Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin

Activity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT4 (5-HT4R) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction. In neuroblastoma cells, this leads to cell rounding and neurite retraction. In hippocampal neurons in situ, 5-HT4R-mediated RhoA activation triggers maturation of dendritic spines. This is paralleled by RhoA-dependent, transient alterations in cell excitability, as reflected by increased spontaneous synaptic activity, apparent shunting of evoked synaptic responses, and enhanced long-term potentiation of excitatory transmission. The 5-HT4R/G13/RhoA signaling thus emerges as a previously unrecognized molecular pathway underpinning use-dependent functional remodeling of excitatory synaptic connections

Neural Mechanisms of Interference Control in Working Memory: Effects of Interference Expectancy and Fluid Intelligence

A critical aspect of executive control is the ability to limit the adverse effects of interference. Previous studies have shown activation of left ventrolateral prefrontal cortex after the onset of interference, suggesting that interference may be resolved in a reactive manner. However, we suggest that interference control may also operate in a proactive manner to prevent effects of interference. The current study investigated the temporal dynamics of interference control by varying two factors - interference expectancy and fluid intelligence (gF) - that could influence whether interference control operates proactively versus reactively.A modified version of the recent negatives task was utilized. Interference expectancy was manipulated across task blocks by changing the proportion of recent negative (interference) trials versus recent positive (facilitation) trials. Furthermore, we explored whether gF affected the tendency to utilize specific interference control mechanisms. When interference expectancy was low, activity in lateral prefrontal cortex replicated prior results showing a reactive control pattern (i.e., interference-sensitivity during probe period). In contrast, when interference expectancy was high, bilateral prefrontal cortex activation was more indicative of proactive control mechanisms (interference-related effects prior to the probe period). Additional results suggested that the proactive control pattern was more evident in high gF individuals, whereas the reactive control pattern was more evident in low gF individuals.The results suggest the presence of two neural mechanisms of interference control, with the differential expression of these mechanisms modulated by both experimental (e.g., expectancy effects) and individual difference (e.g., gF) factors

Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios

Integrin targeting fluorescent proteins: exploration of RGD insertion sites

\u3cp\u3eThe potential of the fluorescent protein scaffold in controlling peptide sequence functionality is illustrated via the exploration of fluorescent proteins as novel probes for targeting of integrins. A library of fluorescent mCitrine proteins with RGD motifs incorporated at several positions in loops within the protein main chain was generated and characterized. Amino acid mutations to RGD as well as RGD motif insertions were evaluated and both approaches led to mCitrine constructs with typical fluorescent properties. Screening experiments against four human integrin receptors revealed two strong binding constructs and two selective integrin binders. The importance of the site of RGD incorporation illustrates the effect of the protein scaffold on RGD sequence functionality, leading to fluorescent protein constructs with the potential for selective integrin targeting.\u3c/p\u3

The Impact of Financial Arrangements and Institutional Form on Housing Prices

Housing prices, Cooperative housing, Condominiums, Credit rationing, G21, R21,