CD38 is critical for social behaviour by regulating oxytocin secretion

CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.     

Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC.

During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases. The Bcl-2 family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis, but how that is achieved is unclear. Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-x(L). In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-x(L). Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.     

Release of 3,5,3′-triiodothyronine,thyroxine and thyroglobulin from TSH-stimulated mouse thyroids in the perifusion system

Summary We established a perifusion system using mouse thyroid glands. In this system, TSH increased the release of T₃ and T₄ significantly, and the response of thyroglobulin to TSH was delayed in comparison with that of T₃ and T₄.     

Hinf family: a novel repeated DNA family of the human genome

The isolation of a mutant adenovirus carrying an insertion of cellular DNA has led to the identification of a new family of human repetitive sequences, which are found tandemly arranged in the genome. The sequence of the viral insert resembles that of eukaryotic transposable elements.     

Retroviruses released from a human tumor xenograft in nude mice induce colony-stimulating factor (CSF) activity in human fibroblastic cells

A human colony-stimulating factor (CSF)-producing tumor transplanted into athymic nude mice released retroviruses in vitro. The viruses induced CSF activity in human fibroblastic cell lines.     

Antiviral substances in starfish

Zusammenfassung Eine Gruppe von teilweise chemisch charakterisierten Verbindungen, welche die Vermehrung des Influenza-Virus in Huhnembryo-Test verhindern, wurde aus den SeesternenAsterias forbesi, Asterias pectinifera undAcanthaster planci isoliert.

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This research was supported by the N.S.F. Sea-Grant Program. The author thanks Dr.H. W. Younken Jr. and Dr.L. R. Worthen for their encouragement and suggestions throughout this work. Thanks are also due to Dr.Hashimoto, Tokyo University, and Dr.Yasumoto, Tohoku University, for the specimen ofAsterina pectinifera, and Dr.B. M. Branham, University of Hawaii, forAcanthaster planci sample. The antiviral test was carried out by Dr.O. Liu, Northeast Shellfish Sanitation Research Center, D. H. E. W., Narragansett, Rhode Island, to whome the author expresses his sincere gratitude.     

Effect of win 18501-2 on the content of catecholamines and the number of catecholamine-containing granules in the rabbit hypothalamus

Zusammenfassung Der Hypothalamus von Kaninchen wurde nach Win 18501-2-Injektion biochemisch und elektronenmikroskopisch untersucht. Die Behandlung erzeugte auffallende Veränderungen im Noradrenalingehalt und in der Anzahl der Katecholamine enthaltenden granulierenden Vesiculae im Hypothalamus. Die Resultate scheinen zu zeigen, dass diese charakteristischen Vesiculae nur Noradrenalin enthalten und dass die Sedation des Kaninchens nach der Injektion von Win 18501-2 auf der Verminderung des Noradrenalins und der charakteristischen Vesiculae beruht.     

Protein-based peptide-bond formation by aminoacyl-tRNA protein transferase

Eubacterial leucyl/phenylalanyl-tRNA protein transferase (LF-transferase) catalyses peptide-bond formation by using Leu-tRNA(Leu) (or Phe-tRNA(Phe)) and an amino-terminal Arg (or Lys) of a protein, as donor and acceptor substrates, respectively. However, the catalytic mechanism of peptide-bond formation by LF-transferase remained obscure. Here we determine the structures of complexes of LF-transferase and phenylalanyl adenosine, with and without a short peptide bearing an N-terminal Arg. Combining the two separate structures into one structure as well as mutation studies reveal the mechanism for peptide-bond formation by LF-transferase. The electron relay from Asp 186 to Gln 188 helps Gln 188 to attract a proton from the alpha-amino group of the N-terminal Arg of the acceptor peptide. This generates the attacking nucleophile for the carbonyl carbon of the aminoacyl bond of the aminoacyl-tRNA, thus facilitating peptide-bond formation. The protein-based mechanism for peptide-bond formation by LF-transferase is similar to the reverse reaction of the acylation step observed in the peptide hydrolysis reaction by serine proteases.     

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.