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Biomedical subjects

D Doherty

Publications and source records attributed to D Doherty.

At least 37 records · Page 2Linked to original sources
PubMed1997

The Drosophila neurogenic gene big brain, which encodes a membrane-associated protein, acts cell autonomously and can act synergistically with Notch and Delta.

In the developing nervous system of Drosophila, cells in each proneural cluster choose between neural and epidermal cell fates. The neurogenic genes mediate the cell-cell communication process whereby one cell adopts the neural cell fate and prevents other cells in the cluster from becoming neural. In the absence of neurogenic gene function, most, if not all of the cells become neural. big brain is a neurogenic gene that encodes a protein with sequence similarity to known channel proteins. It is unique among the neurogenic genes in that previous genetic studies have not revealed any interaction between big brain and the other neurogenic genes. Furthermore, the neural hypertrophy in big brain mutant embryos is less severe than that in embryos mutant for other neurogenic genes. In this paper, we show by antibody staining that bib is expressed in tissues that give rise to neural precursors and in other tissues that are affected by loss of neurogenic gene function. By immunoelectron microscopy, we found that bib is associated with the plasma membrane and concentrated in apical adherens junctions as well as in small cytoplasmic vesicles. Using mosaic analysis in the adult, we demonstrate that big brain activity is required autonomously in epidermal precursors to prevent neural development. Finally, we demonstrate that ectopically expressed big brain acts synergistically with ectopically expressed Delta and Notch, providing the first evidence that big brain may function by augmenting the activity of the Delta-Notch pathway. These results are consistent with bib acting as a channel protein in proneural cluster cells that adopt the epidermal cell fate, and serving a necessary function in the response of these cells to the lateral inhibition signal.

Amino Acid Sequence↗
PubMed1996

Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation.

Wing margin formation in Drosophila requires the Notch receptor and, in the dorsal compartment, one of its ligands, Serrate. We provide evidence that Delta, the other known ligand for Notch, is also essential for this process. Delta is required in ventral cells at the dorsal/ventral compartment boundary, where its expression is specifically elevated in second-instar wing discs during wing margin formation. Moreover, ectopic Delta expression induces wingless, vestigial, and cut and causes adult wing tissue outgrowth in the dorsal compartment. The effect is mediated by Notch, because loss of Notch activity suppresses Delta-induced ectopic wing outgrowth. Whereas ectopic expression of Notch or the truncated activated Notch induces cut in both dorsal and ventral compartments, ectopic Delta expression induces cut only in the dorsal compartment and ectopic Serrate induces cut only in the ventral compartment. These observations indicate that Notch-expressing cells in a given compartment have different responses to Delta and Serrate. We propose that Delta and Serrate function as compartment-specific signals in the wing disc, to activate Notch and induce downstream genes required for wing formation.

Animals↗
PubMed1996

A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis.

HLA molecules associated with rheumatoid arthritis (RA) contain a discrete structural element known as the shared epitope, a set of conserved amino acid residues located on the alpha helical portion of the class II beta chain. Each of the different HLA molecules associated with RA contain the same shared epitope sequence, although they may vary markedly in other regions of the class II structure, which also determine peptide-class II interactions. Previous mutagenesis studies and structural modelling indicate that key polymorphic amino acid side chains within the shared epitope sequence are in locations likely to contact the T cell receptor (TCR) during the trimolecular activation reaction between the HLA-peptide complex and TCR. We have evaluated the potential structural basis for such shared epitope recognition by analysing detailed molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor from T cell clone EM025, specific for HLA-DR4 molecules which carry the shared epitope. A likely orientation for the trimolecular complex was deduced in which the EM025 alpha chain interacts with the DR alpha chain and the EM025 beta chain interacts with the DR beta chain; residues Q70 and R71 within the DR beta chain shared epitope region are positioned for hydrogen bond interactions directly with Q97 of the TCR beta CDR3 region, D30 of the TCR beta CDR1 region, and possibly N51 of the TCR beta CDR2 region, indicating a degree of specific selection and interaction which encompasses multiple TCR contacts. These findings suggest a structural basis for the genetic associations with the HLA shared epitope and the potential contribution of this region to oligoclonal T cell selection and expansion in RA.

Arthritis, Rheumatoid↗
PubMed1994

The molecular genetics of autoimmune liver disease.

The dual observations that human leukocyte antigens have an antigen-binding groove and that the polymorphism we study as human leukocyte antigen types is largely related to amino acid substitutions in and around that groove have provided a new focus for immunogenetic studies. In autoimmune liver disease, recent studies have described specific amino acid substitutions in the antigen-binding groove of human leukocyte antigen DR molecules that may determine both disease susceptibility, through their direct influence on antigen binding, and the severity of the disease. In autoimmune hepatitis, lysine residues at DR beta position 71 in European subjects and arginine or histidine residues at DR beta position 13 in Japanese subjects may be responsible for much human leukocyte antigen-encoded disease susceptibility. Similar claims have been made for leucine residues at DR beta 38 in primary sclerosing cholangitis and for leucine residues at DP beta 35 in Japanese patients with primary biliary cirrhosis. To date, our knowledge of genetic susceptibility to autoimmune liver disease is incomplete. Other genes may contribute to susceptibility to autoimmune liver disease--for example the contribution of TAP genes, upstream promoter sequences and class III genes on chromosome 6 and the T-cell receptor genes and complement genes elsewhere in the human genome is currently unclear. Additional information concerning the immunogenetic contribution to disease severity is needed to complete the picture.

Autoimmune Diseases↗
PubMed1994

Influence of callosal activity on units in the auditory cortex of ferret (Mustela putorius).

1. Callosal neurons in primary auditory cortex project heavily to regions of the contralateral homotopic field that are excited by stimulation of one or both ears and minimally to regions that are excited by stimulation of one ear and inhibited by stimulation of the other ear. The intent of this study is to begin assessing the function of this extensive intercortical projection in determining the response properties of single units in the recipient auditory cortex. 2. Callosal neurons in the right auditory cortex of barbiturate-anesthetized ferrets were stimulated electrically through a pair of monopolar microelectrodes that were separated by 2-3 mm and whose uninsulated tips were located 500 microns below the pial surface. Electrical stimuli consisted of a single 100-microseconds pulse delivered at a fixed intensity and temporal relationship to the onset of each of a set of monaural or binaural acoustic stimuli. Pulse amplitude was almost always < 350 microA. Acoustic stimuli consisted of 100-ms best-frequency tones delivered monaurally or binaurally at 1-s intervals. The influence exerted by electrical stimulation of the right auditory cortex on responses of single units isolated in the left auditory cortex was assessed by comparing responses evoked by the same acoustic stimuli delivered alone and when accompanied by the electrical stimulation. In addition, the latencies of discharges evoked by the electrical stimuli delivered alone were assessed. Three categories of influence were observed: suppression, excitation, and a mixed class consisting of both suppression and excitation. 3. Suppression was the most commonly observed influence of callosal input on acoustically evoked responses. Depending on the strength of the acoustic stimuli and electrical pulse and the temporal relationship between the two kinds of stimulation, responses to acoustic stimuli could be completely suppressed or reduced to a smaller version of the control responses. The duration of the inhibitory influence was often > 100 ms and the suppression was frequently effective at latencies of 2-4 ms. 4. Although unit activity was commonly excited by electrical stimulation of the right auditory cortex, facilitation of acoustically evoked responses was infrequently observed. Apparent facilitation usually was the result of the summation of acoustically and electrically evoked discharges.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Influence of human leukocyte antigen matching on liver allograft survival and rejection: "the dualistic effect".

To date only one published large series of human leukocyte antigen matching and liver allograft survival exists, and considerable confusion has arisen about the advantage or disadvantage of human leukocyte antigen matching. In the present study we have reinvestigated the relationship between human leukocyte antigen mismatch and graft survival in 466 first liver allografts, seeking to clarify the relationship between human leukocyte antigen and both acute rejection and the vanishing bile duct syndrome. In view of current criticism regarding the accuracy of serological tissue typing for human leukocyte antigen-DR, we have used both classic serology and restriction fragment length polymorphism analysis to ensure the accurate assignment of recipient DR types. In addition, we have used polymerase chain reaction amplification and allele-specific and sequence-specific oligonucleotide probes to retest the hypothesis that human leukocyte antigen class II matching may increase susceptibility to the vanishing bile duct syndrome. One-year graft survival was significantly lower in patients with zero or two human leukocyte antigen-A mismatches (52% and 63%, respectively) than in those with one human leukocyte antigen--A mismatch (69%) (p = 0.016 and p = 0.018). A similar effect of B mismatching was observed, with a 1-yr graft survival of 73% for those with one compared with 60% for those with two human leukocyte antigen-B mismatches. In contrast no correlation was found between DR mismatch and graft survival. Human leukocyte antigen class I matching appears to influence graft survival largely through the occurrence of acute rejection and the development of the vanishing bile duct syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Graft Rejection↗
PubMed1992

Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype.

In studies to date seeking associations between human leukocyte antigens (HLA) and primary biliary cirrhosis, no class I association but several different class II associations have been described. The aims of this study were to reassess the DR associations in primary biliary cirrhosis and to examine for the first time the role of DQB. DRB genotypes were determined on standard Taq1 restriction-fragment-length polymorphism analysis in 159 white northern European patients with the disease and 162 racially matched local controls. Polymerase chain reaction gene amplification and sequence-specific oligonucleotide analysis were used to determine DQB genotypes in 89 patients and 181 controls. An increased frequency of human leukocyte antigen DR8 was observed in the patient group (11% vs 4%; relative risk = 3.3; p < 0.01). Although we saw an increased frequency of the DQB1*0402 allele (11% vs. 3%; relative risk = 3.5; p < 0.025), this was not significant after correction for multiple testing. The strongest association was with the two-locus haplotype DR8-DQB1*0402 (11% vs. 2.2%; relative risk 5.5; p < 0.001). The DRB data reported here confirm the findings of previous studies, although the described association with DR8 is considerably weaker. The weak genetic contribution of human leukocyte antigen in the susceptibility to primary biliary cirrhosis is in contrast to its role in other autoimmune liver diseases.

Adult↗
PubMed1988

Rhizobium meliloti mutants that overproduce the R. meliloti acidic calcofluor-binding exopolysaccharide.

The acidic Calcofluor-binding exopolysaccharide of Rhizobium meliloti Rm1021 plays one or more critical roles in nodule invasion and possibly in nodule development. Two loci, exoR and exoS, that affect the regulation of synthesis of this exopolysaccharide were identified by screening for derivatives of strain Rm1021 that formed mucoid colonies that fluoresced extremely brightly under UV light when grown on medium containing Calcofluor. The exopolysaccharide produced in large quantities by the exoR95::Tn5 and exoS96::Tn5 strains was indistinguishable from that produced by the parental strain Rm1021, and its synthesis required the function of at least the exoA, exoB, and exoF genes. Both the exoR and exoS loci were located on the chromosome, and the exo96::Tn5 mutation was 84% linked to the trp-33 mutation by phi M12 transduction. Synthesis of the Calcofluor-binding exopolysaccharide by strain Rm1021 was greatly stimulated by starvation for ammonia. In contrast, the exoR95::Tn5 mutant produced high levels of exopolysaccharide regardless of the presence or absence of ammonia in the medium. The exoS96::Tn5 mutant produced elevated amounts of exopolysaccharide in the presence of ammonia, but higher amounts were observed after starvation for ammonia. The presence of either mutation increased the level of expression of exoF::TnphoA and exoP::TnphoA fusions (TnphoA is Tn5 IS50L::phoA). Analyses of results obtained when alfalfa seedlings were inoculated with the exoR95::Tn5 strain indicated that the mutant strain could not invade nodules. However, pseudorevertants that retained the original exoR95::Tn5 mutation but acquired unlinked suppressors so that they produced an approximately normal amount of exopolysaccharide were able to invade nodules and fix nitrogens. The exoS95::Tn5 strain formed Fix+ nodules, although some minor variability was observed.

Benzenesulfonates↗
PubMed1977

Toxicity kinetics and clinical potential of subarachnoid lymphocyte infusions.

The feasibility of intrathecal lymphocyte infusions was examined since patients with gliomas are known to have circulating, tumor-specific, cytotoxic lymphocytes. Human (xenogenic) and syngenic lymphocytes were infused intrathecally into rabbits, and the toxicity and kinetics of the infused cells evaluated. Cerebrospinal fluid cell counts rose to as high as 70,000 lymphocytes/cu mm 12 hours after infusion and then dropped logarithmically over several days. No infiltration of host cells into the subarachnoid space in response to the lymphocyte infusions was detected. Evidence is presented that intrathecally infused lymphocytes may escape into the systemic circulation. Toxicity was minimal, especially following syngenic intrathecal lymphocyte infusions. A systemic allergic response, characterized by choroid plexitis and pulmonary edema was noted following a second xenogenic but not after a second or even a third syngenic lymphocyte infusion.

Animals↗
PubMedDate not supplied

Efficacy of fibrinolysis in the emergency department for acute myocardial infarction.

BACKGROUND: Patients with an acute myocardial infarction require a rapid response to their symptoms and the earlier fibrinolysis is given (where indicated), the better the outcome. AIMS: The aim of this study is to compare 'door to needle times' for fibrinolysis in Acute Myocardial Infarction (AMI) in three phases of one year each, at Letterkenny General Hospital. METHODS: In the PREINTERVENTION year all fibrinolysis was performed in the Coronary Care Unit (CCU). In the INTERVENTION year Emergency Department (ED) fast track fibrinolysis was introduced and in the POST INTERVENTION year most fibrinolysis was performed on fast track in the ED. RESULTS: The time saved by the introduction of ED fibrinolysis was significant, 41 minutes on average per patient. Elderly, female patients were more likely to bypass ED fast track fibrinolysis and to be brought to CCU for fibrinolysis, with attendant delays. This has educational implications in relation to the variation in clinical presentation of AMI with age and sex. CONCLUSION: The ED fast track fibrinolysis system is recommended as an effective, safe, achievable and worthwhile intervention towards improving 'door to needle times' for fibrinolysis in AMI.

Acute Disease↗