Imputation-Based Population Genetics Analysis of Plasmodium falciparum Malaria Parasites

Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r² for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r², 0.87-0.96), but the performance of IMPUTE was mixed (allelic r², 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima’s D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.     

Structure-activity relationship study between Ornithyl-Proline and Lysyl-Proline based tripeptidomimics as angiotensin-converting enzyme inhibitors

A designed library of tripeptidomimics of Ornithyl-Proline (Orn-Pro) and Lysyl-Proline (Lys-Pro) conjugated with various unnatural amino acids and carboxylic acid derived heterocyclics was synthesized and screened for possible inhibitors of angiotensin-converting enzyme (ACE). Among the tripeptidomimics 10[MTP-Orn-Pro], 11[HTP-Orn-Pro], 14[TA-Orn-Pro] and 20[BPA-Orn-Pro] showed prominent inhibition with IC50 values in micromolar concentrations. Structure-activity relationship study indicated that C3 side chain of Orn as compared to C4 side chain of Lys at P1' position was better suited to inhibit ACE, with propionic acid (C3) derived heterocyclics and unnatural amino acids.     

N-(2-hydroxy phenyl) acetamide produces profound inhibition of c-Fos protein and mRNA expression in the brain of adjuvant-induced arthritic rats

Chronic pain and cognitive decline are characteristic symptoms of rheumatoid arthritis. One of the immediate early gene c-fos is overexpressed during peripheral and central noxious conditions and can be used as a marker for neuronal activity/excitability. In the adjuvant-induced arthritis Sprague–Dawley rat model, we examined the dynamics of c-Fos protein and mRNA expression in the amygdala, cortex, hippocampus, and thalamus and evaluated the effects of N-(2-hydroxy phenyl) acetamide (NA-2), a derivative of salicylic acid. The paw volume was assessed as an indicator of peripheral edema and the hyperalgesia associated with arthritis was monitored by gait analysis. The region of interests of the brain from arthritic and non-arthritic animals were used to isolate the RNA and were then reverse transcribed into cDNA. The PCR products were electrophoresed on 1 % agarose gel and the gels were visualized in gel-doc system. The frozen brain sections were stained for c-Fos using immunohistochemistry. Negative control experiments were performed without the primary and secondary antibodies to rule out the nonspecific tissue binding of antibodies. We report a significant increase in the c-Fos expression in the arthritic control animals. In comparison to the control group, the treatment of NA-2 treatment was found to block the development of the arthritis-induced c-Fos protein and mRNA expression and peripheral edema. It also significantly reduces the gait deficits which were otherwise observed in the arthritic control group. Both the immunohistochemistry and PCR analysis revealed NA-2 to be more potent in comparison to member of non-steroidal anti-inflammatory drug.     

A whole genome analyses of genetic variants in two Kelantan Malay individuals

BackgroundThe sequencing of two members of the Royal Kelantan Malay family genomes will provide insights on the Kelantan Malay whole genome sequences. The two Kelantan Malay genomes were analyzed for the SNP markers associated with thalassemia and Helicobacter pylori infection. Helicobacter pylori infection was reported to be low prevalence in the north-east as compared to the west coast of the Peninsular Malaysia and beta-thalassemia was known to be one of the most common inherited and genetic disorder in Malaysia.ResultBy combining SNP information from literatures, GWAS study and NCBI ClinVar, 18 unique SNPs were selected for further analysis. From these 18 SNPs, 10 SNPs came from previous study of Helicobacter pylori infection among Malay patients, 6 SNPs were from NCBI ClinVar and 2 SNPs from GWAS studies. The analysis reveals that both Royal Kelantan Malay genomes shared all the 10 SNPs identified by Maran (Single Nucleotide Polymorphims (SNPs) genotypic profiling of Malay patients with and without Helicobacter pylori infection in Kelantan, 2011) and one SNP from GWAS study. In addition, the analysis also reveals that both Royal Kelantan Malay genomes shared 3 SNP markers; HBG1 (rs1061234), HBB (rs1609812) and BCL11A (rs766432) where all three markers were associated with beta-thalassemia.ConclusionsOur findings suggest that the Royal Kelantan Malays carry the SNPs which are associated with protection to Helicobacter pylori infection. In addition they also carry SNPs which are associated with beta-thalassemia. These findings are in line with the findings by other researchers who conducted studies on thalassemia and Helicobacter pylori infection in the non-royal Malay population.     

A New Antimicrobial Fatty Acid from the Calcareous Sponge Paragrantia cf. waguensis

A new acetylenic fatty acid, 1 , has been isolated from the title sponge. The structure of the molecule was elucidated to contain an enyne and a thiophene by spectroscopic methods. Compound 1 showed a weak cytotoxic effect against NBT‐T2 rat bladder epithelial cells (IC₅₀>20 μg/ml), and antimicrobial activity with minimal‐inhibitory concentrations (MIC) of 64 and 128 μg/ml against Staphylococcus aureus and Escherichia coli, respectively.     

Development and Evaluation of Hydrophilic Colloid Matrix of Famotidine Tablets

The objective of the present study was to develop a once-daily sustained-release (SR) matrix tablet of famotidine. Nine different formulations (F1–F9) were prepared by direct compression method using Avicel PH101 as filler/binder in the range of 41–27% in F1–F3, 18–22% in F4–F7, and 16–18% in F8–F9 and hydroxypropyl methylcellulose (4,000 cps) as hydrophilic matrix was used in F1–F3 from 19% to 30%, around 40% in F4–F7, and 42–45% in F8–F9. Talc and Aerosil were added in the ratio of 0.7–1.2%. The tablets were subjected to various physical parameters including weight variation test, hardness, thickness, diameter, friability, and in vitro release studies. Assay was also performed according to the USP 30 NF 25 procedure. The results of the physical parameters and assay were found to be within the acceptable range. In vitro dissolution results indicated that formulation F4–F7, having around 40% of rate control polymer, produced a SR pattern throughout 24 h. F1–F3 showed drug release at a faster rate, while F8–F9 released much slower, i.e., <80% in 24 h. Model-dependent and model-independent methods were used for data analysis and the best results were observed for F4 in zero order (r ² = 0.984) and F6 in Korsmeyer and Higuchi (r ² = 0.992 and 0.988). The parameter n indicated anomalous diffusion, while β in Weibull showed a parabolic curve with higher initial slope. The f ₂ similarity test was performed taking F4 as a reference formulation. Only the F5–F7 formulations were similar to the reference formulation F4. The mean dissolution time was around 10 h for the successful formulation.     

Length–weight and length‐length relationships of four endemic fish species caught from Payra River,Southern Bangladesh

The present study estimated the length–weight relationship (LWR) and length‐length relationships (LLR) of four fish species, Ompok pabo (Hamilton, 1822), Acentrogobius cyanomos (Bleeker, 1849), Acentrogobius caninus (Valenciennes, 1837) and Gagata cenia (Hamilton, 1822) collected from the Payra river over a period of 1 year between July 2015–June 2016 using set bag nets and cast nets with a mesh size of 0.5 cm and <0.5 cm, respectively. Altogether 593 individuals of O. pabo (59), A. cyanomos (221), A. caninus (240) and G. cenia (73) were sampled and studied. LWRs of O. pabo, A. cyanomos, and A. caninus are presented for the first time in Fishbase.