Westerlund, A. | Search bioRxiv

bioRxiv2018

Child Growth Predicts Brain Functional Connectivity and Future Cognitive Outcomes in Urban Bangladeshi Children Exposed to Early Adversities

BackgroundFaltered growth has been shown to affect 161 million children worldwide and derail cognitive development from early childhood. The neural pathways by which growth faltering in early childhood affects future cognitive outcomes remain unclear, which is partially due to the scarcity of research using both neuroimaging and sensitive behavioral techniques in low-income settings. We employed EEG to examine the association between growth faltering and brain functional connectivity and whether brain functional connectivity mediates the effect of early adversity on cognitive development.\n\nMethodsWe recruited participants from an urban impoverished neighborhood in Dhaka, Bangladesh. One sample consisted of 85 children whose EEG and growth measures (height for age, weight for age, and weight to height) were collected at 6 months and cognitive outcomes were assessed at 27 months. Another sample consisted of 115 children whose EEG and growth measures were collected at 36 months and IQ scores were assessed at 48 months. Path analysis was used to test the effect of growth measures on cognitive outcomes through brain functional connectivity.\n\nFindingsFaltered growth was found to be accompanied by overall increased functional connectivity in the theta and low-beta frequency bands for the 36-month-old cohort. For both cohorts, brain functional connectivity was negatively predictive of later cognitive outcomes at 27 and 48 months, respectively. Faltered growth was found to have a negative impact on childrens IQ scores in the older cohort, and this effect was found to be mediated by brain functional connectivity in the low-beta band.\n\nInterpretationThe association found between growth measures and brain functional connectivity may reflect a broad deleterious effect of malnutrition on childrens brain development. The mediation effect of functional connectivity on the relation between physical growth and later IQ scores provides the first experimental evidence that brain functional connectivity may mediate the effect of biological adversity on cognitive development.\n\nFundingBill and Melinda Gates Foundation (OPP1111625)

neuroscience↗

bioRxiv2018

Effect of Ca2+ on the promiscuous target-protein binding mechanism of calmodulin

Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling path- ways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question.\n\nHere, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity.\n\nThis work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.\n\nAuthor summaryCalmodulin is a protein involved in the regulation of a variety of cell signaling pathways. It acts by making usually calcium-insensitive proteins sensitive to changes in the calcium concentration inside the cell. Its two lobes bind calcium and allow the energetically unfavorable exposure of hydrophobic residues to the aqueous environment which can then bind target proteins. The mechanisms behind the simultaneous specificity and variation of target protein binding is yet unknown but will aid understanding of the calcium-signaling and regulation that occur in many of our cellular processes.\n\nHere, we used molecular dynamics simulations and data analysis techniques to investigate what effect calcium has on the binding modes of calmodulin. The simulations and analyses allow us to observe and differentiate specific states. One domain of calmodulin is shown to be selective with binding involving short- distance interactions between hydrophobic residues, while the other binds target proteins through a more flexible mechanism involving long-distance electrostatic interactions.

biophysics↗