Barosaurus and its circulation.
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Animals↗
Biomedical subjects
J W Hicks
Publications and source records attributed to J W Hicks.
The human MUC2 intestinal mucin has cysteine-rich subdomains located both upstream and downstream of its central repetitive region.
The human MUC2 mucin is a large secretory glycoconjugate that coats the epithelia of the intestines, airways, and other mucus membrane-containing organs. Previous work has shown that this mucin contains an extended tandem repeat-containing domain rich in Thr and Pro. In the present work we describe two additional regions of this mucin located both upstream and downstream of the tandem repeat array. The carboxyl-terminal domain contains 984 residues and can be divided into mucin-like (139 residues) and cysteine-rich (845 residues) subdomains. This latter subdomain exhibits varying degrees of sequence similarity to a wide range of mucins and mucin-like proteins including those isolated from rats, pigs, cows, and frogs. We also report here the sequence of 1270 residues lying immediately upstream of the tandem repeats. This region contains a repetitive, mucin-like subdomain and a second cysteine-rich stretch of more than 700 residues. Both cysteine-rich subdomains of this mucin have sequence similarity with von Willebrand factor, a serum protein that exists as a disulfide-linked polymer. This suggests that these cysteine-rich subdomains are important in the catenation of mucin monomers into oligomers, the structures that confer viscoelasticity upon mucus.
Amino Acid Sequence↗
Hemodynamics of vascular 'waterfall': is the analogy justified?
The concept of 'vascular waterfall' has been used for collapsible vessels in different hemodynamic states which have little similarity to each other from a dynamic standpoint. Examples include (a) flow through large systemic veins entering the thorax, (b) flow through microvessels, such as pulmonary, cardiac, hepatic, cerebral, and (c) flow through the jugular vein of the giraffe. The dynamics of freely falling liquids (waterfall) as compared with flow through collapsible blood vessels (in vivo and in vitro) and in collapsible tubes are dissimilar in too many respects to justify analogy. The flow through collapsible tubes and blood vessels can be explained satisfactorily on the basis of elementary principles of fluid mechanics (Bernoulli-Poiseuille). Hence, the term waterfall as a metaphor is misleading and unjustified. We suggest that the use of the term be discontinued for describing vascular dynamics.
Animals↗
Gravity and the circulation: "open" vs. "closed" systems.
The elementary principles of liquid dynamics are described by the equations of Bernoulli and Poiseuille. Bernoulli's equation deals with nonviscous liquids under steady streamline flow. Pressures in such flows are related to gravity and/or acceleration. Changes in elevation affect the gravitational potential energy of the liquid and the velocity of flow determines the kinetic energy. The sum of these three factors represented in the Bernoulli equation remains constant, but the variables are interconvertible. In contrast, the Poiseuille equation describes the pressures related to viscous resistance only, and the energy of flow is dissipated as heat. A combination of the two equations describes the flow in tubes more realistically than either equation alone. In "open" systems gravity hinders uphill flow and causes downhill flow, in which the liquid acts as a falling body. In contrast, in "closed" systems, like the circulation, gravity does not hinder uphill flow nor does it cause downhill flow, because gravity acts equally on the ascending and descending limbs of the circuit. Furthermore, in closed systems, the liquid cannot "fall" by gravity from higher levels of gravitational potential to lower levels of potential. Flow, up or down, must be induced by some source of energy against the resistance of the circuit. In the case of the circulation, the pumping action of the heart supplies the needed energy gradients. Flow in collapsible tubes, like veins, obeys the same basic laws of liquid dynamics except that transmural pressures near zero or below zero reduce markedly the cross-sectional area of the tube, which increases the viscous resistance to flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Adaptation, Physiological↗
Mechanism of intracardiac shunting in the turtle Pseudemys scripta.
Two principal hypotheses account for right-left (R-L) intracardiac shunting in reptiles. The "pressure shunting" hypothesis proposes no functional separation between the ventricular cava during systole. The "washout shunting" hypothesis suggests that during systole, the cavum pulmonale (CP) is functionally separate from the rest of the ventricle. The purpose of this study was to test these hypotheses during control, after acetylcholine (ACh) administration, after epinephrine (Epi) administration, and during apnea. Anesthetized (pentobarbital) turtles (Pseudemys scripta) were mechanically ventilated and three nonocclusive catheters were implanted into the right atrium (RAt), left atrium (LAt), and CP. In addition, three blood gas catheters connected to a mass spectrometer were implanted into the RAt, LAt, and right or left aortic arch for measurement of PO2. A tracer gas, He dissolved in saline, was sequentially injected into the three cardiac chambers and was detected by the mass spectrometer. The presence of R-L shunting was assessed with the blood PO2 and PHe measurements. ACh produced R-L shunting in all animals. No R-L shunting occurred after Epi administration and 20 min of apnea. In all animals after ACh administration, He was detected in an aorta after He infusion in the RAt and LAt, but never after infusion of He into the CP. These results from this preparation are inconsistent with the pressure hypothesis and support the washout hypothesis of intracardiac shunting.
Acetylcholine↗
Purification and biological activity of alligator bradykinin.
Incubation of plasma form the alligator (Alligator mississipiensis) with glass beads in the presence of a kininase inhibitor resulted in the activation of the kallikrein-kinin system and generation of bradykinin-like immunoreactivity. The kinin peptides were purified to homogeneity and were shown to comprise [Thr6]-bradykinin and des-Arg9[Thr6]bradykinin in the molar ratio of approximately 10:1. Bolus injections of synthetic [Thr6]bradykinin into the jugular vein of the anesthetized alligator resulted in a dose-dependent decrease in mean arterial blood pressure. The minimum dose of kinin producing a significant fall in pressure was 0.07 micrograms/kg body wt and the maximum response (25 +/- 6% fall; mean +/- SD, n = 8) was produced by a dose of 0.56 micrograms/kg body wt. The dose producing a half-maximum response was 0.19 +/- 0.08 micrograms/kg. The data indicate that alligator plasma contains all the components of the kallikrein-kinin system found in mammals and suggest that the system may be of physiological importance in the regulation of cardiovascular function in these reptiles.
Alligators and Crocodiles↗
Molecular cloning of rat intestinal mucin. Lack of conservation between mammalian species.
We have prepared antisera to deglycosylated rat intestinal mucin and used it to obtain immunoreactive clones from a rat jejunum cDNA library. Four of these clones were sequenced, and all were found to be partial cDNAs that contained 18-base pair tandem repeats characteristic of a mucin. These cDNAs encoded a repetitive peptide with a consensus sequence of TTTPDV. Thus, they bear little resemblance to either of the two human intestinal mucin cDNAs isolated previously (Gum, J. R., Byrd, J. C., Hicks, J. W., Toribara, N. W., Lamport, D. T. A., and Kim, Y. S. (1989) J. Biol. Chem. 264, 6480-6487 and Gum, J. R., Hicks, J. W., Swallow, D. M., Lagace, R. E., Byrd, J. C., Lamport, D. T. A., Siddiki, B., and Kim, Y. S. (1990) Biochem. Biophys. Res. Commun. 171, 407-415). One of these rat mucin clones, designated RMUC 176, was chosen for further analysis. This clone recognized a band of approximately 9 kilobases when used to probe RNA blots. A strong hybridization band was present using rat small intestine and colon RNA but was not detectable when RNA isolated from heart, liver, or kidney was tested. The RMUC 176 clone and the two previously isolated human intestinal mucin cDNA clones were used to probe blots prepared from BamHI-digested DNA of various species. Here, the human probes detected fragments present only in human and chimpanzee DNA, whereas the RMUC 176 clone recognized fragments only in rat and mouse DNA. Thus, the repetitive portions of intestinal mucin genes are apparently not well conserved between phylogenetically distant species.
Amino Acid Sequence↗
MUC-2 human small intestinal mucin gene structure. Repeated arrays and polymorphism.
MUC-2, the first described intestinal mucin gene, has become important as a prototype for secreted mucins in several organ systems. However, little is known about its protein backbone structure and hence its role in diseases such as colon cancer, ulcerative colitis, and cystic fibrosis, which are known to have mucin abnormalities. Studies in this manuscript show that MUC-2 contains two distinct regions with a high degree of internal homology, but the two regions bear no significant homology to each other. Region 1 consists mostly of 48-bp repeats which are interrupted in places by 21-24-bp segments. Several of these interrupting sequences show similarity to each other, creating larger composite repeat units. Region 1 has no length polymorphisms. Region 2 is composed of 69-bp tandem repeats arranged in an uninterrupted array of up to 115 individual units. Southern analysis of genomic DNA samples using TaqI and HinfI reveals both length and sequence polymorphisms which occur within region 2. The sequence polymorphisms have different ethnic distributions, while the length polymorphisms are due to variable numbers of tandem repeats.
Amino Acid Sequence↗
Molecular cloning of cDNAs derived from a novel human intestinal mucin gene.
A human small intestinal lambda gt11 cDNA library was screened with antibodies to deglycosylated small intestinal mucin. Four partial cDNA clones were isolated that define a novel human mucin gene. These include two partial cDNA clones, SIB 124 and SIB 139, that contain 51 nucleotide tandem repeats which encode a seventeen amino acid repetitive peptide with a consensus sequence of HSTPSFTSSITTTETTS. SIB 139 hybridized to messages produced by small intestine, colon, colonic tumors and also by high mucin variant LS174T colon cancer cells. The gene from which cDNAs SIB 124 and SIB 139 are derived (proposed name MUC 3) maps to chromosome 7, distinct from other known human mucin genes.
Amino Acid Sequence↗
Molecular cloning of complementary DNAs encoding alkaline phosphatase in human colon cancer cells.
We have isolated a set of complementary DNA (cDNA) clones that together encode the alkaline phosphatase of human colon cancer LS174T cells. These clones include two cDNAs isolated from a conventionally prepared oligodeoxythymidylate-primed lambda ZAP cDNA library and three cDNA clones prepared by using the polymerase chain reaction. The deduced amino acid sequence of the alkaline phosphatase primary transcript contains 532 amino acids. This enzyme is similar to, but not identical with, placental alkaline phosphatase (PLAP); it exhibits 12-19 amino acid substitutions when compared to the various alleles of PLAP. Also, it is similar to PLAP in that it is apparently attached to the cell membrane by a phosphatidylinositol-containing anchor as judged by the ability of phosphatidylinositol-specific phospholipase C to release it from membranes. It is different from PLAP however, in terms of its signal sequence which only contains 19 amino acids as compared to 22 for PLAP. Moreover, the 3'-untranslated region of the LS174T cell alkaline phosphatase message diverges considerably from the PLAP message. The LS174T cell alkaline phosphatase cDNAs are actually much more similar to the "germ cell" alkaline phosphatase gene than they are to PLAP. Only 7 amino acid substitutions exist between the LS174T cell enzyme and the alkaline phosphatase encoded by the germ cell alkaline phosphatase genomic DNA clone isolated by Millan and Manes (Proc. Natl. Acad. Sci. USA, 85: 3024-3028, 1988). Furthermore, the 3'-untranslated region of the LS174T cell alkaline phosphatase message is very similar to the sequence immediately downstream of the coding region of the germ cell alkaline phosphatase genomic DNA clone. Thus, these results indicate that this colon cancer cell alkaline phosphatase is likely to represent an allelic variant encoded at the germ cell alkaline phosphatase locus.
Alkaline Phosphatase↗
Isolation and biological activity of a novel kinin ([Thr6] bradykinin) from the turtle, Pseudemys scripta.
Incubation of plasma from the red-eared turtle with glass beads in the presence of the kininase inhibitor 1,10-phenanthroline resulted in activation of the kallikrein-kinin system and generation of bradykinin-like immunoreactivity. The immunoreactive material comprised a single molecular form that was purified to homogeneity by reverse phase HPLC. The primary structure of the peptide was determined by automated Edman degradation and fast atom bombardment mass spectrometry. The amino acid sequence of the turtle kinin Arg-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg contains the substitution Thr for Ser at position 6 compared with mammalian bradykinin. [Thr6] bradykinin was synthesized using solid phase methodology, and bolus injections of the peptide into the left atrium of the anaesthetized turtle produced rapid vasodilation. A dose-dependent increase in blood flow in the left aortic arch was accompanied by a decrease in peripheral vascular resistance, so that systemic blood pressure did not change. The data suggest that the kallikrein-kinin system may play an important physiological role in the regulation of cardiovascular function in reptiles.
Amino Acid Sequence↗
Evidence that neuromedin U may regulate gut motility in reptiles but not in mammals.
Neuromedin U-8 induced a monophasic and concentration-dependent contraction of intact small intestine from the turtle, Pseudemys scripta, whereas the peptide had no effect upon the motility of rat and guinea pig gut. The maximum response produced by neuromedin U-8 was 56% of that produced by acetylcholine and 62% of that produced by potassium chloride. The potency and maximum response to neuromedin U-8 were unaffected by tetrodotoxin and atropine. The data suggest that neuromedin U may play a role in regulation of gut motility in lower vertebrates but not in mammals.
Acetylcholine↗
Molecular cloning of human intestinal mucin cDNAs. Sequence analysis and evidence for genetic polymorphism.
A human small intestine lambda gt11 cDNA library was screened using antisera prepared against the deglycosylated protein backbone of human colon cancer xenograft mucin. Three cDNAs were isolated from this screening, designated SMUC 40-42. These cDNAs were all found to contain tandem repeats of 69 nucleotides which encoded a threonine- and proline-rich protein consensus sequence of PTTTPITTTTTVTPTPTPTGTQT. RNA blots probed with one of these cDNAs, SMUC 41, exhibited large, polydisperse hybridization bands at approximately 7,600 bases. Band intensities were strongest when human small intestine, colon, and colon cancer poly(A)+ RNA was used. In vitro translation of poly(A)+ RNA from human small intestine, colon, and colon cancer cells produced a 162,000-dalton peptide that was immunoprecipitated with antibodies to deglycosylated mucin. SMUC 41 was also used to probe DNA blots, which indicated the presence of restriction fragment length polymorphisms in the intestinal mucin gene. These findings may be important in assessing the abnormal mucins found associated with several human diseases.
Amino Acid Sequence↗
Effect of sodium butyrate, a differentiating agent, on cell surface glycoconjugates of a human pancreatic cell line.
The effects of sodium butyrate, a differentiating agent, on growth properties and glycoconjugates of a human pancreatic carcinoma cell line (CAPAN-1) were studied. Butyrate caused marked changes of in vitro growth properties including prolongation of doubling time and greatly reduced colony forming efficiency in soft agar. Cell surface labeling revealed significant alterations in proteins and glycoproteins after treatment with sodium butyrate (appearance of glycoproteins of molecular weight 250,000, 220,000, and 70,000; reduction of glycoproteins of 164,000, 148,000, 110,000, and 66,800 sizes; increases in proteins/glycoproteins of 85,000 and 78,000). Metabolic labeling of the cells with [3H]fucose or [3H]galactose revealed that sodium butyrate treatment caused a marked reduction in the fucose-containing neutral glycolipids with six or more carbohydrate side chains and an increase in [3H]galactose-labeled neutral glycolipids, particularly GL-3a, GL-4a, and GL-5a. There was marked reduction in the labeling of a ganglioside with mobility similar to that of GM4 and of sulfogalactosylceramide. An increase in a ganglioside with mobility above GM1 was also caused by butyrate. These data indicate that sodium butyrate may be useful in the identification of differentiation or malignancy-associated glycoconjugate markers of human pancreatic cells.
Butyrates↗
Relationship between respiratory state and intracardiac shunts in turtles.
Injection of radioactively labeled microspheres and blood O2 analysis from central vascular sites was utilized to assess intracardiac shunts in the unanesthetized and unrestrained turtle, Pseudemys scripta, at 15 degrees C. Both methods indicated a simultaneously occurring right-to-left (R-L) and left-to-right (L-R) shunt during ventilation and apnea. During ventilation, the O2 method estimated a R-L shunt of 24%. In contrast, injection of microspheres during ventilation estimated a R-L shunt of 65%, which was significantly greater than the value determined from the O2 method. During apnea, both methods indicated a significantly larger R-L shunt. Estimates of the R-L shunt from O2 analysis were between 60 and 90% of the venous return. The R-L shunt estimated from the O2 content of left aortic arch blood was significantly greater than the value determined from right aortic arch blood. During apnea, the microsphere method estimated a R-L shunt of 79%, which was in the intermediate range calculated by the O2 method using two aortic arches. Our results verify previous reports of significant differences in R-L shunt levels between ventilation and apnea during the normal ventilatory cycle of turtles.
Animals↗
Siphon mechanism in collapsible tubes: application to circulation of the giraffe head.
Controversy exists over the principles involved in determining blood flow to the head of a giraffe, specifically over the role of gravity pressure (pgh) in the collapsible jugular vein in facilitating uphill flow in arteries. This study investigated the pressures within vertically oriented models containing both rigid and collapsible tubes. An inverted U tube was constructed (height = 103 cm) of thick rubber tubing in the ascending limb and collapsible dialysis tubing in the descending limb. Water flow was induced by a variable speed pump maintained at the reservoir level such that the descending limb was partially collapsed. Pressure measurements were made at various levels within the U tube by two methods: 1) with the transducer at same level as the tip of the water-filled catheter and 2) with the transducer at the reservoir level. During flow, the pressure at any point was nearly atmospheric along the length of the descending limb. Such methods of obtaining pressure indicated that the pressure gradient within the partially collapsed descending limb was the sum of viscous flow pressure (P1-P2 of Poiseuille) and gravitational pressure (pgh). To study the facilitatory effect of a siphon, the descending limb was compared with a horizontally placed limb (length = 100 cm), and the flow was kept constant. Calculations of hydraulic "work" (pressure x flow) indicated that with a partially collapsed descending limb, work of the pump was reduced by 15% compared with uphill flow to the elevated horizontal position. It is concluded that the siphon mechanism operates in a partially collapsed descending limb of a siphon loop.
Animals↗
Effect of temperature on chemical control of ventilation in Mexican black iguanas.
The impact of temperature on the chemical control of respiration in the Mexican black iguana Ctenosaura pectinata was examined by measuring ventilatory responses to graded hypoxia with and without 2.9% inspired CO2 at 25, 30, and 35 degrees C. Black iguanas increased pulmonary ventilation in response to hypoxia by increasing both tidal volume and respiratory frequency. Breathing 2.9% CO2 stimulated an increased pulmonary ventilation primarily through increases in tidal volume. The fractional O2 concentration at which ventilation began to increase (hypoxic threshold) varied with temperature, increasing from 0.067 at 25 degrees C to 0.085 at 30 degrees C and 0.112 at 35 degrees C. At 35 degrees C, breathing 2.9% CO2 promoted a further, although statistically insignificant, shift in the ventilatory hypoxic threshold to approximately 0.130 fractional inspired O2 concentration. A "gasping" ventilatory pattern was also observed, the frequency of which increased with progressive hypoxia and increasing temperature. These results suggest that the chemical control of ventilation in this lizard is susceptible to changes in temperature, although the mechanism underlying the temperature sensitivity remains obscure.
Animals↗
Analysis of intracardiac shunting in the lizard, Varanus niloticus: a new model based on blood oxygen levels and microsphere distribution.
The central sites of the cardiovascular system (right and left aortic arches, RAo and LAo, pulmonary artery, PA, and right and left atria, RAt and LAt) were chronically and non-occlusively cannulated for an analysis of intracardiac shunting in Varanus niloticus. Oxygen partial pressure (PO2) and oxygen concentration (CO2) were significantly higher in right aortic blood than values determined in left aortic blood. The difference was larger in animals acclimated to 25 degrees C (RAo CO2 = 4.5 +/- 1.00 vol %, LAo CO2 = 3.8 +/- 1.14, X +/- SD, n = 19) than at 35 degrees C (RAo CO2 = 5.8 +/- 1.24, LAo CO2 = 5.4 +/- 1.35, n = 18) (P less than 0.001 for both temperatures, paired t-test). These data are explained by a new model describing the differential shunting patterns of the two aortae in addition to the conventional overall right-to-left and left-to-right shunt fractions. This model was solved on the basis of blood gas data collected by simultaneous multiple-site gas analysis, together with data on the differential blood flow in the central vascular system, collected by application of the microsphere method. At 35 degrees C both right-to-left and left-to-right shunts were relatively small (about 9%), with the right-to-left shunt fraction directed exclusively into the left aorta. Thus right aortic blood represented left atrial blood, whereas left aortic blood was composed of 80% left atrial and 20% right atrial blood. Ninety percent of the pulmonary arterial blood was derived from the right atrium and 10% from the left atrium. At 25 degrees C the composition pattern of effluent blood for each vessel was similar, the absolute flow distribution, however, was different from that at 35 degrees C. These findings are discussed with respect to their significance and compatibility with the wash-out shunt model.
Animals↗