Early handling modulates outcome of neonatal dexamethasone exposure

Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1–21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1–3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.     

Global non-covalent SUMO interaction networks reveal SUMO-dependent stabilization of the non-homologous end joining complex

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A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot‐Marie‐Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C‐terminal region, which interacts weakly with the structured core domain of HSP27. Here, we observed that the P182L mutation disrupts the chaperone activity and significantly increases the size of HSP27 oligomers formed in vivo, including in motor neurons differentiated from CMT patient‐derived stem cells. Using NMR spectroscopy, we determined that the P182L mutation decreases the affinity of the HSP27 IxI/V motif for its own core domain, leaving this binding site more accessible for other IxI/V‐containing proteins. We identified multiple IxI/V‐bearing proteins that bind with higher affinity to the P182L variant due to the increased availability of the IxI/V‐binding site. Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27 and suggest that the IxI/V motif plays an important, regulatory role in modulating protein–protein interactions.     

Need-based transfer systems are more vulnerable to cheating when resources are hidden

Need-based transfer systems pool risk among interdependent individuals. Such arrangements are bound by two simple rules: Ask for help only when in need and, if you are able, give help to others who ask. But there may be a temptation for individuals to break these rules for short-term personal profit. Here, we study one factor that may enforce honesty in need-based transfer relationships: the visibility of resources. Across three experiments employing a novel experimental economic game, breaking of both need-based transfer rules increased when resources were hidden rather than visible (Experiment 1: n = 82, online convenience sample from the US; Experiment 2: n = 80, student sample from the US; Experiment 3: n = 42, online convenience sample from the US). Participants with hidden resources were (1) more likely to request help when not actually in need (greediness), and (2) more likely to not fulfill requests from others for help, even when they had sufficient resources available to help (stinginess). These findings highlight the visibility of resources as one potential limitation of cooperative risk pooling systems.