Još od prapovijesnih vremena ljudi su nastojali postići siguran način kako da odrede gdje se nalaze te kako da dođu do nekog određenog mjesta. Tako su u početku pomorci plovili uz obalu kako se ne bi ...izgubili. Kasnije, kada su otkrili da se mogu orijentirati pomoću zvijezda, počeli su ploviti na otvoreno more.1 Veliki napredak u potrazi za savršenim načinom navigacije bio je izum magnetnog kompasa i sekstanta. No, mornari i dalje nisu bili u mogućnosti odrediti zemljopisnu širinu na kojoj se nalaze. To je bio tako ozbiljan problem da su Britanci u XVII. stoljeću osnovali specijalnu skupinu od tada najpoznatijih znanstvenika koji su ga trebali riješiti. Ponuđena je i nagrada od tadašnjih 20.000 funti (danas oko milijun američkih dolara) onome tko nađe rješenje za određivanje zemljopisne širine unutar 30 nautičkih milja. Nagrada je pripala Johnu Harrisonu koji je izumio kronometar, koji je kasnio ili brzao samo jednu sekundu na dan, stoje za ono vrijeme bilo nevjerojatno precizno. Tako su u sljedeća dva stoljeća sekstant i kronometar bili korišteni za određivanje zemljopisne dužine i širine.
The main etiological factor of precancerous lesion and invasive cervical cancer are oncogenic human papillomaviruses types (HPVs). The objective of this study was to establish the distribution of the ...most common HPVs in different cervical lesions and cancer prior to the implementation of organized population-based cervical screening and HPV vaccination in Croatia. In this study, 4,432 cervical specimens, collected through a 16-year period, were tested for the presence of HPV-DNA by polymerase chain reaction (PCR) with three sets of broad-spectrum primers and type-specific primers for most common low-risk (LR) types (HPV-6, 11) and the most common high-risk (HR) types (HPV-16, 18, 31, 33, 45, 52, 58). Additional 35 archival formalin-fixed, paraffin embedded tissue of cervical cancer specimens were analyzed using LiPA25 assay. The highest age-specific HPV-prevalence was in the group 18-24 years, which decreased continuously with age (P<0.0001) regardless of the cytological diagnosis. The prevalence of HR-HPV types significantly increased (P<0.0001) with the severity of cervical lesions. HPV-16 was the most common type found with a prevalence (with or without another HPV-type) of 6.9% in normal cytology, 15.5% in atypical squamous cells of undetermined significance, 14.4% in low-grade squamous intraepithelial lesions, 33.3% in high-grade squamous intraepithelial lesions, and 60.9% in cervical cancer specimens (P<0.0001). This study provides comprehensive and extensive data on the distribution of the most common HPV types among Croatian women, which will enable to predict and to monitor the impact of HPV-vaccination and to design effective screening strategies in Croatia.
Kelch-like ECH associated protein 1 (Keap1) is a cellular sensor for oxidative stress and a negative regulator of the transcription factor Nrf2. Keap1 and Nrf2 control expression of nearly 500 genes ...with diverse cytoprotective functions and the Nrf2-Keap1 signaling pathway is a major regulator of cytoprotective responses to oxidative and electrophilic stress. It was found that the metallopeptidase dipeptidyl peptidase III (DPP III) contributes to Nrf2 activation by binding to Keap1, probably by binding to the Kelch domain, and thereby influences Nrf2 activity in cancer. We here first determined that the K.sub.D of the DPP III-Kelch domain complex is in the submicromolar range. In order to elucidate the molecular details of the DPP III--Kelch interaction we then built models of the complex between human DPP III and the Keap1 Kelch domain and performed coarse-grained and atomistic simulations of the complexes. In the most stable complexes, the ETGE motif in the DPP III flexible loop binds near the central pore of the six-blade β-propeller Kelch domain. According to the preliminary HD exchange experiments DPP III binds to the more unstructured end of Kelch domain. According to the results of MD simulations DPP III binding to the Kelch domain does not influence the overall DPP III structure or the long-range domain fluctuations. We can conclude that DPP III forms the stable complexes with the Keap1 Kelch domain by inserting the flexible loop into the entrance to the central pore of the six blade β-propeller Kelch domain at its more unstructured, N-terminus. Keywords: 'protein-protein interaction', dipeptidyl peptidase III, docking, molecular dynamics, Keap1, microscale thermophoresis (MST).
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