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Colibactin, a DNA cross-linking agent produced by gut bacteria, is implicated in colorectal cancer. Its biosynthesis uses a prodrug resistance mechanism: a non-toxic precursor assembled in the cytoplasm is activated after export to the periplasm. This activation is mediated by ClbP, an inner-membrane peptidase with an N-terminal periplasmic catalytic domain and a C-terminal three-helix transmembrane domain. Although the transmembrane domain is required for colibactin activation, its role in catalysis is unclear. Our structure of full-length ClbP bound to a product analog reveals an interdomain interface important for substrate binding and enzyme stability and interactions that explain the selectivity of ClbP for the N -acyl- d -asparagine prodrug motif. Based on structural and biochemical evidence, we propose that ClbP dimerizes to form an extended substrate-binding site that can accommodate a pseudodimeric precolibactin with its two terminal prodrug motifs in the two ClbP active sites, thus enabling the coordinated activation of both electrophilic warheads. Structure and mutagenesis of the colibactin-activating peptidase ClbP reveals a dimer with a substrate-binding transmembrane domain and a conserved polar network in its periplasmic domain that enforces selectivity for d -asparagine prodrug motifs.

The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis. A substrate-guided design strategy generated highly potent inhibitors of the biosynthesis of the genotoxin colibactin by human gut bacteria. These inhibitors also enable a generalizable approach for chemically guided natural product discovery.

The gut bacterial genotoxin colibactin has been linked to the development of colorectal cancer. In the final stages of colibactin's biosynthesis, an inactive precursor (precolibactin) undergoes proteolytic cleavage by ClbP, an unusual inner membrane-bound periplasmic peptidase, to generate the active genotoxin. This enzyme presents an opportunity to monitor and modulate colibactin biosynthesis, but its active form has not been studied in vitro and limited tools exist to measure its activity. Here, we describe the in vitro biochemical characterization of catalytically active, full-length ClbP. We elucidate its substrate preferences and use this information to develop a fluorogenic activity probe. This tool will enable the discovery of ClbP inhibitors and streamline identification of colibactin-producing bacteria.

Magnetic resonance imaging (MRI) has played an increasingly relevant role in understanding infant, child, and adolescent neurodevelopment, providing new insight into developmental patterns in neurotypical development, as well as those associated with potential psychopathology, learning disorders, and other neurological conditions. In addition, studies have shown the impact of a child's physical and psychosocial environment on developing brain structure and function. A rate-limiting complication in these studies, however, is the high cost and infrastructural requirements of modern MRI systems. High costs mean many neuroimaging studies typically include fewer than 100 individuals and are performed predominately in high resource hospitals and university settings within high income countries (HICs). As a result, our knowledge of brain development, particularly in children who live in lower and middle income countries (LMICs) is relatively limited. Low field systems, with magnetic fields less than 100mT offer the promise of lower scanning costs and wide-spread global adoption, but routine low field pediatric neuroimaging has yet to be demonstrated. Here we present the first pediatric MRI data collected on a low cost and assessable 64mT scanner in children 6 weeks to 16 years of age and replicate brain volumes estimates and developmental trajectories derived from 3T MRI data. While preliminary, these results illustrate the potential of low field imaging as a viable complement to more conventional high field imaging systems, and one that may further enhance our knowledge of neurodevelopment in LMICs where malnutrition, psychosocial adversities, and other environmental exposures may profoundly affect brain maturation.

Background: While early life exposures such as mode of birth, breastfeeding, and antibiotic use are established regulators of microbiome composition in early childhood, recent research suggests that the social environment may also exert influence. Two recent studies in adults demonstrated associations between socioeconomic factors and microbiome composition. This study expands on this prior work by examining the association between family socioeconomic status (SES) and host genetics with microbiome composition in infants and children. Methods: Family SES was used to predict a latent variable representing six genera abundances generated from whole-genome shotgun sequencing. A polygenic score derived from a microbiome genome-wide association study was included to control for potential genetic associations. Associations between family SES and microbiome diversity were assessed. Results: Anaerostipes, Bacteroides, Eubacterium, Faecalibacterium, and Lachnospiraceae spp. significantly loaded onto a latent factor, which was significantly predicted by SES (p < 0.05) but not the polygenic score (p > 0.05). Our results indicate that SES did not predict alpha diversity but did predict beta diversity (p < 0.001). Conclusions: Our results demonstrate that modifiable environmental factors influence gut microbiome composition at an early age. These results are important as our understanding of gut microbiome influences on health continue to expand.

Given that many schools have limited resources and a high proportion of students who present with deficits in early literacy skills, supports aimed at preventing reading failure must be simple and efficient and generate meaningful changes in student learning. We used a randomized group design with a wait-list control to extend the work of Volpe, Burns, DuBois, and Zaslofsky (2011) , who found a computer-assisted tutoring program designed to teach young children letter sounds using incremental rehearsal to be an efficient and acceptable intervention for students who were slow to respond to class-wide early literacy intervention. In our study, a total of 30 kindergarten and first-grade students were randomly assigned to either 2 weeks of computer-aided tutoring or a wait-list control group. The effects of the intervention were investigated using multiple-level modeling over four assessment periods (pretreatment, 1 week of intervention, 2 weeks of intervention, and 1-week follow-up). Results were consistent across dependent measures, with rates of growth and follow-up scores significantly higher for the intervention group as compared with the control group. Given that these skills were enhanced in an efficient manner and maintained for at least 1 week, the computer-assisted tutoring intervention appears to be an appropriate support for rapidly improving early skill deficits related to letter-sound knowledge and decoding.

The brain demands oxygen and glucose to fulfill its roles as the master regulator of body functions as diverse as bladder control and creative thinking. Chemical and electrical transmission in the nervous system is rapidly disrupted in stroke as a result of hypoxia and hypoglycemia. Despite being highly evolved in its architecture, the human brain appears to utilize phylogenetically conserved homeostatic strategies to combat hypoxia and ischemia. Specifically, several converging lines of inquiry have demonstrated that the transcription factor hypoxia-inducible factor-1 (HIF1-1) mediates the activation of a large cassette of genes involved in adaptation to hypoxia in surviving neurons after stroke. Accordingly, pharmacological or molecular approaches that engage hypoxic adaptation at the point of one of its sensors (e.g., inhibition of HIF prolyl 4 hydroxylases) leads to profound sparing of brain tissue and enhanced recovery of function. In this review, we discuss the potential mechanisms that could subserve protective and restorative effects of augmenting hypoxic adaptation in the brain. The strategy appears to involve HIF-dependent and HIF-independent pathways and more than 70 genes and proteins activated transcriptionally and post-transcriptionally that can act at cellular, local, and system levels to compensate for oxygen insufficiency. The breadth and depth of this homeostatic program offers a hopeful alternative to the current pessimism towards stroke therapeutics.

Parkinson's disease (PD) is a genetically heterogeneous disease. Recently, significant linkage has been reported to a 39.5 cM region on the long arm of chromosome 2 (2q36-37; PARK11 ) in North American Parkinson families under an autosomal dominant model of inheritance. We have performed a replication study to confirm linkage to this region in a European population. Linkage analysis in 153 individuals from 45 European families with a strong family history of PD did not show any significant LOD score in this region. Therefore, PARK11 does not seem to play a major role for familial PD in the European population.