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Biomedical subjects

J Ellis

Publications and source records attributed to J Ellis.

At least 199 records · Page 11Linked to original sources
PubMed1993

The regulation of human globin gene switching.

This paper describes the mechanism of regulation of the human beta-globin on the basis of a number of natural mutations and experiments in transgenic mice. From these data we conclude that this multigene locus is regulated at a number of different levels involving specific interactions between the Locus Control Region (LCR) and the individual genes. Most important is the action of stage specific transcription factors acting on sequences immediately flanking the genes. In addition, specificity is obtained through specific interaction of the genes with the LCR and through competition of the genes for interaction with the LCR.

Animals↗
PubMed1993

Synthetic human beta-globin 5'HS2 constructs function as locus control regions only in multicopy transgene concatamers.

Transgenes linked to the beta-globin locus control region (LCR) are transcribed in a copy-dependent manner that is independent of the integration site. It has previously been shown that the LCR 5'HS2 region does not require its NF-E2 dimer binding site for LCR activity. In this paper we analyse synthetic 5'HS2 core constructs containing point mutations in the other factor binding sites 3' of the NF-E2 dimer site. The results show that 5'HS2 core is a partially active LCR that functions in a concatamer of at least two copies but not when present as a single copy in transgenic mice and that no single binding site within 5'HS2 is required for position-independent expression. In addition, the H-BP factor is identical to upstream stimulatory factor (USF) and full enhancement levels by 5'HS2 core in MEL cells require a combination of all the factor binding sites. We suggest that 5'HS2 cores in a concatamer interact with each other to establish an area of open chromatin and that this process may be the basis of LCR function.

Animals↗
PubMed1993

Thalamic vacuolation in acute Wernicke's encephalopathy [corrected].

Two patients with acute Wernicke's encephalopathy, with the diagnosis confirmed pathologically at autopsy, showed substantial vacuolation and neuronal degeneration in discrete nuclei of the thalamus. Thalamic vacuolation has not been described previously in acute Wernicke's encephalopathy. The use of frozen sections to minimize processing artifact was fundamental in demonstrating this pathology. The pathogenic mechanism underlying this change appears to be different to that seen in the more typical periventricular, mamillary body and brainstem lesions. We hypothesize that a specific neural pathway may be involved and suggest that this pathway could be the ascending nitric oxide-containing cholinergic pathway from the brainstem.

Adult↗
PubMed1993

Structure/function relationships of muscarinic acetylcholine receptors.

The regions of muscarinic receptors that specify G-protein-coupling and ligand-binding have been defined in several recent studies. Overall, these studies have shown that amino acids within the third cytoplasmic loop of the receptors define their selectivity for different G-proteins, and that multiple, discontinuous epitopes contribute to their selectivities for different ligands. In fact, several competitive and allosteric antagonists can be classified into groups based on which of these epitopes contribute to their subtype selectivity. Site-directed mutagenesis, combined with covalent-labeling studies have suggested that ligands bind to a hydrophobic core of the receptors that is formed by multiple transmembrane (TM) domains. An aspartic acid located in TM3 is likely to bind to the ammonium headgroup of muscarinic ligands, and multiple hydroxyl-containing amino acids contribute to agonist but not antagonist binding. These data are discussed in the context of a computational model of a muscarinic receptor. Our model is based on a sequence alignment with bacteriorhodopsin, a seven TM protein for which a higher resolution structure is available. Most of the mutagenic data can be rationalized in the context of this model, and predict testable hypotheses concerning the mechanism by which ligands control the activity of muscarinic receptors.

Animals↗
PubMed1993

Muscarinic acetylcholine receptor subtypes: localization and structure/function.

Based on the sequence of the five cloned muscarinic receptor subtypes (m1-m5), subtype selective antibody and cDNA probes have been prepared. Use of these probes has demonstrated that each of the five subtypes has a markedly distinct distribution within the brain and among peripheral tissues. The distributions of these subtypes and their potential physiological roles are discussed. By use of molecular genetic manipulation of cloned muscarinic receptor cDNAs, the regions of muscarinic receptors that specify G-protein coupling and ligand binding have been defined in several recent studies. Overall, these studies have shown that amino acids within the third cytoplasmic loop of the receptors define their selectivities for different G-proteins and that multiple discontinuous epitopes contribute to their selectivities for different ligands. The residues that contribute to ligand binding and G-protein coupling are described, as well as the implied structures of these functional domains.

Animals↗
PubMed1993

Instability of the L6 gene for rust resistance in flax is correlated with the presence of a linked Ac element.

In a programme aimed at tagging rust-resistance genes in flax with the maize transposable element Ac, a primary transformant of a line called 'Forge' that is homozygous for four rust-resistance genes, L6, M, N and P2, was identified that possessed 10 copies of the Ac element, one of which was linked (29 map units) to L6. Descendants of this plant, which had from 8 to 15 copies of Ac, were crossed to a rust-susceptible line and the progeny screened for rust-susceptible mutants. When the Ac linked to L6 was present in the parent, a high frequency of L6 mutants was observed (29 mutants in 30,575). By contrast, when this Ac was absent, no such mutants were observed in 9258 progeny. The background frequency of L6 mutants was low (five in 124,088). A detailed analysis was made of the first 11 L6 mutants recovered from parents carrying the L6-linked Ac element. While none of the mutants possessed a tagged resistance gene, all lacked an RFLP marker closely linked to L6, suggesting that deletions were responsible for loss of the L6 specificity. In many of the mutants, one or more RFLP markers in the vicinity of the linked Ac were also absent. These findings suggest that the linked Ac may be inducing chromosome breakage.

Base Sequence↗
PubMed1993

Brainstem serotonergic neurons in chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

There are several lines of evidence to suggest that serotonergic neurons in the brain are detrimentally affected by chronic alcohol consumption. The present study aims to quantify pathological changes in brainstem regions containing serotonergic neurons in chronic alcoholics compared to age-matched non-alcoholic controls. An antibody specific for tryptophan hydroxylase was used to immunohistochemically demonstrate serotonergic neurons in serial sections of postmortem brainstem. The cases analyzed were divided into four groups on the basis of their clinical and pathological presentation; chronic alcoholics with Wernicke's encephalopathy, chronic alcoholics with additional Korsakoff's psychosis, non-alcoholic controls, and a single chronic alcoholic without neurological complications. There was an overall reduction in the number of serotonergic neurons in all alcoholic cases when compared with controls. All brainstem regions were affected, but the largest neuronal loss was found in areas of the medullary and caudal pontine reticular formation (reduced by 80-90%). Alcoholics with Korsakoff's psychosis did not differ in the amount or extent of pathology from the other alcoholic cases analyzed. The data indicate that significant numbers of serotonergic neurons degenerate in chronic alcoholics. Such a loss is likely to have significant clinical consequences.

Adult↗
PubMed1993

Cytogenetic studies in splenic lymphoma with villous lymphocytes.

We report the cytogenetic findings on 31 cases of splenic lymphoma with villous lymphocytes (SLVL). TPA stimulated cells from peripheral blood (28 cases), spleen (two cases) and lymph node (one case) with SLVL have been analysed. A clonal chromosome abnormality was found in 27/31 patients (87%); this was identified as a simple abnormality in 12 cases and a complex one in 15. Four recurring abnormalities were seen: t(11;14)(q13;q32) in five patients, deletions or translocations involving 7q in seven patients, iso 17q in four patients and translocations involving 2p11 in four patients. The high frequency of clonal chromosome abnormalities in SLVL contrasts with the usually benign clinical course of this disease. Abnormalities found frequently in patients with chronic lymphocytic leukaemia (CLL) such as trisomy 12 and deletions or translocations involving 13q14 were each seen in only one patient. No case had the t(14;18) characteristic of follicular lymphoma. Our findings demonstrate the high frequency of clonal and often complex chromosome abnormalities in SLVL. Although a unique chromosome rearrangement has not been identified, a pattern of four recurrent abnormalities has emerged. Our results suggest that SLVL is distinct on cytogenetic grounds from B-CLL and follicular lymphoma but shows similarity with mantle cell lymphoma, lymphoplasmacytic lymphoma and B-PLL.

Adult↗
PubMed1993

Analyzing the red-shift characteristics of azulenic, naphthyl, other ring-fused and retinyl pigment analogs of bacteriorhodopsin.

Prompted by the near infrared-absorbing properties of some of the azulenic bacteriorhodopsin (bR) analogs, we have analyzed their absorption characteristics along with 11 new related ring-fused analogs and the corresponding Schiff bases (SB) and protonated Schiff bases (PSB). The following three factors are believed to contribute to the total red shift of each of the pigment analogs (sigma RS): perturbation of the basic chromophore (SB shift, delta SB), protonation of the SB (PSB shift, PSBS) and protein perturbation (the opsin shift, OS). For each factor, effects of structural modifications were examined. For the red-shifted pigments, percent OS has been suggested as an alternate way of measuring protein perturbation. Computer-simulated chromophores provided evidence against any explanation involving altered shapes of the binding pocket as a major cause for absorption differences. Implications of the current bR results on preparation of further red-shifted bR and possible application to visual pigment analogs are discussed.

Absorption↗
PubMed1993

Use of chimeric muscarinic receptors to investigate epitopes involved in allosteric interactions.

All five (m1-m5) muscarinic receptors are sensitive to allosteric regulation, but gallamine is considerably more potent in slowing the dissociation of N-[3H]methylscopolamine (NMS) from the m2 subtype than from the m3 or m5 subtypes. To study the structural basis for the preference of gallamine for the m2 subtype, we evaluated [3H]NMS-gallamine interactions with chimeric receptors in which segments of the m5 receptor were systematically replaced with the corresponding m2 sequence. Substitutions that included the sixth transmembrane domain and third extracellular loop resulted in marked increases in the potency of gallamine, but substitutions that did not include these regions were without effect. A similar substitution was investigated using m2/m3 chimeric receptors, in which a segment extending from the middle of the sixth transmembrane domain to the carboxyl terminus was exchanged. As with the m2/m5 constructs, substitution of the m2 carboxyl-terminal segment into the m3 subtype significantly increased the potency of gallamine. Furthermore, the converse substitution reduced the potency of gallamine dramatically, to approximately that seen for the m3 subtype itself. It appears that this portion of the receptor is a critical determinant for the binding of gallamine and/or the allosteric interactions between gallamine and [3H]NMS.

Allosteric Site↗
PubMed1993

Formative evaluation: implementation of primary nursing.

Staff nurses initiated the change from a total patient care to a primary nursing delivery system. The effects of the change were measured on the following: nurses' perceptions of their work environment; communication and collaboration with other health care professionals; parent satisfaction and quality of care provided, and direct and indirect nursing activities. The measurements were taken prior to, six months and twelve months post implementation. Action was taken based on the findings of this evaluation process which enabled the facilitation of the change process.

Attitude of Health Personnel↗
PubMed1992

The locus coeruleus and memory: a study of chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

The loss of noradrenergic locus coeruleus neurons has been identified as the possible critical lesion inducing amnesia in alcoholic patients with the Wernicke-Korsakoff syndrome. The present study aims to test this hypothesis by quantifying the number of pigmented locus coeruleus neurons in 4 alcoholics with the Wernicke-Korsakoff syndrome, 5 alcoholics with Wernicke's encephalopathy alone but no amnesia, and 1 alcoholic and 5 age-matched controls with no neurological disorders. Apart from an increased vascularity in the locus coeruleus of alcoholics, no significant differences in the number, morphology or distribution of pigmented locus coeruleus neurons was noted between any of the groups analysed. There was a significant correlation between the number of locus coeruleus neurons and brain weight. These data demonstrate that neither alcohol neurotoxicity nor thiamine deficiency result in a reduction in the number of pigmented cells in the locus coeruleus and refute the hypothesis that locus coeruleus cell loss is critical for the amnesia in the Wernicke-Korsakoff syndrome.

Adult↗