Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin’s nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method’s sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures

Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition

The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition

Early life child micronutrient status, maternal reasoning, and a nurturing household environment have persistent influences on child cognitive development at age 5 years: Results from MAL-ED

Background: Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown. Objective: The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y. Methods: Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression. Results: Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: −1.81, 95% CI: −2.75, −0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition. Conclusions: A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.publishedVersio

Relationships between outdoor time, physical activity, sedentary time, and body mass index in children : a 12-country study

Purpose: This study investigated the relationship between outdoor time and physical activity (PA), sedentary time (SED), and body mass index z scores among children from 12 lower-middle-income, upper-middle-income, and high-income countries. Methods: In total, 6478 children (54.4% girls) aged 9-11 years participated. Outdoor time was self-reported, PA and SED were assessed with ActiGraph GT3X+ accelerometers, and height and weight were measured. Data on parental education, neighborhood collective efficacy, and accessibility to neighborhood recreation facilities were collected from parent questionnaires. Country latitude and climate statistics were collected through national weather data sources. Gender-stratified multilevel models with parental education, climate, and neighborhood variables as covariates were used to examine the relationship between outdoor time, accelerometry measures, and body mass index z scores. Results: Each additional hour per day spent outdoors was associated with higher moderate-to vigorous-intensity PA (boys: +2.8 min/d; girls: +1.4 min/d), higher light-intensity PA (boys: +2.0 min/d; girls: +2.3 min/d), and lower SED (boys: -6.3 min/d; girls: -5.1 min/d). Effect sizes were generally weaker in lower-middle-income countries. Outdoor time was not associated with body mass index z scores. Conclusions: Outdoor time was associated with higher PA and lower SED independent of climate, parental education, and neighborhood variables, but effect sizes were small. However, more research is needed in low-and middle-income countries

Sleep characteristics and health-related quality of life in 9- to 11-year-old children from 12 countries

Introduction: Previous studies have linked short sleep duration, poor sleep quality, and late sleep timing with lower health-related quality of life (HRQoL) in children. However, almost all studies relied solely on self-reported sleep information, and most studies were conducted in high-income countries. To address these gaps, we studied both device-measured and self-reported sleep characteristics in relation to HRQoL in a sample of children from 12 countries that vary widely in terms of economic and human development. Methods: The study sample included 6,626 children aged 9-11 years from Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. Waist-worn actigraphy was used to measure total sleep time, bedtime, wake-up time, and sleep efficiency on both weekdays and weekends. Children also reported ratings of sleep quantity and quality. HRQoL was measured by the KIDSCREEN-10 survey. Multilevel regression models were used to determine the relationships between sleep characteristics and HRQoL. Results: Results showed considerable variation in sleep characteristics, particularly duration and timing, across study sites. Overall, we found no association between device-measured total sleep time, sleep timing or sleep efficiency, and HRQoL. In contrast, self-reported ratings of poor sleep quantity and quality were associated with HRQoL. Conclusions: Self-reported, rather than device-based, measures of sleep are related to HRQoL in children. The discrepancy related to sleep assessment methods highlights the importance of considering both device-measured and self-reported measures of sleep in understanding its health effects

Max-weight scheduling across multiple timescales

Many systems consist of a mixture of various resource types that together support better performance relative to those with a single resource type. One important characteristic of these systems is the fact that the various comprising resource types can operate on different timescales, implying that the corresponding control decisions are not made simultaneously. To address the resulting scheduling problem, we present and analyze two variants of max-weight scheduling that are designed to deal with the different timescales of such systems