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Biomedical subjects

N Ferguson

Publications and source records attributed to N Ferguson.

At least 19 recordsLinked to original sources
PubMed2004

Safety of Mycoplasma gallisepticum vaccine strain 6/85 after backpassage in turkeys.

The objective of this research was to evaluate the safety of the 6/85 strain vaccine strain of Mycoplasma gallisepticum in turkeys by backpassing the vaccine strain up to 10 times by contact infection in turkeys and challenging turkeys with the resulting backpassaged strain. The vaccine strain, however, did not spread to in-contact turkeys, and it was necessary to reisolate the organism before challenging turkeys for the next passage. The challenge strain, therefore, was one that had been backpassaged four times in turkeys, with a total in vivo time in turkeys of 66 days. The backpassaged 6/85 vaccine strain was no different in pathogenicity than the original vaccine strain, except that at 10 days postchallenge, it was isolated in higher numbers from air sacs. Both the original 6/85 vaccine strain and the backpassaged strain were apathogenic in turkeys, except for a slightly increased diameter of the tracheal mucosa at 10 days postchallenge; at 20 days postchallenge the tracheal mucosal thickness was no different from that of controls.

Air Sacs↗
PubMed2003

Intellectual prognosis of the Dandy-Walker malformation in children: the importance of vermian lobulation.

Half of patients with the Dandy-Walker malformation (DWM) have normal intellectual development. We aimed to identify feature on MRI associated with good intellectual prognosis. We reviewed 20 patients with DWM diagnosed on MRI, mean age 14.6+/-9.9 years. We assessed their intellectual development and related it to the MRI features. We found two groups with a statistically different intellectual outcome. All 14 patients with normal intellectual development had a normal lobulation of the vermis, without supratentorial anomalies. Of the six patients with mental retardation, three had an abnormal vermis, together with dysgenesis of the corpus callosum. In the other three, there were normal vermian anatomy with associated anomalies. Normal lobulation of the vermis, in the absence of any supratentorial anomaly, appears to be a good prognostic factor in DWM. Preservation of cerebrocerebellar pathways and neonatal plasticity could explain the normal intellectual development. These findings might be useful in prenatal diagnosis.

Adolescent↗
PubMed2001

Ultrafast folding of WW domains without structured aromatic clusters in the denatured state.

Ultrafast-folding proteins are important for combining experiment and simulation to give complete descriptions of folding pathways. The WW domain family comprises small proteins with a three-stranded antiparallel beta-sheet topology. Previous studies on the 57-residue YAP 65 WW domain indicate the presence of residual structure in the chemically denatured state. Here we analyze three minimal core WW domains of 38-44 residues. There was little spectroscopic or thermodynamic evidence for residual structure in either their chemically or thermally denatured states. Folding and unfolding kinetics, studied by using rapid temperature-jump and continuous-flow techniques, show that each domain folds and unfolds very rapidly in a two-state transition through a highly compact transition state. Folding half-times were as short as 17 micros at 25 degrees C, within an order of magnitude of the predicted maximal rate of loop formation. The small size and topological simplicity of these domains, in conjunction with their very rapid two-state folding, may allow us to reduce the difference in time scale between experiment and theoretical simulation.

Amino Acid Sequence↗
PubMed2001

Using flexible loop mimetics to extend phi-value analysis to secondary structure interactions.

Chemical synthesis allows the incorporation of nonnatural amino acids into proteins that may provide previously untried probes of their folding pathway and thermodynamic stability. We have used a flexible thioether linker as a loop mimetic in the human yes kinase-associated protein (YAP 65) WW domain, a three-stranded, 44-residue, beta-sheet protein. This linkage avoids problems of incorporating sequences that constrain loops to the extent that they significantly change the nature of the denatured state with concomitant effects on the folding kinetics. An NMR solution structure shows that the thioether linker had little effect on the global fold of the domain, although the loop is apparently more dynamic. The thioether variants are destabilized by up to 1.4 kcal/mol (1 cal = 4.18 J). Preliminary Phi-value analysis showed that the first loop is highly structured in the folding transition state, and the second loop is essentially unstructured. These data are consistent with results from simulated unfolding and detailed protein-engineering studies of structurally homologous WW domains. Previously, Phi-value analysis was limited to studying side-chain interactions. The linkers used here extend the protein engineering method directly to secondary-structure interactions.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Using chimeric immunity proteins to explore the energy landscape for alpha-helical protein folding.

To address the role of sequence in the folding of homologous proteins, the folding and unfolding kinetics of the all-helical bacterial immunity proteins Im2 and Im9 were characterised, together with six chimeric derivatives of these proteins. We show that both Im2 and Im9 fold rapidly (k(UN)(H(2)O)) approximately 2000 s(-1) at pH 7.0, 25 degrees C) in apparent two-state transitions, through rate-limiting transition states that are highly compact (beta(TS)0.93 and 0.96, respectively). Whilst the folding and unfolding properties of three of the chimeras (Im2 (1-44)(Im9), Im2 (1-64)(Im9 )and Im2 (25-44)(Im9)) are similar to their parental counterparts, in other chimeric proteins the introduced sequence variation results in altered kinetic behaviour. At low urea concentrations, Im2 (1-29)(Im9) and Im2 (56-64)(Im9) fold in two-state transitions via transition states that are significantly less compact (beta(TS) approximately 0.7) than those characterised for the other immunity proteins presented here. At higher urea concentrations, however, the rate-limiting transition state for these two chimeras switches or moves to a more compact species (beta(TS) approximately 0.9). Surprisingly, Im2 (30-64)(Im9) populates a highly collapsed species (beta(I)=0.87) in the dead-time (2.5 ms) of stopped flow measurements. These data indicate that whilst topology may place significant constraints on the folding process, specific inter-residue interactions, revealed here through multiple sequence changes, can modulate the ruggedness of the folding energy landscape.

Amino Acid Sequence↗
PubMed2000

Children's conceptions of characteristic features of category members.

The authors investigated children's conceptions of the characteristic features of category members and found that their conceptions underwent qualitative developmental changes. They hypothesized that (a) children initially tend to perceive category members in terms of individual characteristics (i.e., internal dispositions and behavioral patterns) and (b) only later do they conceive of category members in terms of their shared beliefs and values. They explored these hypotheses in 2 studies: In Study 1, they investigated how Protestant and Catholic children in Northern Ireland understood the religious intergroup context in their own country; in Study 2, children in Italy were presented with a fictional scenario of intergroup conflict and asked to explain the causes of the conflict. The results of both studies confirmed the 2 hypotheses.

Child↗
PubMed1999

Rapid folding with and without populated intermediates in the homologous four-helix proteins Im7 and Im9.

The kinetics and thermodynamics of the folding of the homologous four-helix proteins Im7 and Im9 have been characterised at pH 7.0 and 10 degrees C. These proteins are 60 % identical in sequence and have the same three-dimensional structure, yet appear to fold by different kinetic mechanisms. The logarithm of the folding and unfolding rates of Im9 change linearly as a function of urea concentration and fit well to an equation describing a two-state mechanism (with a folding rate of 1500 s-1, an unfolding rate of 0. 01 s-1, and a highly compact transition state that has approximately 95 % of the native surface area buried). By contrast, there is clear evidence for the population of an intermediate during the refolding of Im7, as indicated by a change in the urea dependence of the folding rate and the presence of a significant burst phase amplitude in the refolding kinetics. Under stabilising conditions (0.25 M Na2SO4, pH 7.0 and 10 degrees C) the folding of Im9 remains two-state, whilst under similar conditions (0.4 M Na2SO4, pH 7.0 and 10 degrees C) the intermediate populated during Im7 refolding is significantly stabilised (KUI=125). Equilibrium denaturation experiments, under the conditions used in the kinetic measurements, show that Im7 is significantly less stable than Im9 (DeltaDeltaG 9.3 kJ/mol) and the DeltaG and m values determined accord with those obtained from the fit to the kinetic data. The results show, therefore, that the population of an intermediate in the refolding of the immunity protein structure is defined by the precise amino acid sequence rather than the global stability of the protein. We discuss the possibility that the intermediate of Im7 is populated due to differences in helix propensity in Im7 and Im9 and the relevance of these data to the folding of helical proteins in general.

Amino Acid Sequence↗
PubMed1999

The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens.

Cross-reactive antibodies produced by a mammalian host during infection by a particular microparasitic strain usually have the effect of reducing the probability of the host being infected by a different, but closely related, pathogen strain. Such cross-reactive immunological responses thereby induce between-strain competition within the pathogen population. However, in some cases such as dengue virus, evidence suggests that cross-reactive antibodies act to enhance rather than restrict the severity of a subsequent infection by another strain. This cooperative mechanism is thought to explain why pre-existing immunity to dengue virus is an important risk factor for the development of severe disease (i.e., dengue shock syndrome and dengue hemorrhagic fever). In this paper, we explore the effect of antibody-dependent enhancement on the transmission dynamics of multistrain pathogen populations. We show that enhancement frequently may generate complex and persistent cyclical or chaotic epidemic behavior. Furthermore, enhancement acts to permit the coexistence of all strains where in its absence only one or a subset would persist.

Animals↗
PubMed1999

Structural and mechanistic basis of immunity toward endonuclease colicins.

The crystal structure of the cytotoxic endonuclease domain from the bacterial toxin colicin E9 in complex with its cognate immunity protein Im9 reveals that the inhibitor does not bind at the active site, the core of which comprises the HNH motif found in intron-encoded homing endonucleases, but rather at an adjacent position leaving the active site exposed yet unable to bind DNA because of steric and electrostatic clashes with incoming substrate. Although its mode of action is unorthodox, Im9 is a remarkably effective inhibitor since it folds within milliseconds and then associates with its target endonuclease at the rate of diffusion to form an inactive complex with sub-femtomolar binding affinity. This hyperefficient mechanism of inhibition could be well suited to other toxic enzyme systems, particularly where the substrate is a polymer extending beyond the boundaries of the active site.

Amino Acid Sequence↗
PubMed1998

Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents.

The effects of selection by host immune responses on transmission dynamics was analyzed in a broad class of antigenically diverse pathogens. Strong selection can cause pathogen populations to stably segregate into discrete strains with nonoverlapping antigenic repertoires. However, over a wide range of intermediate levels of selection, strain structure is unstable, varying in a manner that is either cyclical or chaotic. These results have implications for the interpretation of longitudinal epidemiological data on strain or serotype abundance, design of surveillance strategies, and the assessment of multivalent vaccine trials.

Alleles↗
PubMed1996

Multiplicity of fibronectin-binding alpha V integrin receptors in colorectal cancer.

Current data from in vitro and in vivo animal models indicate that fibronectin-binding integrin receptors expressed by colon cancer cells may regulate tumour growth. While individual members of the beta 1 subfamily of integrins have now been clearly identified in colorectal cancer, little information exists with respect to the alpha V subfamily. In the present study we show that alpha V can associate with multiple and different beta subunits capable of binding fibronectin in this tumour type. This is likely to have functional implications for growth and spread of colorectal cancer.

Antigens, CD↗
PubMed1992

Sexuality in a natural population of bacteria--Bacillus subtilis challenges the clonal paradigm.

Reproduction by binary fission necessarily establishes a clonal genotypic structure in bacterial populations unless a high rate of genetic recombination opposes it. Several genetic properties were examined for a wild population of Bacillus subtilis in the Sonoran Desert of Arizona to assess the extent of recombination in a natural population. These properties included allozyme variation revealed by multilocus enzyme electrophoresis, phage and antibiotic resistance, and restriction fragment length polymorphism with Southern hybridization. Evidence of extensive genetic recombination was found along with evidence of modest clonal structure. Recombination must be frequent relative to binary fission in this population. This mixed population structure provides broader options for bacterial evolution than would a purely clonal structure.

Bacillus subtilis↗
PubMed1991

Autopsies in an area health service: a quality assurance review.

The Hunter Area Health Service Quality Liaison Group reviewed autopsy practice in the Hunter Area, focussing upon clinical and resource utilisation effectiveness. Findings are discussed. Conclusions support views expressed in recent literature on the subject. The conclusion is reached that despite increase in consumption of limited resources, autopsies remain an integral component of quality care and should increase in number. Some recommendations are proffered to maximise utility and cost effectiveness in the future.

Australia↗
PubMed1975

Pictographs and prereading skills.

This paper draws upon data collected in conjunction with the Schools Council (Great Britain) Research and Development Project in Compensatory Education to demonstrate that a picture reading task can provide a fairly good prediction of the later reading performance of 100 5-year-olds and that it is a sufficiently interesting clinical tool to merit further consideration from nursery and infant school teachers. The test's success seems to relate to its ability to measure differences in children's understanding of the nature and purpose of reading.

Child Development↗