Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

Translating HbA1c measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA1c measurements are applicable to pregnant women with diabetes. Methods CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA1c measure. In total, 688 average glucose–HbA1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA1c. Results There was a strong association between HbA1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. Conclusions/interpretation The HbA1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care

Charge identification of fragments with the emulsion spectrometer of the FOOT experiment

The FOOT (FragmentatiOn Of Target) experiment is an international project designed to carry out the fragmentation cross-sectional measurements relevant for charged particle therapy (CPT), a technique based on the use of charged particle beams for the treatment of deep-seated tumors. The FOOT detector consists of an electronic setup for the identification of Z ≥ 3 fragments and an emulsion spectrometer for Z ≤ 3 fragments. The first data taking was performed in 2019 at the GSI facility (Darmstadt, Germany). In this study, the charge identification of fragments induced by exposing an emulsion detector, embedding a C2 H4 target, to an oxygen ion beam of 200 MeV/n is discussed. The charge identification is based on the controlled fading of nuclear emulsions in order to extend their dynamic range in the ionization response

Neuropeptide Receptor Transcriptome Reveals Unidentified Neuroendocrine Pathways

Neuropeptides are an important class of molecules involved in diverse aspects of metazoan development and homeostasis. Insects are ideal model systems to investigate neuropeptide functions, and the major focus of insect neuropeptide research in the last decade has been on the identification of their receptors. Despite these vigorous efforts, receptors for some key neuropeptides in insect development such as prothoracicotropic hormone, eclosion hormone and allatotropin (AT), remain undefined. In this paper, we report the comprehensive cloning of neuropeptide G protein-coupled receptors from the silkworm, Bombyx mori, and systematic analyses of their expression. Based on the expression patterns of orphan receptors, we identified the long-sought receptor for AT, which is thought to stimulate juvenile hormone biosynthesis in the corpora allata (CA). Surprisingly, however, the AT receptor was not highly expressed in the CA, but instead was predominantly transcribed in the corpora cardiaca (CC), an organ adjacent to the CA. Indeed, by using a reverse-physiological approach, we purified and characterized novel allatoregulatory peptides produced in AT receptor-expressing CC cells, which may indirectly mediate AT activity on the CA. All of the above findings confirm the effectiveness of a systematic analysis of the receptor transcriptome, not only in characterizing orphan receptors, but also in identifying novel players and hidden mechanisms in important biological processes. This work illustrates how using a combinatorial approach employing bioinformatic, molecular, biochemical and physiological methods can help solve recalcitrant problems in neuropeptide research

Charge identification of fragments with the emulsion spectrometer of the FOOT experiment

The FOOT (FragmentatiOn Of Target) experi- ment is an international project designed to carry out the fragmentation cross-sectional measurements relevant for charged particle therapy (CPT), a technique based on the use of charged particle beams for the treatment of deep-seated tumors. The FOOT detector consists of an electronic setup for the identification of Z >= 3 fragments and an emulsion spectrometer for Z <= 3 fragments. The first data taking was performed in 2019 at the GSI facility(Darmstadt, Germany). In this study, the charge identifi-cation of fragments induced by exposing an emulsion detector, embedding a C2H4 target, to an oxygen ion beam of 200 MeV/n is discussed. The charge identifica-tion is based on the controlled fading of nuclear emulsions in order to extend their dynamic range in the ionization response

Measuring the Impact of Nuclear Interaction in Particle Therapy and in Radio Protection in Space: the FOOT Experiment

In Charged Particle Therapy (PT) proton or 12C beams are used to treat deep-seated solid tumors exploiting the advantageous characteristics of charged particles energy deposition in matter. For such projectiles, the maximum of the dose is released at the end of the beam range, in the Bragg peak region, where the tumour is located. However, the nuclear interactions of the beam nuclei with the patient tissues can induce the fragmentation of projectiles and/or target nuclei and needs to be carefully taken into account when planning the treatment. In proton treatments, the target fragmentation produces low energy, short range fragments along all the beam path, that deposit a non-negligible dose especially in the first crossed tissues. On the other hand, in treatments performed using 12C, or other (4He or 16O) ions of interest, the main concern is related to the production of long range fragments that can release their dose in the healthy tissues beyond the Bragg peak. Understanding nuclear fragmentation processes is of interest also for radiation protection in human space flight applications, in view of deep space missions. In particular 4He and high-energy charged particles, mainly 12C, 16O, 28Si and 56Fe, provide the main source of absorbed dose in astronauts outside the atmosphere. The nuclear fragmentation properties of the materials used to build the spacecrafts need to be known with high accuracy in order to optimise the shielding against the space radiation. The study of the impact of these processes, which is of interest both for PT and space radioprotection applications, suffers at present from the limited experimental precision achieved on the relevant nuclear cross sections that compromise the reliability of the available computational models. The FOOT (FragmentatiOn Of Target) collaboration, composed of researchers from France, Germany, Italy and Japan, designed an experiment to study these nuclear processes and measure the corresponding fragmentation cross sections. In this work we discuss the physics motivations of FOOT, describing in detail the present detector design and the expected performances, coming from the optimization studies based on accurate FLUKA MC simulations and preliminary beam test results. The measurements planned will be also presented

CC9 Livestock-Associated Staphylococcus aureus Emerges in Bloodstream Infections in French Patients Unconnected With Animal Farming

We report 4 bloodstream infections associated with CC9 agr type II Staphylococcus aureus in individuals without animal exposure. We demonstrate, by microarray analysis, the presence of egc cluster, fnbA, cap operon, lukS, set2, set12, splE, splD, sak, epiD, and can, genomic features associated with a high virulence potential in human