Exosomes regulate neurogenesis and circuit assembly.

Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development

Two‐Dimensional Phase Separation: Co-Adsorption of Hydrogen and Carbon Monoxide on the (111) Surface of Rhodium

The co‐adsorption of CO and H_2 on Rh(111) at low temperature (∼ 100 K) has been studied using thermal desorption mass spectrometry (TDS) and Low‐Energy Electron Diffraction(LEED). The probability of adsorption of CO on rhodium pretreated with hydrogen has been found to decrease slowly with increasing amounts of hydrogen on the surface. In addition, the effect of surface hydrogen on the CO LEED patterns indicates segregation of hydrogen and CO. These results can be explained in terms of a strong repulsive CO–H interaction and a mobile precursor model of CO adsorption

Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation

Pheromone-Dependent Destruction of the Tec1 Transcription Factor Is Required for MAP Kinase Signaling Specificity in Yeast

AbstractThe yeast MAPK pathways required for mating versus filamentous growth share multiple components yet specify distinct programs. The mating-specific MAPK, Fus3, prevents crosstalk between the two pathways by unknown mechanisms. Here we show that pheromone signaling induces Fus3-dependent degradation of Tec1, the transcription factor specific to the filamentation pathway. Degradation requires Fus3 kinase activity and a MAPK phosphorylation site in Tec1 at threonine 273. Fus3 associates with Tec1 in unstimulated cells, and active Fus3 phosphorylates Tec1 on T273 in vitro. Destruction of Tec1 requires the F box protein Dia2 (Digs-into-agar-2), and Cdc53, the Cullin of SCF (Skp1-Cdc53-F box) ubiquitin ligases. Notably, mutation of the phosphoacceptor site in Tec1, deletion of FUS3, or deletion of DIA2 results in a loss of signaling specificity such that pheromone pathway signaling erroneously activates filamentation pathway gene expression and invasive growth. Signal-induced destruction of a transcription factor for a competing pathway provides a mechanism for signaling specificity

Introduction to the Molecules Special Edition Entitled 'Heparan Sulfate and Heparin: Challenges and Controversies': Some Outstanding Questions in Heparan Sulfate and Heparin Research

The scope of this article is to provide a brief general introduction to heparan sulfate (HS) and heparin, and attempt to identify some of the central challenges regarding research into the chemistry and biology of glycosaminoglycans (GAGs), some of which are the subject of contributions to the special issue of Molecules (published in volume 23, 2018) entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’ [...

Development and Performance of the Nanoworkbench: A Four Tip STM for Electrical Conductivity Measurements Down to Sub-micrometer Scales

A multiple-tip ultra-high vacuum (UHV) scanning tunneling microscope (MT-STM) with a scanning electron microscope (SEM) for imaging and molecular-beam epitaxy growth capabilities has been developed. This instrument (nanoworkbench) is used to perform four-point probe conductivity measurements at micrometer spatial dimension. The system is composed of four chambers, the multiple-tip STM/SEM chamber, a surface analysis and preparation chamber, a molecular-beam epitaxy chamber and a load-lock chamber for fast transfer of samples and probes. The four chambers are interconnected by a unique transfer system based on a sample box with integrated heating and temperature-measuring capabilities. We demonstrate the operation and the performance of the nanoworkbench with STM imaging on graphite and with four-point-probe conductivity measurements on a silicon-on-insulator (SOI) crystal. The creation of a local FET, whose dimension and localization are respectively determined by the spacing between the probes and their position on the SOI surface, is demonstrated.Comment: 39 pages, 15 figure

Maternal inflammation at midgestation impairs subsequent fetal myoblast function and skeletal muscle growth in rats, resulting in intrauterine growth restriction at term

Maternal inflammation induces intrauterine growth restriction (MI-IUGR) of the fetus, which compromises metabolic health in human offspring and reduces value in livestock. The objective of this study was to determine the effect of maternal inflammation at midgestation on fetal skeletal muscle growth and myoblast profiles at term. Pregnant Sprague-Dawley rats were injected daily with bacterial endotoxin (MI-IUGR) or saline (controls) from the 9th to the 11th day of gestational age (dGA; term = 21 dGA). At necropsy on dGA 20, average fetal mass and upper hindlimb cross-sectional areas were reduced (P \u3c 0.05) in MI-IUGR fetuses compared with controls. MyoD+ and myf5+ myoblasts were less abundant (P \u3c 0.05), and myogenin+ myoblasts were more abundant (P \u3c 0.05) in MI-IUGR hindlimb skeletal muscle compared with controls, indicating precocious myoblast differentiation. Type I and Type II hindlimb muscle fibers were smaller (P \u3c 0.05) in MI-IUGR fetuses than in controls, but fiber type proportions did not differ between experimental groups. Fetal blood plasma TNFα concentrations were below detectable amounts in both experimental groups, but skeletal muscle gene expression for the cytokine receptors TNFR1, IL6R, and FN14 was greater (P \u3c 0.05) in MI-IUGR fetuses than controls, perhaps indicating enhanced sensitivity to these cytokines. Maternal blood glucose concentrations at term did not differ between experimental groups, but MI-IUGR fetal blood contained less (P \u3c 0.05) glucose, cholesterol, and triglycerides. Fetal-to-maternal blood glucose ratios were also reduced (P \u3c 0.05), which is indicative of placental insufficiency. Indicators of protein catabolism, including blood plasma urea nitrogen and creatine kinase, were greater (P \u3c 0.05) in MI-IUGR fetuses than in controls. From these findings, we conclude that maternal inflammation at midgestation causes muscle-centric fetal programming that impairs myoblast function, increases protein catabolism, and reduces skeletal muscle growth near term. Fetal muscle sensitivity to inflammatory cytokines appeared to be enhanced after maternal inflammation, which may represent a mechanistic target for improving these outcomes in MI-IUGR fetuses

Two‐Dimensional Phase Separation: Co-Adsorption of Hydrogen and Carbon Monoxide on the (111) Surface of Rhodium

The co‐adsorption of CO and H_2 on Rh(111) at low temperature (∼ 100 K) has been studied using thermal desorption mass spectrometry (TDS) and Low‐Energy Electron Diffraction(LEED). The probability of adsorption of CO on rhodium pretreated with hydrogen has been found to decrease slowly with increasing amounts of hydrogen on the surface. In addition, the effect of surface hydrogen on the CO LEED patterns indicates segregation of hydrogen and CO. These results can be explained in terms of a strong repulsive CO–H interaction and a mobile precursor model of CO adsorption