The N-end rule proteolytic system in autophagy

The N-end rule pathway is a cellular proteolytic system that utilizes specific N-terminal residues as degradation determinants, called N-degrons. N-degrons are recognized and bound by specific recognition components (N-recognins) that mediate polyubiquitination of low-abundance regulators and selective proteolysis through the proteasome. Our earlier work identified UBR4/p600 as one of the N-recognins that promotes N-degron-dependent proteasomal degradation. In this study, we show that UBR4 is associated with cellular cargoes destined to autophagic vacuoles and is degraded by the lysosome. UBR4 loss causes multiple misregulations in autophagic pathways, including an increased formation of LC3 puncta. UBR4-deficient mice die during embryogenesis primarily due to defective vascular development in the yolk sac (YS), wherein UBR4 is associated with a bulk lysosomal degradation system that absorbs maternal proteins from the YS cavity and digests them into amino acids. Our results suggest that UBR4 plays a role not only in selective proteolysis of short-lived regulators through the proteasome, but also bulk degradation through the lysosome. Here, we discuss a possible mechanism of UBR4 as a regulatory component in the delivery of cargoes destined to interact with the autophagic core machinery.     

Circular causality in integrative multi-scale systems biology and its interaction with traditional medicine

This paper discusses the concept of circular causality in “biological relativity” (Noble, Interface Focus. 2, 56-64, 2012) in the context of integrative and multi-scale systems approaches to biology. It also discusses the relationship between systems biology and traditional medicine (sometimes called scholarly medical traditions) mainly from East Asia and India. Systems biology helps illuminate circular processes identified in traditional medicine, while the systems concept of attractors in complex systems will also be important in analysing dynamic balance in the body processes that traditional medicine is concerned with. Ways of nudging disordered processes towards good attractors through the use of traditional medicines can lead to the development of new ways not only of curing disease but also of its prevention. Examples are given of cost-effective multi-component remedies that use integrative ideas derived from traditional medicine.     

Responses of the pancreatic digestive enzyme secretion to amino acids, glucose and cholecystokinin in chicks

1. Pancreatic secretion of digestive enzymes, amylase, trypsinogen and chymotrypsinogen, was studied in response to the wing vein injection of digestive end products, various single amino acids and glucose, with or without cholecystokinin (CCK) in chicks. 2. Among amino acids administered, only phenylalanine significantly (P less than 0.05) increased trypsinogen and chymotrypsinogen secretions, while other amino acids did not. 3. Simultaneous injection of single amino acids with CCK increased digestive enzyme secretion to various extents depending on the kind of amino acids whereas the injection of glucose with CCK did not affect when compared with that of CCK alone. 4. By varying doses, a synergetic action of CCK plus amino acid on the secretion of pancreatic digestive enzymes was observed at 0.5 mM for valine and 5 mM for arginine.     

A comparison of electrical activity in the triceps surae at maximum isometric contraction with the knee and ankle at various angles

The purpose of this study was to test the endurance of the soleus muscle, and to examine the joint position at which it is most active, while simultaneously suppressing the activity of the gastrocnemius. Ten young males performed maximum isometric contraction of the triceps surae for 100 s, and the endurance and plantar flexion torque of this muscle were measured at various angles of the knee and ankle joints. The electromyogram was measured simultaneously and subsequently converted into integrated electromyogram (IEMG) values. With the knee flexed at 130 degrees, the rate of change in IEMG values for the soleus (0.454% x s(-1)) with the ankle in a neutral position was significantly higher than that for the medial and lateral gastrocnemius. Both with the ankle dorsiflexed at 10 degrees and in the neutral position, the rate of change in IEMG for the soleus was significantly higher with the knee flexed at 90 degrees and 130 degrees than with the knee fully extended. With the knee flexed at 90 degrees and 130 degrees, the IEMG activity of the soleus during the initial (5-10 s) and final 5 s tended to be higher than those for the medial and lateral gastrocnemius, regardless of the ankle joint position. We conclude that the position in which the soleus acts most selectively during a sustained maximum isometric contraction of the triceps surae is with the ankle in a neutral position and the knee flexed at 130 degrees.     

Cardiovascular risk factors in a tourist town: association with job-related factors

Previous studies have shown that mortality from cardiovascular diseases in fishing villages was lower than that in farming villages. In contrast, few reports on the population living in a tourist village have appeared. Then, we report here the characteristic features of a tourist town, and that in fishing and farming towns. The rural farming town in Gunma prefecture had a population of 15,100. The population working in the primary industry was 17.1%, and the farming population was 17.0%. The fishing town in Shizuoka prefecture had a population of 11,700. The population working in the primary industry was 11.0%, and the fishing population was 10.2%. The rural tourist town in Shizuoka prefecture had a population of 17,800. The population working in the tertiary industry was 60.2%, and the wholesaling or retailing population was 16.6%. Standardized mortality ratios of cardiovascular diseases in the tourist town reported by Shizuoka health officials were higher than the fishing town. The rate of participation at ages of 50-59 years for the basic health examination in the tourist town was lower than the fishing and the farming towns. From the results of the health examination of residents at ages of 50-59 years, the high prevalence of obesity and hypertension in men and high prevalence of hypertension in women were found in the tourist town. In the tourist town, self-employed women at ages of 50-59 years had irregular time of meals and insufficient care of diet in comparison with employed women. Furthermore, the prevalence of hypertension in self-employed women was also higher than that of employed women. We could suggest that health status in communities might be associated with job-related factors.     

Inhaled nitric oxide prevents left ventricular impairment during endotoxemia

We evaluated theeffect of long-term inhalation of nitric oxide (NO) on cardiaccontractility after endotoxemia by using the end-systolicelastance of the left ventricle (LV) as a load-independent contractility index. Chronic instrumentation in 12 pigs included implantation of two pairs of endocardial dimension transducers tomeasure LV volume and a micromanometer to measure LV pressure. One weeklater, the animals were divided into a control group (n = 6) or a NO group(n = 6). All animals receivedintravenous Escherichia coliendotoxin (10 µg · kg¹ · h¹)and equivalent lactated Ringer solution. NO inhalation (20 parts/million) was begun 30 min after the initiation of endotoxemia andwas continued for 24 h. In both groups, tachycardia, pulmonaryhypertension, and systemic hyperdynamic changes were noted. Theend-systolic elastance in the control group was significantly decreasedbeyond 7 h. NO inhalation maintained the end-systolic elastance atbaseline levels and prevented its impairment. These findings indicatethat NO exerts a protective effect on LV contractility in this model of endotoxemia.

     

Decomposition Analysis of Waste Generation From Stocks in a Dynamic System

We conducted a decomposition analysis of material flows in a dynamic system, focusing on factors in the generation of waste consumer durables. A methodology for the analysis of consumer durables was developed and applied to three common consumer durables: cathode ray tube TVs, refrigerators, and passenger cars. The methodology decomposed changes in the numbers of waste products into three factors: changes in lifespan distribution, past trends in replacement sales, and past trends in sales for additional purchases. The decomposed equation clearly showed that the number of waste products would not necessarily be reduced by lifespan extension alone. This is because the number of waste products generated is affected not only by current lifespan distribution but also by past trends in sales for replacement and in additional purchases. The results show that changes in past replacement sales influence the current generation of waste, even if current replacement sales are declining. To reduce the generation of waste products on a short‐term basis, lifespan must be extended until the waste‐reducing effect of lifespan extension exceeds the waste‐increasing effect of the other two factors. From a long‐term perspective, controlling current replacement and additional purchases can be used to prevent future waste product generation.     

Hypermetabolism of fat in V1a vasopressin receptor knockout mice

[Arg8]Vasopressin (AVP) has an antilipolytic action on adipocytes, but little is known about the mechanisms involved. Here, we examined the involvement of the V1a receptor in the antilipolytic effect of AVP using V1a receptor-deficient (V1aR-/-) mice. The levels of blood glycerol were increased in V1aR-/- mice. The levels of ketone bodies, such as acetoacetic acid and 3-hydroxybutyric acid, the products of the lipid metabolism, were increased in V1aR-/- mice under a fasting condition. Triacylglyceride and free fatty acid levels in blood were decreased in V1aR-/- mice. Furthermore, measurements with tandem mass spectrometry determined that carnitine and acylcarnitines in serum, the products of beta-oxidation, were increased in V1aR-/- mice. Most acylcarnitines were increased in V1aR-/- mice, especially in the case of 2-carbon (C2), C10:1, C10, C14:1, C16, C18:1, and hydroxy-18:1-carbon (OH-C18:1)-acylcarnitines under feeding rather than under fasting conditions. The analysis of tissue C2-acylcarnitine level showed that beta-oxidation was promoted in muscle under the feeding condition and in liver under the fasting condition. An in vitro assay using brown adipocytes showed that the cells of V1aR-/- mice were more sensitive to isoproterenol for lipolysis. These results suggest that the lipid metabolism is enhanced in V1aR-/- mice. The cAMP level was enhanced in V1aR-/- mice in response to isoproterenol. The phosphorylation of Akt by insulin stimulation was reduced in V1aR-/- mice. These results suggest that insulin signaling is suppressed in V1aR-/- mice. In addition, the total bile acid, taurine, and cholesterol levels in blood were increased, and an enlargement of the cholecyst was observed in V1aR-/- mice. These results indicated that the production of bile acid was enhanced by the increased level of cholesterol and taurine. Therefore, these results indicated that AVP could modulate the lipid metabolism by the antilipolytic action and the synthesis of bile acid via the V1a receptor.