Design and Optimization of Mefloquine Hydrochloride Microparticles for Bitter Taste Masking

The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 3² full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.     

Background K+ current in isolated canine cardiac Purkinje myocytes.

The current-voltage (I-V) relation of the background current, IK1, was studied in isolated canine cardiac Purkinje myocytes using the whole-cell, patch-clamp technique. Since Ba2+ and Cs+ block IK1, these cations were used to separate the I-V relation of IK1 from that of the whole cell. The I-V relation of IK1 was measured as the difference between the I-V relations of the cell in normal Tyrode (control solution) and in the presence of either Ba2+ (1 mM) or Cs+ (10 mM). Our results indicate that IK1 is an inwardly rectifying K+ current whose conductance depends on extracellular potassium concentration. In different [K+]0's the I-V relations of IK1 exhibit crossover. In addition the I-V relation of IK1 contains a region of negative slope (even when that of the whole cell does not). We also examined the relationship between the resting potential of the myocyte, Vm, and [K+]0 and found that it exhibits the characteristic anomalous behavior first reported in Purkinje strands (Weidmann, S., 1956, Elektrophysiologie der Herzmuskelfaser, Med. Verlag H. Huber), where lowering [K+]0 below 4 mM results in a depolarization.     

Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2

The process of cholesterol absorption has yet to be completely defined at the molecular level. Because of its ability to esterify cholesterol for packaging into nascent chylomicrons, ACAT2 plays an important role in cholesterol absorption. However, it has been found that cholesterol absorption is not completely inhibited in ACAT2-deficient (ACAT2 KO) mice. Because ABCA1 mRNA expression was increased 3-fold in the small intestine of ACAT2 KO mice, we hypothesized that ABCA1-dependent cholesterol efflux sustains cholesterol absorption in the absence of ACAT2. To test this hypothesis, cholesterol absorption was measured in mice deficient in both ABCA1 and ACAT2 (DKO). Compared with wild-type, ABCA1 KO, or ACAT2 KO mice, DKO mice displayed the lowest level of cholesterol absorption. The concentrations of hepatic free and esterified cholesterol and gallbladder bile cholesterol were significantly reduced in DKO compared with wild-type and ABCA1 KO mice, although these measures of hepatic cholesterol metabolism were very similar in DKO and ACAT2 KO mice. We conclude that ABCA1, especially in the absence of ACAT2, can have a significant effect on cholesterol absorption, although ACAT2 has a more substantial role in this process than ABCA1.     

Flow injection chemiluminescence determination of acetochlor and cartap-HCl in freshwater samples using an acidic KMnO4–rhodamine-B reaction system

A flow injection (FI) methodology using the acidic potassium permanganate (KMnO₄)–rhodamine-B (Rh-B) reaction with chemiluminescence (CL) detection was established to determine acetochlor and cartap-HCl pesticides in freshwater samples. Experimental parameters were optimized, and Chelex-100 cationic exchanger mini column and solid-phase extraction (SPE) were used as phase separation techniques. Linear calibration curves were observed for the standard solutions of acetochlor and cartap-HCl over the ranges 0.005–2.0 mg L⁻¹ [y = 1155.8x + 57.551, R² = 0.9999 (n = 8)] and 0.005–1.0 mg L⁻¹ [y = 979.76x + 14.491, R² = 0.9998 (n = 8)] with LODs and LOQs of 7.5 × 10⁻⁴ and 8.0 × 10⁻⁴ mg L⁻¹ (3σ blank) and 2.5 × 10⁻³ and 2.7 × 10⁻³ mg L⁻¹ (10σ blank), respectively, with an injection throughput of 140 h⁻¹. These methods were used to estimate acetochlor and cartap-HCl with or without the SPE procedure, respectively, in spiked freshwater samples. Results obtained were not significantly different at a 95% confidence level to those of other reported methods. Recoveries for acetochlor and cartap-HCl were obtained over the ranges 93–112% (RSD = 1.9–3.6%) and 98–109% (RSD = 1.7–3.8%), respectively. The most probable CL reaction mechanism was explored.     

Interactive effect of nitrogen fertilizer and plant density on photosynthetic and agronomical traits of cotton at different growth stages

Individual effects of application of nitrogen (N) and plant densities (PD) were reported in various studies; however an interactive effect of N and PD in cotton was not studied. To explore the benefits of interactive effects of N fertilizer and PD to increase the quality of cotton. This study was carried out in randomized complete block design (RCBD) with split plot arrangement. In split plot arrangement, main plot was consisted of N application rate and in sub plots different PD were done. There were two nitrogen levels; low N level (F1) 120 kg ha⁻¹ and high N level (F2) 180 kg ha⁻¹ and three planting densities; 8 plants m⁻² as low density (LD), 10 plants m⁻² as medium density (MD) and 12 plants m⁻² as high density (HD). In this study we observed the interactive effect of N application levels and PD on cotton photosynthetic and agronomic traits of various stages of development. Results showed that cotton growth and N contents was varied among treatments on different development stages. Plant biomass production, photosynthetic rate (Pn), intercellular CO₂ (C_i), water use efficiency (WUE) and N contents were unaffected at the seedling stage by N application rate and PD, however, the highest Pn, C_i and N contents was at squaring stage followed by blooming stage. Higher seed cotton yield and lint yield were obtained F1 with HD, and F2 with MD yielded the highest N contents and cotton yield among treatments. We found that the squaring stage was more critical, followed by the blooming stage when considering N rate and PD.     

Informed consent for controlled human infection studies in low- and middle-income countries: Ethical challenges and proposed solutions

In controlled human infection studies (CHIs), participants are deliberately exposed to infectious agents in order to better understand the mechanism of infection or disease and test therapies or vaccines. While most CHIs have been conducted in high-income countries, CHIs have recently been expanding into low- and middle-income countries (LMICs). One potential ethical concern about this expansion is the challenge of obtaining the voluntary informed consent of participants, especially those who may not be literate or have limited education. In some CHIs in LMICs, researchers have attempted to address this potential concern by limiting access to literate or educated populations. In this paper, we argue that this practice is unjustified, as it does not increase the chances of obtaining valid informed consent and therefore unfairly excludes illiterate populations and populations with lower education. Instead, we recommend that investigators improve the informed consent process by drawing on existing data on obtaining informed consent in these populations and interventions aimed at improving their understanding. Based on a literature review, we provide concrete suggestions for how to follow this recommendation and ensure that populations with lower literacy or education are given a fair opportunity to protect their rights and interests in the informed consent process.     

Development of non-natural flavanones as antimicrobial agents

With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells.     

Comparison of SSRs and SNPs in assessment of genetic relatedness in maize

Advances in high-throughput SNP genotyping and genome sequencing technologies have enabled genome-wide association mapping in dissecting the genetic basis of complex quantitative traits. In this study, 82 SSRs and 884 SNPs with minor allele frequencies (MAF) over 0.20 were used to compare their ability to assess population structure, principal component analysis (PCA) and relative kinship in a maize association panel consisting of 154 inbred lines. Compared to SNPs, SSRs provided more information on genetic diversity. The expected heterozygosity (He) of SSRs and SNPs averaged 0.65 and 0.44, and the polymorphic information content of these two markers was 0.61 and 0.34 in this panel, respectively. Additionally, SSRs performed better at clustering all lines into groups using STRUCTURE and PCA approaches, and estimating relative kinship. For both marker systems, the same clusters were observed based on PCA and the first two eigenvectors accounted for similar percentage of genetic variations in this panel. The correlation coefficients of each eigenvector from SSRs and SNPs decreased sharply when the eigenvector varied from 1 to 3, but kept around 0 when the eigenvector were over 3. The kinship estimates based on SSRs and SNPs were moderately correlated (r (2)?=?0.69). All these results suggest that SSR markers with moderate density are more informative than SNPs for assessing genetic relatedness in maize association mapping panels.     

Short-form OPA1 is a molecular chaperone in mitochondrial intermembrane space

Mitochondria, double-membrane organelles, are known to participate in a variety of metabolic and signal transduction pathways. The intermembrane space (IMS) of mitochondria is proposed to subject to multiple damages emanating from the respiratory chain. The optic atrophy 1 (OPA1), an important protein for mitochondrial fusion, is cleaved into soluble short-form (S-OPA1) under stresses. Here we report that S-OPA1 could function as a molecular chaperone in IMS. We purified the S-OPA1 (amino acid sequence after OPA1 isoform 5 S1 site) protein and showed it protected substrate proteins from thermally and chemically induced aggregation and strengthened the thermotolerance of Escherichia coli (E. coli). We also showed that S-OPA1 conferred thermotolerance on IMS proteins, e.g., neurolysin. The chaperone activity of S-OPA1 may be required for maintaining IMS homeostasis in mitochondria.