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Biomedical subjects

A P Jackson

Publications and source records attributed to A P Jackson.

At least 19 recordsLinked to original sources
PubMed2000

Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21.

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

Abnormalities, Multiple↗
PubMed2000

beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics.

The voltage-sensitive sodium channel confers electrical excitability on neurons, a fundamental property required for higher processes including cognition. The ion-conducting alpha-subunit of the channel is regulated by two known auxiliary subunits, beta1 and beta2. We have identified rat and human forms of an additional subunit, beta3. It is most closely related to beta1 and is the product of a separate gene localized to human chromosome 11q23.3. When expressed in Xenopus oocytes, beta3 inactivates sodium channel opening more slowly than beta1 does. Structural modeling has identified an amino acid residue in the putative alpha-subunit binding site of beta3 that may play a role in this difference. The expression of beta3 within the central nervous system differs significantly from beta1. Our results strongly suggest that beta3 performs a distinct neurophysiological function.

Amino Acid Sequence↗
PubMed2000

Characterisation of the gene for Drosophila amphiphysin.

A sequence similarity search of the Drosophila nucleotide database using vertebrate amphiphysin as a query identified a cDNA that encodes a Drosophila amphiphysin. The predicted protein has conserved sequence domains that should enable it to dimerise and bind to dynamin. Structural modelling suggests that the Src-homology-3 (SH3) domains of vertebrate and Drosophila amphiphysins are highly similar, supporting the putative ability of the latter to bind dynamin. However, the fly amphiphysin shows less conservation to sequences in the vertebrate amphiphysins that bind other endocytic components such as clathrin, AP-2 and endophilin. Amphiphysin is a single-copy gene that maps to position 49B on polytene chromosomes. Messenger RNA of this amphiphysin is expressed widely during embryogenesis and has elevated expression in a number of sites including the foregut, hindgut and epidermis, but not in the central nervous system. Taken together, these data are consistent with a role for Drosophila amphiphysin in endocytosis, but the details of this role may differ from that of vertebrate amphiphysins.

Amino Acid Sequence↗
PubMed2000

Development of a risk assessment methodology for evaluating potential impacts associated with contaminated mud disposal in the marine environment.

In order to assess impacts associated with disposal of contaminated mud arising from Hong Kong's dredging and reclamation projects, a methodology has been formulated to determine the level of risk posed by consumption of seafood/marine prey species to humans and to the Chinese White Dolphin (Sousa chinensis). This methodology improves on previously used techniques by incorporating risks for organic contaminants, accounting for doses from sources other than seafood, and incorporating additional local knowledge on Sousa chinensis behaviour. It thus represents an advance in risk assessment techniques and a new integration of risk assessment and monitoring in environmental management.

Animals↗
PubMed2000

A gene for ataxic cerebral palsy maps to chromosome 9p12-q12.

Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.

Alleles↗
PubMed2000

A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.

Primary autosomal recessive microcephaly is a clinical diagnosis of exclusion in an individual with a head circumference >/=4 SDs below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebral cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical phenotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineous pedigree, using a whole-genome search, and have identified a third locus, MCPH3 at 9q34. The minimal critical region is approximately 12 cM, being defined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD score of 3.76 (recombination fraction 0) observed for the marker D9S290.

Chromosome Mapping↗
PubMed1999

A PC12 variant lacking regulated secretory organelles: aberrant protein targeting and evidence for a factor inhibiting neuroendocrine gene expression.

A variant of the PC12 pheochromocytoma cell line (termed A35C) has been isolated that lacks regulated secretory organelles and several constituent proteins. Northern and Southern blot analyses suggested a block at the transcriptional level. The proprotein-converting enzyme carboxypeptidase H was synthesised in the A35C cell line but was secreted by the constitutive pathway. Transient transfection of A35C cells with cDNAs encoding the regulated secretory proteins dopamine beta-hydroxylase and synaptotagmin I resulted in distinct patterns of mistargeting of these proteins. It is surprising that hybrid cells created by fusing normal PC12 cells with A35C cells exhibited the variant phenotype, suggesting that A35C cells express an inhibitory factor that represses neuroendocrine-specific gene expression.

Animals↗
PubMed1999

The effects of nonresident father involvement on single black mothers and their young children.

Using data from an ongoing study of current and former welfare recipients and their preschool children, the study discussed in this article examined the influence of the presence of nonresident fathers on the well-being and development of 188 low-income, employed and nonemployed single black mothers and their three- and four-year-old children. There is evidence that involvement by nonresident fathers has positive effects on maternal depression symptoms and child problem behaviors. The data show that maternal employment status seems to affect nonresident fathers' relations with single black mothers and their young children. It also seems to make a difference in the mothers' psychological well-being. Policy implications are discussed.

Adaptation, Psychological↗
PubMed1998

Dissection of hepatic receptor-mediated endocytic pathways using self-generated gradients of iodixanol (Optiprep).

Iodixanol is a new, nonionic, iodinated density gradient medium which has an advantage over other similar media in that it rapidly forms self-generated gradients in vertical or near-vertical rotors. Endocytosis of 99mTc-labeled neogalactosyl albumin (99mTc-NGA), a synthetic ligand for the asialoglycoprotein receptor, was studied by administering the ligand as a short pulse to perfused rat livers operating under single-pass conditions. Intracellular processing was arrested at various times after the pulse and the resultant homogenate cleared of nuclei and heavy mitochondria by centrifugation at 3000 g for 10 min. After adjustment to 12.5% (w/v) iodixanol, the 3000 g supernatants were centrifuged at 350,000 g for 60 min to form the gradients in which early, clathrin-containing vesicles, low-density endosomes, and lysosomes were well-resolved. 99mTc-NGA bound to the sinusoidal membrane could be partially resolved from clathrin-containing vesicles by inclusion of 1 mM CaCl2 in the homogenization and gradient buffers. Two populations of early clathrin-containing vesicles could be resolved by rate-zonal centrifugation in preformed iodixanol gradients. Thus, iodixanol is an excellent density gradient medium for the rapid and efficient resolution of endosome compartments.

Albumins↗
PubMed1998

The laryngeal mask airway as an aid to training in fibreoptic nasotracheal endoscopy.

We have investigated the extent to which the laryngeal mask airway, when used as an aid to fibreoptic nasotracheal video-endoscopy training, could reduce endoscopy apnoeic time in anaesthetised, paralysed oral surgery patients. Twenty anaesthetic trainees were randomly allocated to the laryngeal mask airway or control group. Laryngeal mask airway group endoscopies were performed in three stages following insertion of the laryngeal mask airway; stage 1: nasendoscopy, with the lungs ventilated automatically through the laryngeal mask airway; stage 2: removal of the laryngeal mask airway; stage 3: pharyngoscopy, larygoscopy and tracheoscopy. Control group endoscopies were performed conventionally, in one stage. Each trainee performed five nasotracheal intubations. Though total endoscopy time in the laryngeal mask airway group (stage 1 + stage 2 + stage 3 times) was significantly longer (average 136 s vs. 108 s), apnoeic time (stage 2 + stage 3 times) was significantly shorter (average 59 s vs. 108 s) than endoscopy time in the control group. This application of the laryngeal mask airway may have a useful role to play in ensuring patient safety during early fibreoptic training.

Adult↗
PubMed1998

Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter.

Primary (or "true") microcephaly is inherited as an autosomal recessive trait and is thought to be genetically heterogeneous. Using autozygosity mapping, we have identified a genetic locus (MCPH1) for primary microcephaly, at chromosome 8p22-pter, in two consanguineous families of Pakistani origin. Our results indicate that the gene lies within a 13-cM region between the markers D8S1824 and D8S1825 (maximum multipoint LOD score of 8.1 at D8S277). In addition, we have demonstrated the genetic heterogeneity of this condition by analyzing a total of nine consanguineous families with primary microcephaly.

Chromosome Mapping↗
PubMed1997

Crystal structure of the breakage-reunion domain of DNA gyrase.

DNA gyrase is a type II DNA topoisomerase from bacteria that introduces supercoils into DNA. It catalyses the breakage of a DNA duplex (the G segment), the passage of another segment (the T segment) through the break, and then the reunification of the break. This activity involves the opening and dosing of a series of molecular 'gates' which is coupled to ATP hydrolysis. Here we present the crystal structure of the 'breakage-reunion' domain of the gyrase at 2.8 A resolution. Comparison of the structure of this 59K (relative molecular mass, 59,000) domain with that of a 92K fragment of yeast topoisomerase II reveals a very different quaternary organization, and we propose that the two structures represent two principal conformations that participate in the enzymatic pathway. The gyrase structure reveals a new dimer contact with a grooved concave surface for binding the G segment and a cluster of conserved charged residues surrounding the active-site tyrosines. It also shows how breakage of the G segment can occur and, together with the topoisomerase II structure, suggests a pathway by which the T segment can be released through the second gate of the enzyme. Mutations that confer resistance to the quinolone antibacterial agents cluster at the new dimer interface, indicating how these drugs might interact with the gyrase-DNA complex.

Amino Acid Sequence↗
PubMed1997

Clathrin proteins and recognition memory.

Strong converging evidence indicates that the intermediate and medial part of the hyperstriatum ventrale (IMHV) of the chick forebrain is a site of recognition memory for the learning process of imprinting. Clathrin proteins have been implicated in synaptic plasticity. In the present study we demonstrate for the first time that they are involved in vertebrate learning. Chicks were trained by exposure to a conspicuous object and their preference for it versus a novel object subsequently measured as a preference score (an index of learning). Trained chicks with low preference scores were classed as "poor learners" and those with high preference scores as "good learners". An additional group of chicks was untrained ("dark-reared"). Tissue was removed from the left and right IMHV, hyperstriatum accessorium and posterior neostriatum 9.5 h or 24 h after training. Clathrin heavy chain and clathrin light chains a and b were assayed using sodium dodecyl sulphate polyacrylamide gel electrophoresis and immunoblotting. In the IMHV, and only for clathrin heavy chain, was there a significant effect of training. The effect occurred 24 h but not 9.5 h after training, and was significant only in the left IMHV. In this region at 24 h, there was (i) significantly more clathrin heavy chain in good learners than in dark-reared chicks, and (ii) a significant positive correlation between the amount of clathrin heavy chain and preference score; the amount of protein present in the dark-reared chicks did not differ significantly from the amount predicted from the regression line for trained chicks performing at chance (preference score 50). These findings imply that for the left IMHV, visual experience per se, locomotor activity and other side effects of training did not affect the amount of clathrin heavy chain. Rather, the increase observed was a function of the amounts chick learned and, because it was delayed, is likely to be involved in long-term memory. The results for clathrin heavy chain taken together suggest that enhanced presynaptic events in the IMHV, possibly associated with an increase in synaptic vesicle release/uptake, are important in the recognition memory underlying imprinting.

Animals↗
PubMed1997

Effects of concerns about child care among single, employed black mothers with preschool children.

This study investigated whether differences in child care arrangements and mothers' attitudes about leaving their child in nonmaternal care were associated with maternal psychological well-being and perceptions of children in a sample of single, employed, low-income, Black mothers who were former welfare recipients. Feelings of discomfort with regard to nonmaternal care were associated with higher levels of maternal depressive symptomatology, which, in turn, predicted more negative perceptions of children. Preference for employment and increased working hours were associated with greater life satisfaction. Maternal education and the gender of the child were important moderating variables. Type of child care arrangement was nonsignificant. Policy implications are discussed.

Adult↗
PubMed1997

Alpha-adaptin, a marker for endocytosis, is expressed in complex patterns during Drosophila development.

A Drosophila cDNA encoding a structural homologue of the mammalian coated vesicle component alpha-adaptin (AP2 adaptor complex) has been cloned and sequenced. The mammalian and invertebrate sequences are highly conserved, especially within the amino terminal region, a domain that mediates interactions with other components within the AP2 complex and with specific receptors tails. Mammalian alpha-adaptins are encoded by two genes; however, Drosophila alpha-adaptin has a single gene locus, within polytene bands 21C2-C3 on the left arm of the chromosome 2, closely adjacent to the paired homeobox gene aristaless. There seem to be at least two Drosophila alpha-adaptin transcripts expressed, plausibly by alternative splicing. One of the transcripts is more abundant during early embryogenesis and may be of maternal origin. We have studied the distribution of the alpha-adaptin protein throughout embryogenesis and at the neuromuscular junction of the third instar larva. During cellularization of the blastoderm embryo, the protein is seen between and ahead of the elongating nuclei, and then redistributes to the cell surface during gastrulation. These observations suggest a role for endocytosis in cellularization and are consistent with the finding that dynamin (the shibire gene product), another component of the endocytic mechanism, is required for cellularization. At later stages of embryogenesis, alpha-adaptin is expressed in complex and dynamic patterns. It is strongly induced in elements of the central and peripheral nervous system (e.g., in neuroblasts, the presumptive stomatogastric nervous system, and the lateral chordotonal sense organs), in the Garland cells, the adult midgut precursors, the antenno-maxillary complex, the endoderm, the fat bodies, and the visceral mesoderm. In the larva, alpha-adaptin is localized at the plasma membrane in the synaptic boutons of the neuromuscular junctions. The cells expressing high levels of alpha-adaptin are known or expected to support high levels of endocytosis; thus, this coated vesicle protein seems to be an excellent marker for endocytic activity. The expression patterns of dynamin, detected in the embryo by in situ hybridization methods, are very similar to those reported here for alpha-adaptin reflecting the likely coordinated expression of endocytic components. Taken together with previous evidence, our results suggest that endosomal vesicle trafficking, membrane recycling, and the regulation of endocytosis play critical roles in the wide range of developmental processes.

Adaptor Protein Complex 2↗
PubMed1997

Learning curves for fibreoptic nasotracheal intubation when using the endoscopic video camera.

We have followed the progress of 12 anaesthetic trainees as they learnt how to perform fibreoptic nasotracheal intubation with the aid of an endoscopic video camera system. Each trainee had a structured teaching session on a bronchial tree model, viewed an instructional videotape and then performed 20 nasotracheal intubations on anaesthetised oral surgery patients. Trainees were required to perform the endoscopies under full visual control and to demonstrate airway anatomy as they advanced the fibrescope. They were allowed up to two 2 1/2 min periods to complete nasotracheal endoscopy. All 240 endoscopies were completed within the time limit: 228 were completed within 2 1/2 min and 12 (5%) were completed during the second 2 1/2 min period. We constructed a group learning curve from the pooled data. The half-life of the curve was nine endoscopies. The best fit value for the first endoscopy time was 132s, and after the 18th (two half-lives) it was 49 s. We analysed the theoretical basis for deriving a learning curve from raw data. This information could form a rational basis for the design of fibreoptic training programmes using video imaging systems.

Adolescent↗
PubMed1996

Inhibition of hsc70-catalysed clathrin uncoating by HSJ1 proteins.

The uncoating of clathrin-coated vesicles can be mediated in vitro by the 'uncoating ATPase' that has been identified as the constitutive 70 kDa heat shock protein (hsp70), hsc70. It is now established that the activity of hsp70 proteins can be regulated by another family of molecular chaperones, the DnaJ family. In this study, we have investigated the effects of DnaJ-like proteins (the human neuron-specific proteins HSJ1a and HSJ1b) on clathrin uncoating. In order to measure the kinetics of clathrin release from coated vesicles, we have developed a quantitative, two-site ELISA for clathrin triskelions and demonstrated that stoichiometric amounts of HSJ1 proteins inhibit the initial burst of hsc70-mediated clathrin uncoating by over 40%. This inhibition is not a consequence of ADP binding by hsc70 or the aggregation of hsc70, but correlates with an increase in the hsc70 associated with the coated vesicle fraction, suggesting that the inhibition is a consequence of a non-productive stabilization of hsc70 with a component of the coated vesicle fraction. These results strongly suggest that HSJ1 proteins interfere with an endogenous DnaJ-like protein that is involved in uncoating. Recent evidence suggests that the brain-specific vesicle-associated protein auxilin could play such a role. Although we find no evidence for auxilin in our coated vesicle preparation, our results predict that an auxilin-like protein will be a general factor in clathrin uncoating.

Adaptor Proteins, Vesicular Transport↗