NMR quality control of fragment libraries for screening

Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of "poised fragments" with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process

Aspects of loop folding in DNA hairpins: nuclear magnetic resonance, multi-conformational analysis, UV-melting and molecular mechanics calculations

Contains fulltext : mmubn000001_111913292.pdf (publisher's version ) (Open Access)Promotor : C. Hilbers209 p

‘You Just Get Blocked’. Teenage drinkers; reckless rebellion or responsible reproduction?

The purpose of this study is to challenge the discourse that underage drinking is inevitably ‘deviant’. Rather than imposing an adultist lens, the article draws upon focus-group interviews with 14–15 year olds. The meaningful role of drinking is explored, along with the capability of peer cultures to manage some alcohol-related ‘risks’. The data suggest that the prioritisation of adultist constructs over teenage subject experiences appears somewhat misplaced since teenage norms are not complete subversions of the adult world. Apparent transgression is better understood as alternative socialisation, since teenage peer groups creatively reproduce the wider culture

Structure of a stereoregular phosphorothioate DNA/RNA duplex

In this work, we present the first NMR solution structure of a DNA/RNA hybrid containing stereoregular Rp-phosphorothioate modifications of all DNA backbone linkages. The complex of the enzymatically synthesized phosphorothioate DNA octamer (all-R_p)-d(GCGTCAGG) and its complementary RNA r(CCUGACGC) was found to adopt an overall conformation within the A-form family. Most helical parameters and the sugar puckers of the DNA strand assume values intermediate between A- and B-form. The close structural similarity with the unmodified DNA/RNA hybrid of the same sequence may explain why both the natural and the sulfur-substituted complex can be recognized and digested by ribonuclease H

The National Immunisation Programme in the Netherlands : surveillance and developments in 2017-2018.

In 2017, about 760,000 children aged 0 to 19 years received a total of 2,140,000 vaccinations within the National Immunisation Programme (NIP). Participation in the NIP was high among children under 10 years of age, despite the drop by around 2-3% for most vaccinations since 2014. An exception in the high participation is the number of girls who was vaccinated against human papillomavirus (HPV), which has declined by 15% since 2016. The number of reports (1,383) of possible adverse events following immunisation in 2017 was lower than the number of reports in 2016 (1,483). NIP target diseases There is an ongoing increase in the number of cases with meningococcal serogroup W (MenW) disease with 80 cases reported in 2017 and 78 up to August 2018. Because of this increase, since May 2018, the MenC vaccination given at 14 months of age has been replaced by a quadrivalent MenACWY vaccination. The case fatality of MenW disease (17%) was substantially higher than for other serogroups. In 2017, the number of measles cases was low (16 reported cases) but higher than in the previous two years. The number of pertussis reports in 2017 was comparable with 2016 (28.7 compared with 32.6 per 10,000). Three people died from pertussis, one infant and two elderly. The number of reports of acute hepatitis B infections stayed stable (0.7 per 100,000 population). Also, the incidence of vaccine type invasive pneumococcal disease (IPD) remained very low in 2017/2018. Once again, the number of reported cases were in 2017 low for mumps (46), Haemophilus influenzae type b (Hib; 46), meningococcal serogroep C (MenC; 9), diphtheria (4), tetanus (1), rubella (0) and polio (0). The inhabitants of Bonaire, St. Eustatius and Saba are predominantly well protected against NIP diseases. However, protection against measles and diphtheria is suboptimal for some age groups. Awareness is needed to prevent these diseases from spreading from neighboring countries, where outbreaks currently are observed. New advice and decisions In July 2018, the Ministry of Health, Welfare and Sports decided to expand the MenACWY vaccination outbreak programme to 13-14 year olds. In 2019, there will be a catch up campaign for all 15-18 year olds. Furthermore, it was decided that vaccination against disease caused by rotavirus will be included in the NIP for risk groups, and that maternal pertussis vaccination in the NIP will be organised by youth health care organisations. The Dutch Health Council advises to offer vaccination against pneumococcal disease to the people 60 years and older. (aut. ref.