Self-segmentation of sequences: automatic formation of hierarchies of sequential behaviors.

The paper presents an approach for hierarchical reinforcement learning that does not rely on a priori domain-specific knowledge regarding hierarchical structures. Thus, this work deals with a more difficult problem compared with existing work, It involves learning to segment action sequences to create hierarchical structures (for example, for the purpose of dealing with partially observable Markov decision processes, with multiple limited-memory or memoryless modules). Segmentation is based on reinforcement received during task execution, with different levels of control communicating with each other through sharing reinforcement estimates obtained by each other. The algorithm segments action sequences to reduce non-Markovian temporal dependencies, and seeks out proper configurations of long- and short-range dependencies, to facilitate the learning of the overall task. Developing hierarchies also facilitates the extraction of explicit hierarchical plans. The initial experiments demonstrate the promise of the approach.

Regulation of adrenal atrial natriuretic hormone receptor subtypes.

Regulation of atrial natriuretic hormone (ANH) receptor binding and aldosterone suppression was studied in isolated adrenal glomerulosa cells from rats fed a high-salt (HS) or low-salt (LS) diet for 3 days. In plasma of HS rats, aldosterone levels were 5 times lower and immunoreactive ANH two times higher than in LS rats. Competitive binding studies showed the same affinity for human atrial natriuretic hormone (hANH) in both pools of cells, but receptor density was 50% higher on LS cells. A linear ANH analog that binds to non-guanylate-cyclase-coupled receptors did not show increased binding to LS cells. Cyclic GMP production in response to hANH was identical in both groups. The aldosterone-inhibitory effect of hANH on both groups of basal and angiotensin II-stimulated cells was also identical. Thus a short-term high-salt diet causes decreased density of ANH receptors in glomerulosa cells without changing biological activity of ANH. These results suggest that dietary salt content changes the number of ANH receptors and that non-guanylate-cyclase-coupled receptors contain at least two classes of receptors.

Comparative neuroanatomy of the sexually dimorphic hypothalamus in monogamous and polygamous voles.

In the present work we evaluated the degree of sexual dimorphism in two cell groups of the medial preoptic-anterior hypothalamus (MPOA-AH) in monogamous and polygamous voles. Quantitative determinations were made of volume, cell number, and cell density for the anteroventral-periventricular nucleus (AVPV) and the sexually dimorphic nucleus of the preoptic area (SDN-POA). Polygamous montane voles (Microtus montanus) had a greater degree of sexual dimorphism in both cell groups than did monogamous prairie voles (M. ochrogaster). Most notable was the complete absence of the AVPV in male montane voles; male montane voles also had a significantly larger SDN-POA volume than did females. The only sexual dimorphism in prairie voles was a greater cell density in the female AVPV. In addition, prairie voles had larger relative brain size than did montane voles. Comparative behavioral studies have revealed a correlation between the degree of sexual dimorphism in external morphology and mating system, i.e., polygamous species display greater levels of dimorphism than do monogamous species. The present results indicate that the effects of sexual selection can also be seen in those brain regions, like the hypothalamus, that underlie social and reproductive behavior. Moreover, these results support the hypothesis that neuroanatomic dimorphisms in the MPOA-AH may be related to sex differences in behavior.

The physiological role of atrial natriuretic hormone in the regulation of aldosterone and salt and water metabolism.

To investigate the mechanisms by which small changes in plasma levels of atrial natriuretic hormone (ANH) affect aldosterone, 10 normal young men were infused for 2 h with 0.6 pmol/kg.min human [Ser,Tyr28]ANH under 3 study conditions: 1) high salt diet (H), 2) low salt diet (L), and 3) low salt diet plus pretreatment with the angiotensin-converting enzyme inhibitor enalapril (LE). Baseline ANH levels were higher on H than on L or LE. A postural drop in ANH was observed when subjects went from standing to sitting. Plasma ANH levels increased during infusion by up to 4.5 pmol/L (H, 7.0 +/- 1.3 to 11.5 +/- 1.4; L, 4.3 +/- 0.6 to 8.7 +/- 1.1; LE, 4.2 +/- 0.5 to 8.6 +/- 1.5). At all time points, plasma ANH was well within the normal range. Plasma aldosterone did not change during H, decreased by about 60% for both low salt conditions, and remained suppressed at 1 h of recovery for L, but not for LE. This suggests that ANH can suppress aldosterone by both indirect and direct mechanisms, although the indirect mechanism appears to predominate. A prompt increase in urine flow was seen during ANH infusion and was sustained at 1 h of recovery, but little change was seen in urinary sodium or potassium excretion, heart rate, or blood pressure. The difference between the natriuretic and diuretic effects of ANH was seen under all conditions. These results support the hypothesis that within the normal physiological range, ANH is a regulator of salt and water metabolism in normal man.

Interaction of insulin-like growth factor II with rat chondrocytes: receptor binding, internalization, and degradation.

We have characterized the interaction of insulin-like growth factor II (IGF-II) with its plasma membrane receptor(s) on cultured rat chondrocytes. Our studies, paralleling those already reported for IGF-I, demonstrate that [125I]IGF-II binds to these receptors with a high degree of affinity and that this process is reversible, specific, and time, temperature, and concentration dependent. At 4 C, unlabeled IGF-II causes half-maximal displacement of the labeled ligand at a concentration of 22 ng/ml, whereas IGF-I is approximately 1/200th as potent, and insulin does not displace [125I]IGF-II even at a concentration of 10 micrograms/ml. Maximum binding to chondrocytes (44% of added radioactivity) occurred after 4-5 h of incubation at 15 C. Compared to [125I]IGF-I binding, this value is 7-fold higher and is consistent with an affinity constant (Ka = 3.8 X 10(8) M-1) approximately 1 order of magnitude greater. Photoaffinity labeling studies disclose that IGF-II binds primarily to the type II IGF receptor, which has an apparent mol wt of 220K when electrophoresed under nonreducing conditions and 270K under reducing conditions. Nanomolar concentrations of IGF-II stimulated the synthesis of DNA and RNA in a dose-related manner, and micromolar concentrations of insulin demonstrated an additive effect with respect to the incorporation of [3H]thymidine into DNA, but not [3H]uridine into RNA. Preincubation of rat chondrocytes with increasing concentrations of insulin caused a marked dose-related increase in [125I]IGF-II binding, a phenomenon previously reported in several other cell types. In addition to defining the binding characteristics of IGF-II, we used the lysosomotropic agents chloroquine and ammonium chloride to demonstrate that its ligand-receptor complex, like that of IGF-I, is internalized and degraded partially via the lysosomal pathway.

Interaction of insulin-like growth factor I/somatomedin-C with cultured rat chondrocytes: receptor binding and internalization.

We have characterized the interaction of insulin-like growth factor I/somatomedin C (IGF-I/Sm-C) with its plasma membrane receptors on cultured rat chondrocytes. Our studies have demonstrated that [125I]IGF-I/Sm-C binding to these receptors is a relatively specific, reversible, and time-, temperature-, pH-, and concentration-dependent process. Insulin displaces [125I]IGF-I/Sm-C from its receptors on rat chondrocytes, but with a potency only 10(-4) that of IGF (I and II). Using the known lysosomotropic agents chloroquine and ammonium chloride as well as the substituted diamine monodansylcadaverine, we have shown that this 125I-labeled Sm is internalized and partially degraded via the lysosomal pathway. These conclusions have been further supported by photoaffinity labeling studies which, surprisingly, demonstrate that the predominant IGF receptor on chondrocytes is the type II receptor, and that [125I]IGF-I/Sm-C is bound primarily in this ligand-receptor complex which is internalized and degraded, in part, by lysosomes.

Developmental aspects of the renal kallikrein-like activity in fetal and newborn lambs.

The ontogeny of the renal kallikrein-like activity and the interrelationships between this enzyme and the renin-angiotensin-aldosterone and prostaglandin systems were studied in 43 chronically catheterized sheep fetuses between 104 and 142 days of gestation (term, 145 days) and in 8 chronically catheterized newborn lambs between 5 and 23 days of age. Urinary kallikrein (UKall) excretion rate expressed in absolute values (mEU/hr) or corrected for kidney weight (mEU X hr-1 X gKW-1) or glomerular filtration (mEU X hr-1 X ml GFR-1) increased significantly during fetal maturation and after birth. The rise in UKall during fetal and newborn life was not dependent on an increase in urinary flow rate (r = 0.06). The increase in fetal UKall (mEU X hr-1 X gKW-1) correlated closely with the rise in plasma aldosterone concentration for values above 35 pg/ml (r = 0.72, P less than 0.001). A significant negative correlation was found between UKall (mEU X hr-1 X gKW-1) and log of individual urinary sodium excretion values (r = -0.78, P less than 0.001). No correlation was found between UKall and urinary prostaglandins (PGE, PGF2 alpha) excretion during fetal and newborn life, but UKall correlated closely with the rise in renal blood flow during maturation (r = 0.87, P less than 0.001). The present data suggest that aldosterone is an important regulator of UKall release early during development. It is also suggested that conceptional age is an important factor which may modulate the renal sensitivity to aldosterone-stimulated UKall excretion.

Role of aldosterone on renal sodium and potassium excretion during fetal life and newborn period.

The renal response to endogenous aldosterone production at different times during gestation and immediately after birth, as well as factors controlling aldosterone secretion during fetal life have been studied in 34 lamb fetuses (106-142 days of gestation, term 145 days) and in 6 newborn lambs (3-8 days postnatal age). It was demonstrated that the increase in fetal plasma aldosterone concentrations correlated with the increase in fetal plasma renin activity (PRA) (r = 0.67, p < 0.001). Moreover, it was fond that the slope of the regression line between plasma aldosterone and PRA during fetal life was significantly steeper (p < 0.05) than after birth. Significant correlation coefficients were found between the fetal urinary to plasma ratios (U/P) of sodium over potassium [(U/P)Na+/(U/P)K+] and either fetal plasma aldosterone (r = -0.53, p < 0.005) or fetal age (r = -0.52, p < 0.005). Moreover, in 7 out of 9 fetuses over 125 days, frank secretion of potassium by the fetal tubular cells was demonstrated; such a secretion was present in only 1 of the 15 fetuses between 101 and 125 days of gestation. Finally, it was demonstrated that the increase in mean arterial blood pressure during fetal life and after birth is not a major factor in the increase in fetal glomerular filtration rate during gestation or in the adaptation of glomerular filtration rate to extrauterine life.

In vivo demonstration of renal carbonic anhydrase activity in the fetal lamb.

The capacity of the fetal renal carbonic enzyme to facilitate the renal reabsorption of bicarbonate was studied in 8 long-term fetal lamb preparations (103-124 days of gestation). After acetazolamide administration the fetal arterial blood pH and PCO2 values decreased significantly (p less than 0.05). Significant increases in fetal urinary pH (p less than 0.001), and urinary excretion of bicarbonate (p less than 0.001), potassium (p less than 0.05) and total cation (Na+ + K+) were observed after carbonic anhydrase inhibition. It is suggested from these in vivo studies that renal carbonic anhydrase is present and active during fetal life and does not limit the capacity of the fetal kidney to reabsorb bicarbonate.

Metabolic effects of constant hypertonic glucose infusion in well-oxygenated fetuses.

In order to investigate the metabolic effects of a constant hypertonic glucose infusion in well-oxygenated fetuses, ten experiments were carried out in nine long-term experiments in fetal lambs. It appeared that a constant hypertonic glucose infusion did not significantly affect the fetal blood gases, pH, and plasma lactate levels when fetal glucose was kept below 150 mg. per 100 ml. It was also demonstrated that glucose infusions significantly increased the fetal lactate levels and decreased the blood pH when fetal plasma glucose was over 150 mg. per 100 ml. However, there was no decrease in fetal PO2 and pco2 until fetal glucose reached values over 300 mg. per 100 ml. These studies suggest that constant hypertonic glucose infusion does not improve fetal blood gases or pH and that fetal hyperglycemia over 300 mg. per 100 ml. produces severe metabolic acidosis.

Interrelationship between glomerular filtration rate and renal transport of sodium and chloride during fetal life.

The maturation of the glomerular filtration rate (GFR) and the interrelationship between the GFR and the renal transport of sodium and chloride have been evaluated during the last trimester of gestation with the use of long-term experiments in fetal lambs. An increase in GFR (milliliters per minute) parallel to the increase in fetal body weight was demonstrated; however, no significant change was shown when the GFR (milliliters per minute per kilogram of fetal body weight) (1.141 +/- 0.079) was related to fetal body weight or gestational age. There was a constant increase in sodium and chloride reabsorption (microequivalents per minute) during the last third of gestation. This increase in sodium and chloride reabsorption was less than the increase in GFR (milliliters per minute) before 129 days but became higher than the rise of GFR (milliliters per minute) after 129 days of gestation.

Influence of fetal extracellular volume contraction on renal reabsorption of bicarbonate in fetal lambs.

In order to determine the renal threshold for bicarbonate in the fetal lamb and factors that may influence renal reabsorption of bicarbonate in the fetus, 18 acute fetal lamb preparations (110-140 days of gestation) were studied. In the first series of experiments involving nine fetuses, the renal bicarbonate threshold of normal fetuses varied from 12.0 to 23.5 mM/liter with a mean value of 17.7 +/- 1.37 mM/liter. This is significantly lower (P less than 0.005) than the value measured in five adult sheep of 28.7 +/- 1.68 mM/liter. There was a significant and positive correlation between the fetal plasma bicarbonate at threshold level and the fetal kidney weight, as well as fetal age. In a second series of experiments, the excretion of bicarbonate and sodium was studied in nine fetuses before and after dehydration by peritoneal dialysis. After peritoneal dialysis there was a significant decrease in urinary pH (P less than 0.025), bicarbonate excretion (P less than 0.001), sodium excretion (P less than 0.001), fractional excretion of sodium (P less than 0.01). When glucose was replaced by mannitol in the peritoneal dialysis fluid the effects on bicarbonate reabsorption paralleled those when glucose was present in dialysis fluid. It was also shown that when glucose was given intravenously to the fetus, up to a plasma concentration of 200 mg/100 ml, there was no effect on the fetal renal reabsorption of bicarbonate. These data indicate that the low threshold for bicarbonate reabsorption by the fetal kidney is not due to a limited capacity to increase bicarbonate or sodium reabsorption and suggest that the fetal kidney is able to respond to volume depletion by increasing its reabsorption in bicarbonate and electrolytes.

Maturational changes in the fetal glomerular filtration rate.

Few data are available documenting the evolution of glomerular filtration rate (GFR) during gestation. In order to investigate this aspect, 33 fetal sheep have been studied, with the use of an intrauterine fetal preparation. It appears that the actual GFR (AGFR) in milliliters per minute increased during the last third of gestation without a significant increase in GFR expressed as milliliters per minute per kilogram of fetal weight (GFR-FW) and as milliliters per minute per gram of kidney weight (GFR-KW). It is suggested that a parallel and constant increase in AGFR and in total fetal weight or kidney weight might explain the absence of variation if GFR-FW or GFR-KW during the last third of gestation.