interventions, and the various ethical issues that may be raised by these interventions, in addition to the numerous and different contexts in which they may be implemented. DISCUSSION: The ethical issues faced in the development and implementation of nutrition-related public health interventions are varied and cannot be equated with, nor generalized about, when dealing with specific activities in this field. More importantly, these ethical issues cannot be managed without a careful consideration for the complexity of contexts in which nutrition-related interventions are expected to be implemented. These interventions engage a variety of actors with diverse perspectives and interests. We discuss these challenges and also comment on the importance of considering ethical impacts in the monitoring and evaluation of such interventions. CONCLUSION: General ethical frameworks or recommendations-although useful-cannot be expected to provide policy makers, implementators and other public health personnel with sufficient practical ethical guidance as they cannot consider and anticipate the particularities of all specific nutrition-related public health interventions and the complexity of the contexts in which they are implemented. Further research is needed in order to develop more targeted ethical frameworks.

Tuning the Cavity Size and Chirality of Self-Assembling 3D DNA Crystals.

The foundational goal of structural DNA nanotechnology-the field that uses oligonucleotides as a molecular building block for the programmable self-assembly of nanostructured systems-was to use DNA to construct three-dimensional (3D) lattices for solving macromolecular structures. The programmable nature of DNA makes it an ideal system for rationally constructing self-assembled crystals and immobilizing guest molecules in a repeating 3D array through their specific stereospatial interactions with the scaffold. In this work, we have extended a previously described motif (4 × 5) by expanding the structure to a system that links four double-helical layers; we use a central weaving oligonucleotide containing a sequence of four six-base repeats (4 × 6), forming a matrix of layers that are organized and dictated by a series of Holliday junctions. In addition, we have assembled mirror image crystals (l-DNA) with the identical sequence that are completely resistant to nucleases. Bromine and selenium derivatives were obtained for the l- and d-DNA forms, respectively, allowing phase determination for both forms and solution of the resulting structures to 3.0 and 3.05 Å resolution. Both right- and left-handed forms crystallized in the trigonal space groups with mirror image 3-fold helical screw axes P32 and P31 for each motif, respectively. The structures reveal a highly organized array of discrete and well-defined cavities that are suitable for hosting guest molecules and allow us to dictate a priori the assembly of guest-DNA conjugates with a specified crystalline hand.

Sensitive bromine-based screening of potential toxic furanoids in Dioscorea bulbifera L.

Numerous furanoids have been reported to be toxic, and many of them were found in herbal medicines. Toxicities of furanoids are suggested to result from the generation of cis-enedials via biotransformation. The detection of the electrophilic metabolic intermediates is a challenge. Earlier, we developed a selective approach to screen potential toxic furanoids, through which we found two major furanoids, diosbulbin B and 8-epidiosbulbin E acetate, in Dioscorea bulbifera L., a known furanoid-containing and hepatotoxic herbal medicine. In the present study, we improved the approach to analyze furanoids in D. bulbifera L., which allowed us to detect additional six potential furanoids, including diosbulbin A, diosbulbin D, diosbulbin E, diosbulbin F, diosbulbin M, and diosbulbin D glycoside. The achievements of this study enhanced the sensitivity to screen potential toxic furanoids through elevating S/N values by approximately 3 times. This will facilitate the understanding of mechanisms of toxic actions of D. bulbifera L. and other furanoid-containing toxic herbal medicines.

New approach to the fast screening of plant oil samples for F-, Cl-, Br- and S-organic compounds on the trace level.

The fast method of the simultaneous determination of F(-), Cl(-), Br(-) and SO4(2-) anions in the deionized water on the trace level by ion chromatography using thorough cleaning of respective water containers, 10 µM NaHCO3 water solution as eluent, short Metrohm (50 × 4 mm) separation column and a large water volume injection is proposed. Calculated detection limits are 10(-9)-10(-8)% depending on the element. The method for the fast screening of plant oil samples for the total fluorine-, chlorine-, bromine- and sulfur-organic compounds content (calculated for the respective elements) on the trace level is developed. It is based on the high temperature combustion of oil sample in oxygen flow, absorption of the conversion products in deionized water and whole absorbate volume analysis for F(-), Cl(-), Br(-) and SO4(2-) anions, corresponding to the respective elements, using the developed method of these anions analysis by ion chromatography. The samples of soya, olive, sunflower and cotton seed oil were analyzed. The method detection limits (for 1mg sample) were 2 × 10(-6)%, 2 × 10(-6)%, 5 × 10(-6)% and 5 × 10(-6)% for fluorine, chlorine, bromine and sulfur, respectively. The relative standard deviation was ≤ 15%. The method gives the compressed information about the total content of all target and nontarget fluorine-, chlorine-, bromine- and sulfur-organic compounds in plant oils.

Electrochemical bromination of organosulfur containing species for the determination of the strength of garlic (A. sativum).

The extraction by ethyl acetate and subsequent electrochemical detection of organosulfur containing molecules from garlic is demonstrated. The electrochemical results first evidence the high sensitivity of the process towards the model compound propyl disulfide. Through the in situ formation of bromine at a platinum electrode the propyl disulfide can be readily detected at concentrations as low as 12.5 µM. Second, the work focuses on the detection of organosulfur from fresh garlic samples. Extraction of the organosulfur 'flavour' molecules is achieved with ethyl acetate. Addition of this extract to the electrochemical cell results in an analytically useful signal allowing the voltammetric peak height to be successfully correlated with the garlic strength, as measured using an organoleptic tasting panel.

Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a]quinoxalines.

Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a (18)F-labeled PDE10A imaging agent for positron emission tomography. The use of ortho-fluoropyridines as residues could potentially enable the introduction of (18)F through nucleophilic substitution for radiolabeling purposes. 2-Fluoropyridines are introduced by a Suzuki coupling at different positions of the molecule. The reference compounds, 1,8-dipyridinylimidazo[1,5-a]quinoxalines and 1-pyridinylimidazo[1,5-a]quinoxalines, show inhibitory potencies at best in the subnanomolar range and selectivity factors greater than 38 against other PDE's. 1,8-Dipyridinylimidazo[1,5-a]quinoxalines are more potent inhibitors than 1-pyridinylimidazo[1,5-a]quinoxalines. Using 2-fluoro-3-pyridinyl as residue provided the most potent inhibitors 16 (IC50 = 0.12 nM), 17 (IC50 = 0.048 nM) and 32 (IC50 = 0.037 nM).

Synthesis and Antiviral Activity of Quercetin Brominated Derivatives.

Reaction of quercetin (QR) (1) with bromine under various conditions was studied. Interaction of QR with 2-3 equiv. of bromine in glacial acetic acid at 35-40°C for 2-4 h and 20-22°C for 24 h led to the formation of QR 6,8-dibromide (2) (52-54% yields, 96-98% purity by HPLC). Interaction of QR with 2-5 equiv. bromine in absolute ethanol at 0-5°C and 20-22°C for 24 h led to the formation of 3-O-ethyl-QR-2,3,6,8,5'-pentabromide (3) (95-97% purity by HPLC) the output of which depends on the quantity of bromine. It was shown in MDCK cell culture that compound 2 exhibits a moderate inhibitory activity against pandemic influenza virus A/H1N1/pdm09 (EC50 6.0 µg/mL, CTD50 97.7 µg/mL, SI 16). Compound 3 was inactive.

Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide.

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup. The X-ray structure of 6 showed that the dipyridyl diselenide moiety was kept in an almost planar, transoid conformation. According to NBO-analysis, this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on selenium was confirmed by NPA-analysis and seen in calculated and observed (77)Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromo compound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide 6 is a better GPx-catalyst than 11. On the basis of (77)Se-NMR experiments, a catalytic mechanism for diselenide 6 was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 µM) where it showed only minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.

Effect of zinc on the content of chemical elements in the lung tissue during obesity in the experiment.

We found no deviations from normalcy in the content of chemical elements (K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, and Sr) in the lungs of rats with mild alimentary obesity, but revealed redistribution of correlations between the elements indicating impaired metabolism in this organ. Zinc supplementation had no effect on the body weight and content of chemical elements (including zinc) in the lung tissue in rats fed high fat diet, but led to significant changes in the correlations between the elements. Bromine, rubidium, and strontium are actively involved in interelement interactions in the lung tissue. These elements should be given more attention in considering biological processes including alimentary obesity.

Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease.

A library of 68 brominated fragments was screened against a new crystal form of inhibited HIV-1 protease in order to probe surface sites in soaking experiments. Often, fragments are weak binders with partial occupancy, resulting in weak, difficult-to-fit electron density. The use of a brominated fragment library addresses this challenge, as bromine can be located unequivocally via anomalous scattering. Data collection was carried out in an automated fashion using AutoDrug at SSRL. Novel hits were identified in the known surface sites: 3-bromo-2,6-dimethoxybenzoic acid (Br6) in the flap site and 1-bromo-2-naphthoic acid (Br27) in the exosite, expanding the chemistry of known fragments for development of higher affinity potential allosteric inhibitors. At the same time, mapping the binding sites of a number of weaker binding Br-fragments provides further insight into the nature of these surface pockets.

[Antimicrobial activity of some cinnamic acid derivatives]. / Evaluarea actiunii antimicrobiene a unor derivati de acid cinamic.

Due to drug-resistance phenomenon, there is a constant need for discovering new antiinfectious agents. A series of cinnamic acid derivatives was synthesized and then brominated with bromine in the presence of chloroform or acetic acid. The structure of the new compounds was confirmed by elemental and spectral data. Their antimicrobial activity was tested by disc-diffusion method. The tested compounds had mainly antifungal activity and were moderately active against Gram-positive bacteria. Bromination of the double bond determined the enhancement of the antimicrobial activity for all the tested compounds.

Brominated extracts as source of bioactive compounds.

The chemical composition and the biomolecular properties of a crude plant extract were altered through bromination leading to the discovery of an acetylcholinesterase inhibitor.

Selenium derivatization of nucleic acids for crystallography.

The high-resolution structure of the DNA (5'-GTGTACA-C-3') with the selenium derivatization at the 2'-position of T2 was determined via MAD and SAD phasing. The selenium-derivatized structure (1.28 A resolution) with the 2'-Se modification in the minor groove is isomorphorous to the native structure (2.0 A). To directly compare with the conventional bromine derivatization, we incorporated bromine into the 5-postion of T4, determined the bromine-derivatized DNA structure at 1.5 A resolution, and found that the local backbone torsion angles and solvent hydration patterns were altered in the structure with the Br incorporation in the major groove. Furthermore, while the native and Br-derivatized DNAs needed over a week to form reasonable-size crystals, we observed that the Se-derivatized DNAs grew crystals overnight with high-diffraction quality, suggesting that the Se derivatization facilitated the crystal formation. In addition, the Se-derivatized DNA sequences crystallized under a broader range of buffer conditions, and generally had a faster crystal growth rate. Our experimental results indicate that the selenium derivatization of DNAs may facilitate the determination of nucleic acid X-ray crystal structures in phasing and high-quality crystal growth. In addition, our results suggest that the Se derivatization can be an alternative to the conventional Br derivatization.

Analysis of acrylamide in green tea by gas chromatography-mass spectrometry.

Optimization of the solid-phase extraction cleanup procedure enabled the GC-MS analysis of acrylamide in tea samples without the interference of bromination by tea catechins. Although polyvinylpolypyrrolidone (PVPP) is available for removing tea catechins from tea extract, the peaks derived from PVPP had the same retention time as brominated acrylamide in mass chromatograms obtained by GC-MS. A considerable amount of acrylamide was formed at roasting temperatures of > or =120 degrees C; the highest acrylamide level was observed when tea samples were roasted at 180 degrees C for 10 min. Higher temperatures and longer processing times caused a decrease in the acrylamide content. Furthermore, an analysis of 82 tea samples showed that rather than the reducing sugar content, the asparagine content in tea leaves was a significant factor related to acrylamide formation in roasted products. The acrylamide level in roasted tea products was controlled by asparagine in the presence of reducing sugars.

Absolute configurations of brominated sesquiterpenes determined by vibrational circular dichroism.

Two brominated sesquiterpenes, majapolene B (1) and acetylmajapolene B (2), isolated from the red algal genus Laurencia were investigated using vibrational circular dichroism (VCD). The ab initio theoretical VCD and IR calculations of 1 and 2 were performed by density functional theory (DFT) using the B3PW91/6-31G(d,p) basis set. The experimental VCD spectra and corresponding population-weighted theoretical VCD spectra were found to be in excellent agreement in CCl(4) solution in the 1800-850 cm(-1) region, which allowed unambiguous determination of the absolute configurations of (-)-1 and (-)-2 as 7S,10S and 7S,10S, respectively.

Catalytic and electrocatalytic hydrogenolysis of brominated diphenyl ethers.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental contaminants due to their use as additive flame-retardants. Conventional catalytic hydrogenolysis in methanol solution and electrocatalytic hydrogenolysis in aqueous methanol were examined as methods for debrominating mono- and di-bromodiphenyl ethers, as well as a commercial penta-PBDE mixture, in each case using palladium on alumina as the catalyst. Electrocatalytic hydrogenolysis employed a divided flow-through batch cell, with reticulated vitreous carbon cathodes and IrO2/Ti dimensionally stable anodes. Both methods gave efficient sequential debromination, with essentially complete removal of bromine from the PBDEs, but the electrocatalytic method was limited by the poor solubility of PBDEs in aqueous methanol.

Determination of acrylamide in various food matrices: evaluation of LC and GC mass spectrometric methods.

Recent concerns surrounding the presence of acrylamide in many types of thermally processed food have brought about the need for the development of analytical methods suitable for determination of acrylamide in diverse matrices with the goals of improving overall confidence in analytical results and better understanding of method capabilities. Consequently, the results are presented of acrylamide testing in commercially available food products--potato fries, potato chips, crispbread, instant coffee, coffee beans, cocoa, chocolate and peanut butter, obtained by using the same sample extract. The results obtained by using LC-MS/MS, GC/MS (El), GC/HRMS (El)--with or without derivatization--and the use of different analytical columns, are discussed and compared with respect to matrix borne interferences, detection limits and method complexities.