5-Hydroxy-5-methylhydantoin DNA lesion, a molecular trap for DNA glycosylases

DNA base-damage recognition in the base excision repair (BER) is a process operating on a wide variety of alkylated, oxidized and degraded bases. DNA glycosylases are the key enzymes which initiate the BER pathway by recognizing and excising the base damages guiding the damaged DNA through repair synthesis. We report here biochemical and structural evidence for the irreversible entrapment of DNA glycosylases by 5-hydroxy-5-methylhydantoin, an oxidized thymine lesion. The first crystal structure of a suicide complex between DNA glycosylase and unrepaired DNA has been solved. In this structure, the formamidopyrimidine-(Fapy) DNA glycosylase from Lactococcus lactis (LlFpg/LlMutM) is covalently bound to the hydantoin carbanucleoside-containing DNA. Coupling a structural approach by solving also the crystal structure of the non-covalent complex with site directed mutagenesis, this atypical suicide reaction mechanism was elucidated. It results from the nucleophilic attack of the catalytic N-terminal proline of LlFpg on the C5-carbon of the base moiety of the hydantoin lesion. The biological significance of this finding is discussed

HorizonUAM: Safety and Security Considerations for Urban Air Mobility

HorizonUAM is a DLR project to research the vision of urban air mobility. One important topic is the safety and security aspect. This paper discusses the safety and security considerations in the topic areas of: safe autonomy, reliable multisensor navigation, robust and efficient communication, U-space and safe air traffic, and finally cyber-physical safety and security. As a basis for future discussion, the challenges and gaps are identified, furthermore the research in the context of the project is briefly outlined. From a safety perspective, the missing pilot of an autonomous vehicle is equivalent to a missing fallback layer, which has to be mitigated. Additionally, trust needs to be established for new techniques, specifically machine learning, which has recently gained massive interest. To solve this, verification, standardization, and regulation aspects of autonomy have to be addressed. The research is therefore targeted towards assessing and increasing the safety of autonomous operations. Moreover, a multi-sensor navigation system is necessary to achieve required safety levels in challenging environments, while meeting the cost and weight constraints. In order to ensure the integrity of the navigation system, an innovative integrity monitoring architecture for the multi-sensor solution will be investigated in the UAM context. Furthermore, many flying vehicles will need to share information in a reliable and trustworthy manner. Therefore, a robust and efficient communication system is specifically designed to meet the requirements of the future urban air mobility in order to mitigate midair collisions. To achieve safe air traffic, U-space services would have to be established. The project will specifically address gaps in the proposed services and identify additional required information and services. As a last aspect, the cyber physical safety and security has to be considered. With highly connected systems, attacks can happen over the Internet from virtually anywhere. Therefore, it is required to establish a holistic approach for cyber-physical safety and security

Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved