Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

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Context Identification and biological actions of pituitary-derived exosomes remain elusive. Objective To validate production of exosomes derived from human and rat pituitary and elucidate their actions. Methods Isolated extracellular vesicles (EVs) were analyzed by Nanoparticle Tracking Analysis (NTA) and expressed exosomal markers detected by Western blot, using non-pituitary fibroblast FR and myoblast H9C2 cells as controls. Exosome inhibitor GW4869 was employed to detect attenuated EV release. Exosomal RNA contents were characterized by RNA-seq. In vitro and in vivo hepatocyte signaling alterations responding to GH1-derived exosomes (GH1-exo) were delineated by mRNA-seq. GH1-exo actions on protein synthesis, cAMP response, cell motility and metastases were assessed. Results NTA, exosomal marker detection, and GW4869 attenuated EV release, confirming the exosomal identity of pituitary EVs. Hydrocortisone increased exosome secretion in GH1 and GH3 cells, suggesting a stress-associated response. Exosomal RNA contents showed profiles distinct for pituitary cells, and rat primary hepatocytes exposed to GH1-exo exhibited transcriptomic alterations distinct from those elicited by GH or PRL. Intravenous GH1-exo injection into rats attenuated hepatic Eif2ak2 and Atf4 mRNA expression, both involved in cAMP responses and amino acid biosynthesis. GH1-exo suppressed protein synthesis and forskolin-induced cAMP levels in hepatocytes. GH1-exo treated HCT116 cells showed dysregulated p53 and MAPK pathways and attenuated motility of malignant HCT116 cells, and decreased tumor metastases in nude mice harboring splenic HCT116 implants. Conclusions Our findings elucidate biological actions of somatotroph-derived exosomes and implicate exosomes as non-hormonal pituitary-derived messengers.

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A rabbit model in which intrinsic clotting was selectively impaired by injection of a human factor VIII antibody was used to evaluate the mechanism of endotoxin-induced intravascular clotting in cortisone-treated rabbits. Three groups of animals were studied: a control group given factor VIII antibody followed by saline; a second control group given an inert material followed by endotoxin; and an experimental group given factor VIII antibody followed by endotoxin. The following parameters were measured: 125I-fibrinogen kinetics, fibrinogen levels, factor VIII, factor VII, factor V, WBC, platelets, and hematocrit. The kidneys were examined for deposition of fibrin. Mean values for factor VIII at the time of injection of the second test material and mean values for fibrinogen consumed in the 6 hr after the second injection were as follows: antibody-saline group, 8.5% and 11.0 mg/kg; control material-endotoxin group, 90% and 29.6 mg/kg; and antibody endotoxin group, 7.0% and 32.7 mg/kg. Factor V, factor VII, granulocytes, and platelets fell in both groups of animals given endotoxin. One animal in each group given endotoxin developed gross renal cortical necrosis. These data establish that selective impairment of the intrinsic clotting reactions does not reduce the amount of clotting induced by a single injection of endotoxin in the cortisone-treated rabbit.