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Guanine radical cations are precursors to oxidatively induced DNA lesions, and the determination of oxidative DNA hot spots beyond oligonucleotides remains a current challenge. In order to rationalize the finetuned ionization properties of the ∼60 guanines in a nucleosome core particle, we report a robust molecular dynamics-then-FO-DFTB/MM (fragment-orbital tight-binding density functional theory/molecular mechanics) simulation protocol spanning 20 μs. Our work allows us to identify several factors governing guanine ionization potential and map oxidative hotspots. Our results highlight the predominant role of the proximity of positively charged histone residues in the modulation of the guanine ionization potential up to 0.6 eV. Consequently, fast, long-range hole transfer in nucleosomal DNA could be tuned by the proximity of histone tails, which differs, from a biological point of view, on the chromatin state., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Radical cations (holes) produced in DNA by ionizing radiation and other oxidants yield DNA-protein cross-links (DPCs). Detailed studies of DPC formation in chromatin via this process are lacking. We describe here a comprehensive examination of DPC formation within nucleosome core particles (NCPs), which are the monomeric component of chromatin. DNA holes are introduced at defined sites within NCPs that are constructed from the bottom-up. DPCs form at DNA holes in yields comparable to those of alkali-labile DNA lesions that result from water trapping. DPC-forming efficiency and site preference within the NCP are dependent on translational and rotational positioning. Mass spectrometry and the use of mutant histones reveal that lysine residues in histone N-terminal tails and amino termini are responsible for the DPC formation. These studies are corroborated by computational simulation at the microsecond time scale, showing a wide range of interactions that can precede DPC formation. Three consecutive dGs, which are pervasive in the human genome, including G-quadruplex-forming sequences, are sufficient to produce DPCs that could impact gene expression.

Background: Survival of patients with colon cancer has increased in recent years due to advances in treatment and the implementation of multidisciplinary team meetings (MDTm). However, the organization of MDTm can be improved. The objectives of this work were to characterize patients with colon cancer who were not presented in MDTm and to analyse the reasons for their non-presentation., Methods: The study was based on a retrospective cohort including patients with colon cancer diagnosed between 2014 and 2016. Risk factors for non-presentation in MDTm were investigated after 1:1 matching on age, gender and tumour location, using multivariate analysis., Results: amongst 1616 patients diagnosed with colon cancer, 20.5% were not presented in MDTm. The most common reasons for non-presentation were 'advanced age or poor general condition' (22.6%) and 'superficial tumour' (20.5%), while 20.8% of non-presentation remained unexplained. Non-presentation in MDTm was associated with ECOG PS of 2 (OR 0.51, 95%CI 0.32-0.81, p = 0.005), best supportive care (OR 0.05, 95%CI 0.00-0.38, p = 0.016) and early death (OR 0.09, 95%CI 0.04-0.19, p<0.001). By contrast, patients with symptomatic tumours were more likely to be presented in MDTm than patients participating in mass screening (OR 2.16, 95%CI 1.09-4.32, p = 0.028). Presentation was significantly associated with diagnosis by a digestive surgeon (OR 2.16, 95%CI 1.22-3.92, p = 0.01) and a high UICC stage., Conclusions: This study identified factors associated with non-presentation in a multidisciplinary team meeting for colon cancer such as an advanced age or a superficial tumour, paving the way for targeted improvements., Competing Interests: Competing interests The authors declare that they have no conflict of interest related to this work., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

HIV protease inhibitors (PIs) approved by the FDA (US Food and Drug Administration) are a major class of antiretroviral. HIV-2 protease (PR2) is naturally resistant to most of them as PIs were designed for HIV-1 protease (PR1). In this study, we explored the impact of amino-acid substitutions between PR1 and PR2 on the structure of protease (PR) by comparing the structural variability of 13 regions using 24 PR1 and PR2 structures complexed with diverse ligands. Our analyses confirmed structural rigidity of the catalytic region and highlighted the important role of three regions in the conservation of the catalytic region conformation. Surprisingly, we showed that the flap region, corresponding to a flexible region, exhibits similar conformations in PR1 and PR2. Furthermore, we identified regions exhibiting different conformations in PR1 and PR2, which could be explained by the intrinsic flexibility of these regions, by crystal packing, or by PR1 and PR2 substitutions. Some substitutions induce structural changes in the R2 and R4 regions that could have an impact on the properties of PI-binding site and could thus modify PI binding mode. Substitutions involved in structural changes in the elbow region could alter the flexibility of the PR2 flap regions relative to PR1, and thus play a role in the transition from the semi-open form to the closed form, and have an impact on ligand binding. These results improve the understanding of the impact of sequence variations between PR1 and PR2 on the natural resistance of HIV-2 to commercially available PIs.Communicated by Ramaswamy H. Sarma.

Objective: To study trends in the main indicators of health, medical practices and risk factors in France., Population and Method: We collected data from samples of all births in France during one week in 1995 (n=13318), 1998 (n=13718), 2003 (n=14737) and 2010 (n=14903) and have compared them., Results: Between 1995 and 2010, maternal age and body mass index increased steadily, but tobacco use decreased. In 2010, 39.4% of pregnant women had a visit with a midwife in a maternity unit, versus 26.6% in 2003. Deliveries occurred in large public hospitals more and more frequently. The increase in caesarean sections was no longer significant between 2003 and 2010. In general, medical decisions during pregnancy and delivery were closer to professional recommendations in 2010 than in earlier years. Live births before 37 weeks increased steadily from 5.4% in 1995 to 6.6% in 2010, but the proportion of birth weights below 2500g or the 10th percentile stopped increasing after 2003., Conclusion: Routine national perinatal surveys highlight major trends in maternal characteristics, obstetric practices, organisation of services, and perinatal health., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective: To study trends in the main indicators of health, medical practice and risk factors in France., Population and Method: A sample of all births during one week was set-up in 1995 (n=13,318), 1998 (n=13,718), 2003 (n=14,737) and 2010 (n=14,903), and we compared data from these four years., Results: Between 1995 and 2010, maternal age and body mass index increased steadily, but tobacco smoking decreased. In 2010, 39.4% of pregnant women had a visit with a midwife in maternity unit, versus 26.6% in 2003. Deliveries occurred in large public hospitals more and more frequently. The increase in caesarean sections was no longer significant between 2003 and 2010. In general medical decisions during pregnancy and delivery were closer to professional recommendations in 2010 than in the previous years. Live births before 37 weeks increased steadily from 5.4% in 1995 to 6.6% in 2010, but the proportion of births below 2500g or under the 10th percentile stopped increasing since 2003., Conclusion: Routine national perinatal surveys highlight major trends in maternal characteristics, obstetric practice, organisation of services and perinatal health., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)