Impacts of cage culture on physico-chemical and bacteriological water quality in Lake Volta,Ghana

The effects of cage fish farming on physico-chemical and bacteriological water quality in Lake Volta, Ghana, were investigated in 2013–2014. Farmed and unfarmed (control) areas of the lake were selected for monitoring. Nutrients, temperature, dissolved oxygen, conductivity, turbidity, pH, total coliforms, Pseudomonas and Vibrio spp. in the water were monitored monthly. Analyses of the water samples were carried out according to standard procedures. Physico-chemical quality of the water in both farm and control sites were within ranges typical of minimally impacted water and did not vary significantly between the two contrasting sites. The bacteriological analysis, however, revealed contamination of the lake water by fish farming. The bacterial counts at the farmed sites were significantly higher (p < 0.05) than those of the control sites, with figures at the farmed sites ranging from 132 to 1 708 cfu 100 ml?1 for total coliforms, 514 to 5 170 cfu 100 ml?1 Pseudomonas spp. and 14 to 516 cfu 100 ml?1 for Vibrio spp. The results suggested that cage fish farming has increased bacterial loads in the lake water, but has had minimal impact on its physico-chemical quality.     

Serious adverse events following treatment with ivermectin for onchocerciasis control: a review of reported cases

This paper presents a summary of reported cases of Serious Adverse Events (SAEs) following treatment with Mectizan^® (ivermectin, Merck, Sharpe &; Dohme) in onchocerciasis mass treatment programs from January 1, 1989 to December 31, 2001 through a passive surveillance system. A total of 207 SAE cases were reported out of approximately 165 million reported treatments delivered during the period under review, giving rise to a cumulative incidence of 1 reported SAE per 800,000 reported treatments. The mean age was 40 years and 70% of the cases were males. The mean time between ivermectin intake and onset of illness was 1 day. For 57% of the cases (n = 118), that was their first exposure to ivermectin. The majority of cases were reported from Cameroon (n = 176; 85%) with peaks in the incidence of SAE reporting in 1989–1991 and 1994–1995 when the program expanded to ivermectin-naïve populations. Fifty-five percent of the cases from Cameroon (i.e. 97 out of 176 cases) were encephalopathic and were reported from the central-southern region of the country; two-thirds of these cases were 'probable' or 'possible' cases of Loa loa encephalopathy temporally related to ivermectin treatment. Reporting bias may explain some but not all of the differences in SAE reporting between the 34 onchocerciasis-endemic countries that have, or have had, mass treatment programs. Further research is needed to understand the apparent clustering of encephalopathy cases in central-southern Cameroon since L. loa infection alone probably does not explain the increased incidence of this type of SAE from this region.     

Contents Volume 26 (2000)

Volume Contents

Contents Volume 26 (2000)     

Compensatory effects in the PI3K/PTEN/AKT signaling network following receptor tyrosine kinase inhibition

Overcoming de novo and acquired resistance to anticancer drugs that target signaling networks is a formidable challenge for drug design and effective cancer therapy. Understanding the mechanisms by which this resistance arises may offer a route to addressing the insensitivity of signaling networks to drug intervention and restore the efficacy of anticancer therapy. Extending our recent work identifying PTEN as a key regulator of Herceptin sensitivity, we present an integrated theoretical and experimental approach to study the compensatory mechanisms within the PI3K/PTEN/AKT signaling network that afford resistance to receptor tyrosine kinase (RTK) inhibition by anti-HER2 monoclonal antibodies. In a computational model representing the dynamics of the signaling network, we define a single control parameter that encapsulates the balance of activities of the enzymes involved in the PI3K/PTEN/AKT cycle. By varying this control parameter we are able to demonstrate both distinct dynamic regimes of behavior of the signaling network and the transitions between those regimes. We demonstrate resistance, sensitivity, and suppression of RTK signals by the signaling network. Through model analysis we link the sensitivity-to-resistance transition to specific compensatory mechanisms within the signaling network. We study this transition in detail theoretically by variation of activities of PTEN, PI3K, AKT enzymes, and use the results to inform experiments that perturb the signaling network using combinatorial inhibition of RTK, PTEN, and PI3K enzymes in human ovarian carcinoma cell lines. We find good alignment between theoretical predictions and experimental results. We discuss the application of the results to the challenges of hypersensitivity of the signaling network to RTK signals, suppression of drug resistance, and efficacy of drug combinations in anticancer therapy.     

Targeting CoV-2 spike RBD and ACE-2 interaction with flavonoids of Anatolian propolis by in silico and in vitro studies in terms of possible COVID-19 therapeutics

Propolis is a multi-functional bee product rich in polyphenols. In this study, the inhibitory effect of Anatolian propolis against SARS-coronavirus-2 (SARS-CoV-2) was investigated in vitro and in silico. Raw and commercial propolis samples were used, and both samples were found to be rich in caffeic acid, p-coumaric acid, ferulic acid, t-cinnamic acid, hesperetin, chrysin, pinocembrin, and caffeic acid phenethyl ester (CAPE) at HPLC-UV analysis. Ethanolic propolis extracts (EPE) were used in the ELISA screening test against the spike S1 protein (SARS-CoV-2): ACE-2 interaction for in vitro study. The binding energy values of these polyphenols to the SARS-CoV-2 spike and ACE-2 protein were calculated separately with a molecular docking study using the AutoDock 4.2.6 program. In addition, the pharmacokinetics and drug-likeness properties of these eight polyphenols were calculated according to the SwissADME tool. The binding energy value of pinocembrin was highest in both receptors, followed by chrysin, CAPE, and hesperetin. Based on the in silico modeling and ADME (absorption, distribution, metabolism, and excretion) behaviors of the eight polyphenols, the compounds exhibited the potential ability to act effectively as novel drugs. The findings of both studies showed that propolis has a high inhibitory potential against the Covid-19 virus. However, further studies are now needed.     

The Effects of Dietary Selenium and Vitamin E and their Combination on the Fatty Acids of Erythrocytes,Bone Marrow and Spleen Tissue Lipids of Lambs

The object was to determine the influence of dietary vitamin E, selenium and their combination on the fatty acid con-tent of erythrocytes, bone marrow and spleen lipids of Akkaraman lambs. After supplementation for 15 days, the amount of all fatty acids was slightly higher (p < 0·05) in the vitamin E as compared to the control group, whereas the amount of longer fatty acids was significantly higher (p < 0·01, p < 0·001) in the selenium and combination groups. On the thirtieth day, the amount of all fatty acids was slightly high (p < 0·5) in all the supplemented groups in comparison with the control group. In the bone marrow lipids, the amount of longer fatty acids was decreased (p < 0·05, p < 0·01, p < 0·001) in the vitamin E and combination groups as compared to the control. Although the amount of some fatty acids was high (p < 0·05, p < 0·01) in the selenium group compared to the control, linoleic (18:2), linolenic (18:3) and the polyunsaturated fatty acids (PUFA) were lower (p < 0·05, p < 0·001). In the spleen lipids, the amount of longer fatty acids was slightly decreased (p < 0·05) in the vitamin E group as compared with the control; however the amount of longer fatty acids was significantly higher (p < 0·05, p < 0·01) in the selenium and combination groups in comparison to the control group. Thus dietary supplementation with selenium was more effective than dietary vitamin E supplementation in altering the fatty acid content of the erythrocyte, bone marrow and spleen lipids. © 1997 John Wiley & Sons, Ltd.     

Associations between mutations and a VNTR in the human phenylalanine hydroxylase gene.

The HindIII RFLP in the human phenylalanine hydroxylase (PAH) gene is caused by the presence of an AT-rich (70%) minisatellite region. This region contains various multiple of 30-bp tandem repeats and is located 3 kb downstream of the final exon of the gene. PCR-mediated amplification of this region from haplotyped PAH chromosomes indicates that the previously reported 4.0-kb HindIII allele contains three of these repeats, while the 4.4-kb HindIII allele contains 12 of these repeats. The 4.2-kb HindIII fragment can contain six, seven, eight, or nine copies of this repeat. These variations permit more detailed analysis of mutant haplotypes 1, 5, 6, and, possibly, others. Kindred analysis in phenylketonuria families demonstrates Mendelian segregation of these VNTR alleles, as well as associations between these alleles and certain PAH mutations. The R261Q mutation, associated with haplotype 1, is associated almost exclusively with an allele containing eight repeats; the R408W mutation, when occurring on a haplotype 1 background, may also be associated with the eight-repeat VNTR allele. Other PAH mutations associated with haplotype 1, R252W and P281L, do not appear to segregate with specific VNTR alleles. The IVS-10 mutation, when associated with haplotype 6, is associated exclusively with an allele containing seven repeats. The combined use of this VNTR system and the existing RFLP haplotype system will increase the performance of prenatal diagnostic tests based on haplotype analysis. In addition, this VNTR may prove useful in studies concerning the origins and distributions of PAH mutations in different human populations.     

Features of the reversible sensitivity-resistance transition in PI3K/PTEN/AKT signalling network after HER2 inhibition

Systems biology approaches that combine experimental data and theoretical modelling to understand cellular signalling network dynamics offer a useful platform to investigate the mechanisms of resistance to drug interventions and to identify combination drug treatments. Extending our work on modelling the PI3K/PTEN/AKT signalling network (SN), we analyse the sensitivity of the SN output signal, phospho-AKT, to inhibition of HER2 receptor. We model typical aberrations in this SN identified in cancer development and drug resistance: loss of PTEN activity, PI3K and AKT mutations, HER2 overexpression, and overproduction of GSK3β and CK2 kinases controlling PTEN phosphorylation. We show that HER2 inhibition by the monoclonal antibody pertuzumab increases SN sensitivity, both to external signals and to changes in kinetic parameters of the proteins and their expression levels induced by mutations in the SN. This increase in sensitivity arises from the transition of SN functioning from saturation to non-saturation mode in response to HER2 inhibition. PTEN loss or PIK3CA mutation causes resistance to anti-HER2 inhibitor and leads to the restoration of saturation mode in SN functioning with a consequent decrease in SN sensitivity. We suggest that a drug-induced increase in SN sensitivity to internal perturbations, and specifically mutations, causes SN fragility. In particular, the SN is vulnerable to mutations that compensate for drug action and this may result in a sensitivity-to-resistance transition. The combination of HER2 and PI3K inhibition does not sensitise the SN to internal perturbations (mutations) in the PI3K/PTEN/AKT pathway: this combination treatment provides both synergetic inhibition and may prevent the SN from acquired mutations causing drug resistance. Through combination inhibition treatments, we studied the impact of upstream and downstream interventions to suppress resistance to the HER2 inhibitor in the SN with PTEN loss. Comparison of experimental results of PI3K inhibition in the PTEN upstream pathway with PDK1 inhibition in the PTEN downstream pathway shows that upstream inhibition abrogates resistance to pertuzumab more effectively than downstream inhibition. This difference in inhibition effect arises from the compensatory mechanism of an activation loop induced in the downstream pathway by PTEN loss. We highlight that drug target identification for combination anti-cancer therapy needs to account for the mutation effects on the upstream and downstream pathways.     

mRTVP-1, a novel p53 target gene with proapoptotic activities

We identified a novel mouse gene, mRTVP-1, as a p53 target gene using differential display PCR and extensive promoter analysis. The mRTVP-1 protein has 255 amino acids and differs from the human RTVP-1 (hRTVP-1) protein by two short in-frame deletions of two and nine amino acids. RTVP-1 mRNA was induced in multiple cancer cell lines by adenovirus-mediated delivery of p53 and by gamma irradiation or doxorubicin both in the presence and in the absence of endogenous p53. Analysis of RTVP-1 expression in nontransformed and transformed cells further supported p53-independent gene regulation. Using luciferase reporter and electrophoretic mobility shift assays we identified a p53 binding site within intron 1 of the mRTVP-1 gene. Overexpression of mRTVP-1 or hRTVP-1 induced apoptosis in multiple cancer cell lines including prostate cancer cell lines 148-1PA, 178-2BMA, PC-3, TSU-Pr1, and LNCaP, a human lung cancer cell line, H1299, and two isogenic human colon cancer cell lines, HCT116 p53(+/+) and HCT116 p53(-/-), as demonstrated by annexin V positivity, phase-contrast microscopy, and in selected cases 4',6'-diamidino-2-phenylindole staining and DNA fragmentation. Deletion of the signal peptide from the N terminus of RTVP-1 reduced its apoptotic activities, suggesting that a secreted and soluble form of RTVP-1 may mediate, in part, its proapoptotic activities.