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S Hayward

Publications and source records attributed to S Hayward.

At least 55 records · Page 3Linked to original sources
PubMed1998

Mesenchymal-epithelial interactions in bladder smooth muscle development: epithelial specificity.

PURPOSE: We previously showed that mesenchymal-epithelial interactions are necessary for the development of bladder smooth muscle. Specifically without bladder epithelium embryonic bladder mesenchyme does not differentiate into smooth muscle. We determine whether this process is specific to bladder epithelium or whether epithelial cells from other organ systems induce bladder mesenchyme to differentiate into smooth muscle, as well as whether epithelial age is an important variable. MATERIALS AND METHODS: We recombined 14-day bladder mesenchyme before smooth muscle differentiation with rat epithelium from 14-day, 19-day, newborn and adult bladder, ureter, colon, ileum, stomach, cornea and epidermis. In addition, bladder epithelium was recombined with 14-day embryonic small intestinal, 14-day embryonic gastric and newborn seminal vesicle mesenchyme. All tissue recombinants were grafted under the renal capsule of an adult rat syngeneic host for 3 weeks. RESULTS: Immunohistochemical analysis with antibodies directed against smooth muscle alpha-actin revealed that all epithelial types studied induced bladder mesenchyme to differentiate into smooth muscle, although to different degrees. Induction of smooth muscle was independent of urothelial age. In addition, bladder epithelium induced intestinal, gastric and seminal vesicle mesenchyme to differentiate into smooth muscle and express an overall morphological pattern indicative of the bladder fibromuscular wall. CONCLUSIONS: The mechanism whereby urothelium induces bladder mesenchyme to differentiate into smooth muscle is not specific to embryonic urothelium. Older urothelium and heterotypic epithelium also induce smooth muscle differentiation. With the common use of bowel, stomach and ureteral segments for bladder augmentation it is important to understand the interaction of different types of epithelium with the native bladder.

Animals↗
PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 1. Urogenital morphology and placental androgen production during fetal life.

According to common understanding of sexual differentiation, the formation and development of a penile clitoris in female spotted hyaenas requires the presence of naturally circulating androgens during fetal life. The purpose of the present study was to determine potential source(s) of such fetal androgens by investigating the timing of urogenital development and placental production of androgen during early and mid-gestation. Fetuses determined to be female by molecular techniques (lack of SRY gene) at days 33 and 48 of gestation had undifferentiated gonads, but the clitoris was already 'masculinized' and was generally similar to the phallus of a 50-day-old male fetus. Wolffian and Müllerian ducts terminated at the urogenital sinus in both sexes and a urethra was present along the entire length of the clitoris and penis. The adrenal gland was large and histologically differentiated at 33 days. Steroid gradients across the uterus (a drop in delta 4-androstenedione, with increases in oestrogen and androgen), and high androstenedione in ovarian veins indicated that ovarian androstenedione was metabolized and secreted as testosterone by the placenta throughout gestation. In vitro, whole or homogenized placentae at days 48 and 58 of gestation (110 days total) metabolized radiolabelled androstenedione into testosterone and oestradiol; the specific enzymatic activity of early placental tissues was higher than at later stages. A human placental homogenate had higher aromatase activity but did not produce testosterone unless aromatase was inhibited. Infusion of labelled androstenedione into the uterine arteries of hyaenas demonstrated the conversion of this substrate into testosterone and oestradiol and their secretion into the fetal circulation. Evidently, androgen is produced by the placenta and secreted into the fetal circulation from early in pregnancy when masculinization is first evident, before differentiation of the fetal ovary.

Androgens↗
PubMed1997

Model-free methods of analyzing domain motions in proteins from simulation: a comparison of normal mode analysis and molecular dynamics simulation of lysozyme.

Model-free methods are introduced to determine quantities pertaining to protein domain motions from normal mode analyses and molecular dynamics simulations. For the normal mode analysis, the methods are based on the assumption that in low frequency modes, domain motions can be well approximated by modes of motion external to the domains. To analyze the molecular dynamics trajectory, a principal component analysis tailored specifically to analyze interdomain motions is applied. A method based on the curl of the atomic displacements is described, which yields a sharp discrimination of domains, and which defines a unique interdomain screw-axis. Hinge axes are defined and classified as twist or closure axes depending on their direction. The methods have been tested on lysozyme. A remarkable correspondence was found between the first normal mode axis and the first principal mode axis, with both axes passing within 3 A of the alpha-carbon atoms of residues 2, 39, and 56 of human lysozyme, and near the interdomain helix. The axes of the first modes are overwhelmingly closure axes. A lesser degree of correspondence is found for the second modes, but in both cases they are more twist axes than closure axes. Both analyses reveal that the interdomain connections allow only these two degrees of freedom, one more than provided by a pure mechanical hinge.

Animals↗
PubMed1997

Toxicological consequences of Aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys and their nursing infants. Part 3: post-reproduction and pathological findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar rooms (20 monkeys/room) and then to one of five dose groups (four females/dose group/room). Each day the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 microg Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their nuchal fat pad. Concurrently, sebaceous glands were being examined for changes analogous to chloracne. Subsequently, the females were paired with untreated males. The infants' blood PCB levels at birth were not correlated with its dam's dose or blood PCB level. However, there was an association between an infants preweaning blood PCB levels and its dam's dose and PCB milk levels. After weaning, the infants were not dosed with PCB. The half-life for the PCB in the infants' blood was determined and found to be slightly more than 15 wk. After 6 yr on test, three monkeys from the 0, 5, 20 and 40 microg dose groups were randomly allocated to a depletion study to ascertain the half-lives of specific PCB congeners (Mes et al., Chemosphere 1995, 30, 789-800). Concurrently, necropsies began of the remaining females, and of seven infants from the treated dams and four infants from the control dams, which had attained an age of 2 yr. Approximately 3 yr later, the depletion monkeys were necropsied. The only statistically significant treatment-related pathological changes found during the study were in the adult females, in which an involution of the sebaceous glands and a dose related increase in liver weight due to hyperplasia were evident.

Administration, Oral↗
PubMed1997

Effects of postnatal exposure to a PCB mixture in monkeys on nonspatial discrimination reversal and delayed alternation performance.

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 micrograms/kg/day of a PCB mixture representative of the PCBs typically found in human breast milk (8 monkeys) or vehicle (5 monkeys). At 20 weeks of age, PCB levels in fat and blood of treated monkeys were 1.7-3.6 ppm and 2-3 ppb respectively. Beginning at three years of age, monkeys were tested on a series of nonspatial discrimination reversal problems followed by a spatial delayed alternation task. Treated monkeys exhibited decreased median response latencies and variable increases in mean response latencies across the three tasks of the nonspatial discrimination reversal. There were no group differences on accuracy of performance, although some treated individuals made more mistakes at the beginning of the experiment than did control monkeys. On the delayed alteration task, the PCB-exposed group displayed retarded acquisition of the task and increased errors at short delay values, which were tested at the beginning of the experiment. There was no increase in the total number of errors in treated monkeys at long delay values. Treated monkeys engaged in more perseverative responding than controls over the entire course of the experiment, in some instances even in the absence of an increase in overall error rate. These findings are interpreted as a learning/performance decrement rather than an effect on spatial memory per se. The results of this study suggest that PCB exposure which is limited to the early postnatal period and results in environmentally-relevant body burdens produces long-term behavioral impairment.

Adipose Tissue↗
PubMed1997

Effects of fumonisin B1 on the immune system of sprague-dawley rats following a 14-day oral (gavage) exposure.

The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p > 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p >/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.

Administration, Oral↗
PubMed1996

Bending of the calmodulin central helix: a theoretical study.

The crystal structure of calcium-calmodulin (CaM) reveals a protein with a typical dumbbell structure. Various spectroscopic studies have suggested that the central linker region of CaM, which is alpha-helical in the crystal structure, is flexible in solution. In particular, NMR studies have indicated the presence of a flexible backbone between residues Lys 77 and Asp 80. This flexibility is related directly to the function of the protein because it enables the N- and C-terminal domains of the protein to move toward each other and bind to the CaM-binding domain of a target protein. We have investigated the flexibility of the CaM central helix by a variety of computational techniques: molecular dynamics (MD) simulations, normal mode analysis (NMA), and essential dynamics (ED) analysis. Our MD results reproduce the experimentally determined location of the bend in a simulation of only the CaM central helix, indicating that the bending point is an intrinsic property of the alpha-helix, for which the remainder of the protein is not important. Interestingly, the modes found by the ED analysis of the MD trajectory are very similar to the lowest frequency modes from the NM analysis and to modes found by an ED analysis of different structures in a set of NMR structures. Electrostatic interactions involving residues Arg 74 and Asp 80 seem to be important for these bending motions and unfolding, which is in line with pH-dependent NMR and CD studies.

Amino Acid Sequence↗
PubMed1996

Prevalence of endometriosis in rhesus (Macaca mulatta) monkeys ingesting PCB (Aroclor 1254): review and evaluation.

A total of 80 menstruating rhesus monkeys (Macaca mulatta) were equally and randomly divided among groups receiving 0, 5, 20, 40, or 80 mu g of Aroclor 1254/kg body weight/day during a 6-year toxicological-reproduction study. During the first 3 years of the study, 4 of the treated monkeys became moribund and were euthanized; 3 had endometriosis. This finding suggested a possible link between the PCB treatment and the occurrence of endometriosis. However, neither a laparoscopic examination of the control and high-dose monkeys nor the necropsy data provided evidence for a possible link between the PCB treatment and the observed incidence (37% (6/16) of controls; 25% (16/64) of treated monkeys and/or the severity of the endometrial lesions. Additional clinical and historical data not contained in previous reports are presented to facilitate independent evaluation of the relationship between PCB ingestion and endometriosis. We conclude that the incidence and severity of the endometriosis lesions observed in the rhesus monkeys utilized in this study did not have any relationship with the dosages of Aroclor 1254 they ingested.

Animals↗
PubMed1996

Cell surface marker evaluation of infant Macaca monkey leukocytes in peripheral whole blood using simultaneous dual-color immunophenotypic analysis.

Cross-reactivity between several commercially available mouse antihuman monoclonal antibodies (mAbs), conjugated to phycoerythrin (PE) and fluorescein isothiocyanate (FITC) fluorochromes, and peripheral blood leukocyte surface antigens, has been established in infant cynomolgus (Macaca fascicularis) monkeys using whole blood lysis, and two-color, PE and FITC flow cytometric analysis. With the exception of the CD8 marker, the bivariate dot-plot patterns for all other markers were similar in infant monkeys and in humans. For the CD8 marker, however, a CD8+CD2- population of cells was observed in the majority of monkeys tested (10 out of 12). The number of CD8+CD2- cells was higher (13%) in infant monkeys compared to the 3% reported for adult human blood. The mean percentage and absolute numbers for the cell surface markers identified with the human mAbs CD2 (FITC, Ortho, Paritan, NJ), CD4 (PE, B-D, Mountain View, CA), and CD8 (PE, B-D) when these were combined with a series of PE- or FITC-labelled human mAbs were similar across all combinations tested. Statistically significant differences were observed between male and female monkeys for the mean percentage levels of CD4 (females > males) and for the CD4/CD8 ratio (females > males). Such gender differences need to be taken into consideration when infant cynomolgus monkeys are used as models for chemical-induced immunotoxicity studies. Measurement of the interleukin-2 (IL-2) and transferrin proved to be useful in monitoring in vitro cellular activation in infant cynomolgus and possibly in rhesus (M. mulatta) monkeys.

Adult↗
PubMed1995

Harmonicity and anharmonicity in protein dynamics: a normal mode analysis and principal component analysis.

A comparison of a normal mode analysis and principal component analysis of a 200-ps molecular dynamics trajectory of bovine pancreatic trypsin inhibitor in vacuum has been made in order to further elucidate the harmonic and anharmonic aspects in the dynamics of proteins. An anharmonicity factor is defined which measures the degree of anharmonicity in the modes, be they principal modes or normal modes, and it is shown that the principal mode system naturally divides into anharmonic modes with peak frequencies below 80 cm-1, and harmonic modes with frequencies above this value. In general the larger the mean-square fluctuation of a principal mode, the greater the degree of anharmonicity in its motion. The anharmonic modes represent only 12% of the total number of variables, but account for 98% of the total mean-square fluctuation. The transitional nature of the anharmonic motion is demonstrated. The results strongly suggest that in a large subspace, the free energy surface, as probed by the simulation, is approximated by a multi-dimensional parabola which is just a rescaled version of the parabola corresponding to the harmonic approximation to the conformational energy surface at a single minimum. After 200 ps, the rescaling factor, termed the "normal mode rescaling factor," has apparently converged to a value whereby the mean-square fluctuation within the subspace is about twice that predicted by the normal mode analysis.

Animals↗
PubMed1995

Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 2. Reproduction and infant findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated within each room to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Commencing on test month 37, each female was paired with an untreated male until either an impregnation occurred or the 29-month breeding phase of the study was completed. The females continued to receive their daily test dose during mating and gestation. To preclude an infant ingesting the mother's dosing capsule, dosing of the dam was discontinued when a nursing infant was approximately 7 wk old. Treatment was restarted when the infant was weaned at 22 wk of age. At parturition, and every 4 wk until weaning, milk and blood samples were obtained from the dam and a blood sample was obtained from the infant for PCB analysis. When the infant was 20 wk old, immunological testing was initiated and an adipose sample was obtained from the infant and dam for PCB analysis. Subsequently, further adipose and blood samples were obtained from the infant and blood specimens were obtained from the dam for PCB analysis. Concurrently, each infant was subjected to anthropometric measurements and detailed clinical examinations until it was approximately 122 wk old. At 122 wk some of the control and all of the treated infants were killed humanely and autopsied. A statistical analysis of the reproduction data provided evidence for a significant decreasing dose-related trend in conception rates and a significant increasing dose-related trend in foetal mortality. Several comparisons between impregnated and non-impregnated females did not implicate 'age' as a confounding factor regarding these results. The major findings with the infants involved some immunological test differences and mild clinical manifestations of PCB ingestion.

Administration, Oral↗
PubMed1994

Harmonic and anharmonic aspects in the dynamics of BPTI: a normal mode analysis and principal component analysis.

A comparison is made between a 200-ps molecular dynamics simulation in vacuum and a normal mode analysis on the protein bovine pancreatic trypsin inhibitor (BPTI) in order to elucidate the dual aspects of harmonicity and anharmonicity in the dynamics of proteins. The molecular dynamics trajectory is analyzed using principal component analysis, an effective harmonic analysis suited for comparison with the results from the normal mode analysis. The results suggest that the first principal component shows qualitatively different behavior from higher principal components and is associated with apparent barrier crossing events on an anharmonic conformational energy surface. The higher principal components appear to have probability distributions that are well approximated by Gaussians, indicating harmonicity. Eliminating the contribution from the first principal component reveals a great deal of correspondence between the 2 methods. This correspondence, however, involves a factor of 2, as the variances of the distribution of the higher principal components are, on average, roughly twice those found from the normal mode analysis. A model is proposed to reconcile these results with those from previous analyses.

Aprotinin↗
PubMed1994

Comparison of normal mode analyses on a small globular protein in dihedral angle space and Cartesian coordinate space.

Normal mode analyses on the protein, bovine pancreatic trypsin inhibitor, in dihedral angle space and Cartesian coordinate space are compared. In Cartesian coordinate space it is found that modes of frequencies lower than 30 cm(-1) contribute 80% of the total mean-square fluctuation and are represented almost completely by motions in the dihedral angles. Bond angle and length fluctuations dominate in modes above 200 cm(-1), but contribute less than 2% to the total mean-square fluctuation. In the low-frequency modes a good correspondence between patterns of atomic displacements was found, but on average the root-mean-square fluctuations of the Cartesian coordinate modes are 13% greater than their dihedral angle counterparts. The main effect of fluctuations in the bond angles and lengths, therefore, is to allow the dihedral angles to become more flexible. As the important subspaces determined from the two methods overlap considerably, dihedral angle space analysis can be applied to proteins too large for Cartesian coordinate space analysis.

Journal Article↗
PubMed1993

Effect of solvent on collective motions in globular protein.

Two molecular dynamics simulations on bovine pancreatic trypsin inhibitor (BPTI), have been made, one in vacuum, the other in water, in order to assess the effect of the solvent water on collective motions. Principal component analysis has been performed to determine collective modes, the principal components, which are assumed to behave as effectively independent harmonic oscillators. Projection of the protein's motion in water onto the plane defined by the first two principal components shows a clustering effect in the trajectory, absent in the vacuum trajectory. This is thought to be due to many local minima in the free energy surface caused by solute-solvent interactions. In order to assess the viscous effect of the solvent, friction coefficients for the principal components were determined by analyzing their velocity correlation functions in terms of the Langevin equation for an independent damped oscillator. Consistent with this analysis is that all modes have friction coefficients centered on the value of 47 cm-1 in a range of +/- 10 cm-1. With this friction coefficient, all modes of effective frequencies below 23.5 cm-1 display overdamped motion. By assuming the harmonic approximation for the conformational energy surface for BPTI in vacuum to be valid for BPTI in water, and treating each mode as an independent damped oscillator with a friction coefficient of 47 cm-1, the shift to higher frequencies in the water spectrum relative to the vacuum spectrum could be almost exactly reproduced, indicating this shift is due solely to the viscous effect of the solvent. By analyzing the time correlation functions of the first four principal components it is found that they can be very well described as independent damped oscillators each with a friction coefficient of 47 cm-1.

Animals↗
PubMed1992

Limits on alpha-helix prediction with neural network models.

Using a backpropagation neural network model we have found a limit for secondary structure prediction from local sequence. By including only sequences from whole alpha-helix and non-alpha-helix structures in our training and test sets--sequences spanning boundaries between these two structures were excluded--it was possible to investigate directly the relationship between sequence and structure for alpha-helix. A group of non-alpha-helix sequences, that was disrupting overall prediction success, was indistinguishable to the network from alpha-helix sequences. These sequences were found to occur at regions adjacent to the termini of alpha-helices with statistical significance, suggesting that potentially longer alpha-helices are disrupted by global constraints. Some of these regions spanned more than 20 residues. On these whole structure sequences, 10 residues in length, a comparatively high prediction success of 78% with a correlation coefficient of 0.52 was achieved. In addition, the structure of the input space, the distribution of beta-sheet in this space, and the effect of segment length were also investigated.

Amino Acid Sequence↗
PubMed1992

More in sorrow than in anger: the British nurses' strike of 1988.

In early 1988 the nurses of Britain's National Health Service reached a peak of frustration. They took unprecedented industrial action to bring the state of nursing, and problems within the Health Service, to the attention of the nation. Throughout the crisis there was acrimonious debate between the Royal College of Nursing, which acts as both a professional association and a negotiating unit and opposed the strike, and the trade unions, which organized it. Their conflict undermined the nurses' solidarity and highlighted deep and complex tensions within the profession. On the day of action, labor withdrawal was widespread but inconsistent. In the end, the nurses made some gains, but most of their concerns were ignored. The government promoted the divisions between nursing unions; the media were critical of the nurses' actions; however, the labor movement supported them, and the British Medical Journal voiced the merits of the nurses' case. The struggle of the British nurses exemplifies issues and dilemmas facing nurses throughout the world. The increasing militancy of nurses in many countries reflects their dissatisfaction with pay, working conditions, and career opportunities. Many nurses are torn between the ideals of professionalism and the realities of their workplace and are ambivalent about the principles of collective bargaining. This article addresses these ambivalences and stresses the need to find creative solutions to match nurses' unique place in the political economy of health care.

Career Mobility↗
PubMed1991

Effects of PCB (Aroclor 1254) on non-specific immune parameters in rhesus (Macaca mulatta) monkeys.

The effects of low level, chronic polychlorinated biphenyl--Aroclor 1254--(PCB) exposure were investigated on non-specific immune parameters in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys were orally administered with PCB at concentrations of 0, 5, 20, 40 or 80 micrograms/kg bw/day. Immunotoxicity testing was initiated after 55 months of exposure. The serum hemolytic complement activity in all PCB treated groups was significantly higher (P less than 0.05) than that in the control group. A statistically significant dose-related increase in natural killer cell activity was evident at the 75:1 effector to target cell ratio. Similarly, a statistically significant dose-related increase was noted for thymosin alpha-1 levels but not for thymosin beta-4 levels. Statistically significant increased interferon levels were noted in the 20 and 80 micrograms/kg groups compared with the control group while the levels in the 40 micrograms/kg group were decreased significantly compared with the control group. The production of tumor necrosis factor by monocytes in the PCB treated groups was not different to that in the control group. The results indicated that long term exposure to PCB modulate several non-specific immune parameters.

Animals↗