Yeast silencers create domains of nuclease-resistant chromatin in an SIR4-dependent manner

Previous analysis of the repression of the silent mating type loci in Saccharomyces cerevisiae has linked the mechanism of silencing to the formation of a chromatin domain at the silenced loci. In this study, a TRP1 reporter gene was used to examine changes in chromatin structure in a neutral environment. This enabled the chromatin structure organized by yeast silencers to be compared directly with changes effected by the yeast alpha2 repressor. It was found that silencers mediate the formation of lengthy nuclease-resistant domains on the DNA, rather than specifically positioning nucleosomes over promoter regions as the alpha2 repressor does. Silencing at the TRP1 reporter gene closely resembled silencing at the HMR and HML loci. Repression of the test gene was optimal when two silencers flanking the reporter gene were used, mimicking the situation at the silent loci. In addition, both repression of the reporter gene and the formation of nuclease-resistant chromatin domains was SIR4 dependent.     

Dendritic release of vasopressin and oxytocin

In addition to the release of neurotransmitters from their axon terminals, several neuronal populations are able to release their products from their dendrites. The cell bodies and dendrites of vasopressin- and oxytocin-producing neurones are mainly located within the hypothalamic supraoptic and paraventricular nuclei and neuropeptide release within the magnocellular nuclei has been shown in vitro and in vivo. Local release is induced by a range of physiological and pharmacological stimuli, and is regulated by a number of brain areas; locally released peptides are mainly involved in pre- and postsynaptic modulation of the electrical activity of magnocellular neurones. Spatial and temporal differences between peptide release within the nuclei and that from the distant axonal varicosities indicate that the release mechanisms are at least partially independent, supporting the hypothesis of locally regulated dendritic release of vasopressin and oxytocin. In this respect, magnocellular neurones show similarities to other neuronal populations and thus autoregulation of neuronal activity by dendritic neuromodulator release may be a general phenomenon within the brain.     

Metabolic clearance of immunoreactive vasopressin and immunoreactive [131I]iodo vasopressin in the hypophysectomized dog

Fourteen acutely hypophysectomized, anesthetized dogs were given a constant infusion of arginine vasopressin (AVP) and 131I-labeled arginine vasopressin ([131I]AVP). After 90 min, 3 blood samples were collected at 15 min intervals for determination of total body clearances of immunoreactive AVP and immunoreactive [131I]AVP. Seven dogs were then nephrectomized. Ninety minutes later, a second set of 3 blood samples was collected at 15 min intervals for clearance measurements in these and the 7 time-control dogs. Prenephrectomy AVP clearance averaged 5.1+/-1.0 ml/min-kg (mean +/- SE, n=7), and the 210-240 min postnephrectomy AVP clearance average 4.9+/-0.8. The 90-120 min average clearance in the time-control dogs was 6.1+/-0.9 ml/min-kg (n=7) and AVP clearance in these dogs increased (P less than 0.01) with time to 7.3+/-0.9 ml/min-kg during the 210-240 min period of constant infusion. Although the postnephrectomy AVP clearance was not significantly changed from prenephrectomy levels, it was significantly lower (P less than 0.05) than the 210-240 min average clearance in the time-controls. Clearance of [131I]AVP was 3.3+/-0.2 ml/min-kg (n=7) before nephrectomy and 2.9+/-0.2 ml/min-kg after nephrectomy. This was a significant 12% reduction (P less than 0.01). [131I]AVP clearance in the time control dogs was 3.9+/-0.3 during 90-120 min of infusion and 3.9+/-0.4 during 210-240 min of infusion. [131I]AVP clearance before nephrectomy was 79+/-12% of AVP clearance (P less than 0.005) and afther nephrectomy was 74+/-16% of AVP clearance (P less than 0.05). Although these results might suggest that [131I]AVP clearance is at least a qualitative indicator of AVP clearance, there was no significant correlation (P less than 0.20) between AVP clearance and [131I]AVP clearance.     

Effects of electroconvulsive therapy on plasma vasopressin and oxytocin

BACKGROUND: Animal studies suggest that vasopressin has cognitive-enhancing properties and oxytocin may have amnestic effects. A clinical report suggests that the acute increase in oxytocin-associated neurophysin predicts clinical response to electroconvulsive therapy (ECT) in depressed patients. METHODS: Medication-free patients with major depression were randomized to receive right unilateral or bilateral ECT administered with electrical stimulus intensity at either just above seizure threshold or at 150% above seizure threshold. The associations between plasma vasopressin, oxytocin, ECT treatment parameters, clinical outcome, and cognitive effects were assessed. RESULTS: The sample comprised 55 patients. At the second ECT, patients receiving ECT at 150% above initial seizure threshold had significantly greater increases in plasma vasopressin than patients receiving low-dose ECT (ps < .01-.04), with no effects of electrode placement. At the second and ninth ECT treatments, the vasopressin or oxytocin surges were not associated with clinical improvement, seizure duration, time to orientation, or memory test performance. There were inverse trend-level associations between the acute surge in oxytocin levels at the ninth ECT and clinical response, contradicting a report in the literature. CONCLUSIONS: Overall, these findings do not support the hypothesis that diencephalic seizure propagation is central to the mechanism of action of ECT.     

Effects of vasopressin on human renal arteries

The effects of vasopressin were studied in isolated rings from branches (2-3 mm in external diameter) of human renal arteries obtained from 18 patients undergoing nephrectomy for non-obstructive neoplasia. In arterial rings under resting tension, vasopressin produced concentration-dependent and endothelium-independent contractions with an EC50 of 9.1 X 10(-10) molL-1. The vasopressin V1 receptor antagonist d(CH2)Tyr(Me)AVP (10(-6) molL-1) displaced the control curve to vasopressin 564-fold to the right in a parallel manner. In precontracted arterial rings and previously treated with the V1 antagonist (10(-6) molL-1) vasopressin caused endothelium-independent relaxation. The relaxation to vasopressin was reduced significantly by indomethacin (10(-6) molL-1) and unaffected by the V1/V2 receptor antagonist desGly d(CH2)5-D-Tyr(Et)ValAVP(10(-6) molL-1) or by NG-nitro-L-arginine methyl ester (10(-4) molL-1). These observations indicate that vasopressin is primarily a constrictor of human renal arteries by V1-receptor stimulation. Vasopressin causes prostaglandin-mediated dilation of human renal arteries only if V1-receptor blockade is present. The effects of vasopressin on human renal arteries may be relevant in those clinical situations characterized by increased plasma vasopressin levels.     

Bioactive diversity and screening library selection via affinity fingerprinting

The Similarity Principle provides the conceptual framework behind most modern approaches to library sampling and design. However, it is often the case that compounds which appear to be very similar structurally may in fact exhibit quite different activities toward a given target. Conversely, some targets recognize a wide variety of molecules and thus bind compounds that have markedly different structures. Affinity fingerprints largely overcome the difficulties associated with selecting compounds on the basis of structure alone. By describing each compound in terms of its binding affinity to a set of functionally dissimilar proteins, fundamental factors relevant to binding and biological activity are automatically encoded. We demonstrate how affinity fingerprints may be used in conjunction with simple algorithms to select active-enriched diverse training sets and to efficiently extract the most active compounds from a large library.     

Effects of vasopressin on human memory functions

Arginine vasopressin and a number of its synthetic analogs augment memory functions in experimental animals. One of these analogs, 1-desamino-8-D-arginine vasopressin (DDAVP), influences human learning and memory. Cognitively unimpaired, as well as cognitively impaired adults, treated with DDAVP for a period of several days, learn information more effectively, as measured by the completeness, organization, and consistency (reliability) of recall. DDAVP also appears to reverse partially the retrograde amnesia that follows electroconvulsive treatment.     

Synthesis and some pharmacological properties of deamino(4-threonine,8-D-arginine)vasopressin and deamino(8-D-arginine)vasopressin, highly potent and specific antidiuretic peptides, and (8-D-arginine)vasopressin and deamino-arginine-vasopressin

Deamino[4-threonine,8-D-arginine]vasopressin (dTDAVP), deamino[8-D-arginine]vasopressin (dDAVP), [8-D-arginine[vasopressin (DAVP), and deamino-arginine-vasopressin (dAVP) were synthesized by the solid-phase method and tested for their biological activities. dTDAVP has an antidiuretic potency of 793+/-95 units/mg and undetectable vasporessor activity, less than 0.02unit/mg. The antidiuretic-pressor (A/P) ratio of dTDAVP is greater than 39 000. dDAVP has an antidiuretic potency of 1200+/-126 units/mg and a vasopressor potency of 0.39+/-0.02; its A/P ratio is thus 3000. DAVP has an antidiuretic potency of 253+/-44 units/mg, a vasopressor potency of 1.1+/-0.04 units/mg, and an A/P ratio of 240. The A/P ratios of dDAVP and DAVP are much higher than those originally reported. dAVP has an antidiuretic potency of 1745+/-385 units/mg, a vasopressor potency of 346+/-13, and an A/P ratio of 5; values are in general agreement with those in the literature. Threonine subsitution has thus brought about a significant enhancement in antidiuretic specificity, a finding entirely consistent with earlier observations that enhancement of lipophilicity at position 4 alone or in combination in arginine-vasopressin can lead to enhanced antidiuretic specificity.     

The relative effects of selective intra-arterial and intravenous vasopressin infusion

The relative effects of selective intra-arterial and intravenous infusions of vasopressin were evaluated in 16 normotesive dogs. One group was infused via the left gastric artery, one was infused via a peripheral vein, and a control group was not infused. Flow to the stomach and bowel was reduced by an average of 73% and 45%, respectively. There was no significant difference between selective intra-arterial and intravenous infusions with regard to their effects on visceral flow or their systemic parameters. Control animals demonstrated only minor variations from base-line flow.     

Plasma arginine vasopressin and motor activity in major depression

The aim of this study was to test whether the effect of surfactant treatment on lung function in a surfactant-deficient animal model can be influenced by the rate at which surfactant is administered. Surfactant deficiency was induced in 18 New Zealand white rabbits (weighing approx. 1 kg each) by lung lavage with normal saline. The arterial/alveolar oxygen ratio (a/A ratio), functional residual capacity (FRC), dynamic compliance of the respiratory system (Crs), tidal volume (V(T)), alveolar portion of the tidal volume (V(A)) and arterial P(CO2) (P(a,CO2)) were measured before and after lavage and 15, 30, 60, 90, and 120 min after administration of a single dose of surfactant (Survanta, 100 mg/kg). Two surfactant administration protocols were compared over a 2-h interval: an infusion lasting 4 min and an infusion over 2 min. Both administrations were given during continuous mechanical ventilation. The six lung function and gas exchange parameters improved significantly following surfactant administration over 2 min compared with a control group. However, only the a/A ratio and V(A) improved following the 4-min protocol. Comparison of the two intervention protocols yielded significantly differences in V(A) and P(a,CO2), favoring the shorter administration. These results support the hypothesis that fast (2 min) administration of surfactant will improve its distribution to formerly collapsed alveoli and results in better lung function, improved ventilation, and (to a lesser extent) better oxygenation than prolonged infusions (4 min).     

等离子体喷涂新型生物活性涂层研究

为改善骨植入体涂层材料在临床应用中存在的不足之处,如生物活性不高、抗感染能力缺乏、长期稳定性不够等,对等离子体喷涂生物活化钛涂层、抗菌羟基磷灰石涂层以及抗降解硅酸钙复合涂层等新型生物活性涂层进行了研究。所获得的涂层材料综合性能优良,有望用于新一代骨植入体。     

Bioactive conformation of Arg-Gly-Asp by x-ray data analyses and molecular mechanics

Analysis of well resolved x-ray crystal structure data of proteins (Brookhaven protein data bank) has been combined with molecular mechanics methods using MM2, to determine possible bioactive conformations for the sequence Arg-Gly-Asp, which is believed to be involved in interactions of adhesive proteins with the glycoprotein complexes on activated platelets. In spite of the very flexible nature of this tripeptide fragment, only three general classes of structures were obtained. In one of them, the guanidinium and carboxylate moieties are in hydrogen-bonding proximity, while in the other they are separated by distances of greater than 8 A. Recent literature on the binding affinity of some rigid platelet-aggregation inhibitors seems to support the latter class of structures to correspond to the bioactive conformation.