Cytochrome P450 Inhibition by Antimicrobials and Their Mixtures in Rainbow Trout Liver Microsomes In Vitro

Antimicrobials are ubiquitous in the environment and can bioaccumulate in fish. In the present study, we determined the half-maximal inhibitory concentrations (IC50) of 7 environmentally abundant antimicrobials (ciprofloxacin, clarithromycin, clotrimazole, erythromycin, ketoconazole, miconazole, and sulfamethoxazole) on the cytochrome P450 (CYP) system in rainbow trout (Oncorhynchus mykiss) liver microsomes, using 7-ethoxyresorufin O-deethylation (EROD, CYP1A) and 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD, CYP3A) as model reactions. Apart from ciprofloxacin and sulfamethoxazole, all antimicrobials inhibited either EROD or BFCOD activities or both at concentrationsPeer reviewe

Role of MAPK in apolipoprotein CIII-induced apoptosis in INS-1E cells

<p>Abstract</p> <p>Background</p> <p>Individuals with type 2 diabetes mellitus (T2DM) have elevated levels of circulating apolipoprotein CIII (apoCIII). ApoCIII plays an important role for plasma triglyceride levels and elevated levels of the apolipoprotein have been connected with dyslipidemia in T2DM subjects. In addition, apoCIII has been linked to enhanced β-cell apoptosis. The present study was undertaken to investigate apoptotic mechanisms induced by the apolipoprotein.</p> <p>Results</p> <p>ApoCIII (10 μg/ml) enhanced apoptosis 2-fold in insulin-producing INS-1E cells after 24 hours exposure to the apolipoprotein. At this time point phosphorylation of mitogen activated protein kinase (MAPK) p38 had doubled but ERK1/2 and JNK were not activated. Instead, ERK1/2 showed rapid and transient phosphorylation (2-fold after 0.5 hour). No JNK phosphorylation was observed. In support of a role of activation of not only p38 but also ERK1/2 in apoCIII-induced apoptosis, inclusion of p38 inhibitor SB203580 (10 μM) or ERK1/2 inhibitor PD98059 (100 μM) normalized apoptosis. Whereas influx of Ca²⁺was linked to apoCIII-induced ERK1/2 activation, pro-apoptotic protein CHOP/GADD of the unfolded protein response (UPR) was not affected by apoCIII.</p> <p>Conclusion</p> <p>It is suggested that elevated circulating apoCIII levels may contribute to β-cell apoptosis via activation of p38 and ERK1/2 in individuals with T2DM. Therapies aiming at normalizing levels of apoCIII could be beneficial not only for the function of the β-cell but also for cardiovascular protection.</p

Ontogeny of hallucal metatarsal rigidity and shape in the rhesus monkey (Macaca mulatta) and chimpanzee (Pan troglodytes)

Life history variables including the timing of locomotor independence, along with changes in preferred locomotor behaviors and substrate use during development, influence how primates use their feet throughout ontogeny. Changes in foot function during development, in particular the nature of how the hallux is used in grasping, can lead to different structural changes in foot bones. To test this hypothesis, metatarsal midshaft rigidity [estimated from the polar second moment of area (J) scaled to bone length] and cross-sectional shape (calculated from the ratio of maximum and minimum second moments of area, Imax /Imin ) were examined in a cross-sectional ontogenetic sample of rhesus macaques (Macaca mulatta; n = 73) and common chimpanzees (Pan troglodytes; n = 79). Results show the hallucal metatarsal (Mt1) is relatively more rigid (with higher scaled J-values) in younger chimpanzees and macaques, with significant decreases in relative rigidity in both taxa until the age of achieving locomotor independence. Within each age group, Mt1 rigidity is always significantly higher in chimpanzees than macaques. When compared with the lateral metatarsals (Mt2-5), the Mt1 is relatively more rigid in both taxa and across all ages; however, this difference is significantly greater in chimpanzees. Length and J scale with negative allometry in all metatarsals and in both species (except the Mt2 of chimpanzees, which scales with positive allometry). Only in macaques does Mt1 midshaft shape significantly change across ontogeny, with older individuals having more elliptical cross-sections. Different patterns of development in metatarsal diaphyseal rigidity and shape likely reflect the different ways in which the foot, and in particular the hallux, functions across ontogeny in apes and monkeys

Aldo-Keto Reductases and Cancer Drug Resistance

Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Furthermore, this cellular stress activates the Nuclear factor-erythroid 2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines, mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the elimination of progestogens and are involved in hormonal-dependent malignancies. They are upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance and/or syndergize the effects of existing drugs. SIGNIFICANCE STATEMENT: Aldo-keot reductases (AKRs) are overexpressed in a large number of human tumors and mediate resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR pan-inhibitors to improve clinical outcome

Unveiling evolutionary algorithm representation with DU maps

Evolutionary algorithms (EAs) have proven to be effective in tackling problems in many different domains. However, users are often required to spend a significant amount of effort in fine-tuning the EA parameters in order to make the algorithm work. In principle, visualization tools may be of great help in this laborious task, but current visualization tools are either EA-specific, and hence hardly available to all users, or too general to convey detailed information. In this work, we study the Diversity and Usage map (DU map), a compact visualization for analyzing a key component of every EA, the representation of solutions. In a single heat map, the DU map visualizes for entire runs how diverse the genotype is across the population and to which degree each gene in the genotype contributes to the solution. We demonstrate the generality of the DU map concept by applying it to six EAs that use different representations (bit and integer strings, trees, ensembles of trees, and neural networks). We present the results of an online user study about the usability of the DU map which confirm the suitability of the proposed tool and provide important insights on our design choices. By providing a visualization tool that can be easily tailored by specifying the diversity (D) and usage (U) functions, the DU map aims at being a powerful analysis tool for EAs practitioners, making EAs more transparent and hence lowering the barrier for their use

Genotyping of human papillomavirus high-risk types and correlation with potential risk factors

Human papillomavirus (HPV) is one of the most common sexually transmitted disease (STD) worldwide. HPV is a small, double-stranded DNA virus that infects mucosal and coetaneous epithelia trough tiny cuts and abrasion, exposed by the cells of the basal layer. If diagnosed on time HPV can be successfully treated, however, in some cases it can lead to the development of tumor. Most of cervical tumors contain HPV DNA, and majority of them contain high-risk types HPV16 and HPV18. Different risk factors are associated with HPV infection, including behavioral and biological predispositions. Aim of this study is to genotype potentially infected patients on high-risk types HPV DNA and to correlate the results with patient’s different biological and lifestyle factors. For this purpose 20 gynecological smear samples were collected from women, previously subjected to the survey. Methodology included DNA extraction and real-time polymerase chain reaction (RT-PCR). Results showed that out of 20 patients five were positive for high risk HPV. Four of five positive patients were positive on HPV16 type of which one had HPV16 together with others high risk types. One of five positive patients was positive on HPV18 type and other high risk types not identified. Final outcome indicates the correlation of potentially endangered patients with specific sexual behavior and lifestyles, and furthermore represent the general consensus and awareness level this disease has on the publi

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

BACKGROUND: Before the emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination reduced transmission of SARS-CoV-2 from vaccinated persons who became infected, potentially by reducing viral loads. Although vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated persons who are infected with the delta variant call into question the degree to which vaccination prevents transmission. METHODS: We used contact-testing data from England to perform a retrospective observational cohort study involving adult contacts of SARS-CoV-2–infected adult index patients. We used multivariable Poisson regression to investigate associations between transmission and the vaccination status of index patients and contacts and to determine how these associations varied with the B.1.1.7 (alpha) and delta variants and time since the second vaccination. RESULTS: Among 146,243 tested contacts of 108,498 index patients, 54,667 (37%) had positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests. In index patients who became infected with the alpha variant, two vaccinations with either BNT162b2 or ChAdOx1 nCoV-19 (also known as AZD1222), as compared with no vaccination, were independently associated with reduced PCR positivity in contacts (adjusted rate ratio with BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78). Vaccine-associated reductions in transmission of the delta variant were smaller than those with the alpha variant, and reductions in transmission of the delta variant after two BNT162b2 vaccinations were greater (adjusted rate ratio for the comparison with no vaccination, 0.50; 95% CI, 0.39 to 0.65) than after two ChAdOx1 nCoV-19 vaccinations (adjusted rate ratio, 0.76; 95% CI, 0.70 to 0.82). Variation in cycle-threshold (Ct) values (indicative of viral load) in index patients explained 7 to 23% of vaccine-associated reductions in transmission of the two variants. The reductions in transmission of the delta variant declined over time after the second vaccination, reaching levels that were similar to those in unvaccinated persons by 12 weeks in index patients who had received ChAdOx1 nCoV-19 and attenuating substantially in those who had received BNT162b2. Protection in contacts also declined in the 3-month period after the second vaccination. CONCLUSIONS: Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time. PCR Ct values at diagnosis of the index patient only partially explained decreased transmission. (Funded by the U.K. Government Department of Health and Social Care and others.

Redefining the technical and organizationalcompetences of children vaccination clinics in order to improve performance. A practical experience at the ULSS 12 Venetian Public Health and Hygiene Service

Introduction. Since Regione Veneto suspended compulsory vaccination for children in 2008, and because of an increasing disaffection of parents to the vaccine practice, the vaccination rates have been slowly but steadily decreasing. The aim of this study was to analyze internal and external factors of immuniza- tion reduction and to implement potential solutions of the prob- lem. Methods. Servizio Igiene e Sanita? Pubblica of ULSS 12 Venezi- ana (SISP ? Hygiene and Public Health Service) analyzed and addressed both, the reasons of parents who do not vaccinate their children and the internal problems regarding vaccination clinics management, information to families, procedures and guidelines and, in general, the communication skills of the vaccination staff. Results. A positive trend in vaccination rates was observed, espe- cially in Venice historical centre. Moreover the staff reported a better working atmosphere and benefit from sharing common goals and procedures, even though the workforce was reduced of about 30% in terms of equivalent unit (EU). Discussion. The continuous quality improvement method fol- lowed in this experience led to a steady increase in vaccination coverage in all territorial clinics, to a better adhesion of guide- lines and standard operating procedures and to a general pro- fessional empowerment of SISP staff. The service now offered to the population is better and more efficient, since the workforce has been reduced. Future goals are to improve information about vaccinations among the population