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Biomedical subjects

A C Young

Publications and source records attributed to A C Young.

16 recordsLinked to original sources
PubMed1992

Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition.

To study the structure of a homogenous major histocompatibility complex (MHC) class I molecule containing a single bound peptide, a complex of recombinant mouse H-2Kb, beta 2-microglobulin (beta 2m), and a fragment of the vesicular stomatitis virus (VSV) nuclear capsid protein, VSV-(N52-59) octapeptide (Arg-Gly-Tyr-Val-Tyr-Gln-Gly-Leu), was prepared by exploiting a high-yield bacterial expression system and in vitro cocomplex formation. The structure of mouse H-2Kb revealed its similarity to three human class I HLA molecules, consistent with the high primary sequence homology and common function of these peptide-presenting molecules. Electron density was located in the peptide-binding groove, to which a single peptide in a unique conformation was unambiguously fit. The peptide extends the length of the groove, parallel to the alpha-helices, and assumes an extended, mostly beta-strand conformation. The peptide is constrained within the groove by hydrogen bonding of its main-chain atoms and by contacts of its side chains with the H-2Kb molecule. The amino-terminal nitrogen atom of the peptide forms a hydrogen bond with the hydroxyl group of Tyr-171 of H-2Kb at one end of the groove, while the carboxyl-terminal oxygen forms a hydrogen bond with the hydroxyl group of Tyr-84 at the other end. Since the amino acids at both ends are conserved among human and mouse MHC molecules, this anchoring of each end of the peptide appears to be a general feature of peptide-MHC class I molecule binding and imposes restrictions on its length. The side chains of residues Tyr-3, Tyr-5, and Leu-8 of the VSV octapeptide fit into the interior of the H-2Kb molecule with no appreciable surface exposure, a finding in support of previous biological studies that showed the importance of these residues for binding. Thus, the basis for binding of specific peptide sequences to the MHC class I molecule is the steric restriction imposed on the peptide side chains by the architecture of the floor and sides of the groove. The side chains of Arg-1, Val-4, and Gln-6 and the main-chain of Gly-7 of the octapeptide are exposed on the surface of the complex, thus confirming their availability for T-cell receptor contact, as previously demonstrated by T-cell recognition experiments.

Amino Acid Sequence↗
PubMed1990

Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

Amino Acid Sequence↗
PubMed1988

Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.

The human and rat genes for a fifth muscarinic receptor have been cloned and expressed in mammalian cells. The 532 amino acid human protein has 89% sequence identity to the 531 amino acid rat protein and is most closely related to the m3 receptor. Both proteins are encoded by single exons. The receptor has intermediate affinity for pirenzepine and low affinity for AF-DX 116, and it increases metabolism of phosphatidylinositol when stimulated with carbachol. Expression of mRNA has yet to be observed in brain or selected peripheral tissues, suggesting that either it is substantially less abundant than m1-m4 or its distribution is quite different.

Amino Acid Sequence↗
PubMed1987

Identification of a family of muscarinic acetylcholine receptor genes.

Complementary DNAs for three different muscarinic acetylcholine receptors were isolated from a rat cerebral cortex library, and the cloned receptors were expressed in mammalian cells. Analysis of human and rat genomic clones indicates that there are at least four functional muscarinic receptor genes and that these genes lack introns in the coding sequence. This gene family provides a new basis for evaluating the diversity of muscarinic mechanisms in the nervous system.

Amino Acid Sequence↗
PubMed1987

A cDNA encoding the precursor of the rat neuropeptide, neurokinin B.

We have isolated a cDNA clone from a rat cerebral cortex library which encodes the 116 amino acid precursor of the neuropeptide, neurokinin B. The precursor has 68% amino acid homology to the bovine precursor and encodes a single peptide of the tachykinin family. Except for possible small variations at both ends of the message, there appears to be only a single species of neurokinin B mRNA in rat cerebral cortex. In situ hybridization histochemistry indicates that the message is widely distributed in the rat brain in a pattern distinct from that of substance P message.

Amino Acid Sequence↗
PubMed1979

Measurements of the dead space volume.

The "anatomical" dead space is commonly measured by sampling an inert gas (N2) and volume in the exhalation following a large breath of oxygen (VD(F)). It may also be measured from an inert gas washout (VD(O)) that describes both volume and the delivery of VD(O) throughout the expiration. VD(O) is known to increase with age and is enlarged in some obstructive syndromes. VD(O) was appreciably larger than VD(F) in our normal subjects. Both measures increased with lung volume, the increase being entirely due to an increase in the volume of phase I. Physiological dead space (VD(p)) however, did not change significantly with lung volume, showing "alveolar" dead space to diminish as a result. An increase in VD(O) occurred with increasing respiratory frequency that was explained by the increase in volume of phase I. Although an increase in VD(F) occurred with frequency, this was significantly less than that seen by VD(O), i.e., VD(F) did not see the progressive increase in phase I volume with frequency. No lung volume or frequency changes, parasympatholytic or sympathomimetic drugs, or altered patterns of breathing simulated the late delivery of dead space seen in age and some obstructive syndromes.

Aging↗
PubMed1976

Cerebrospinal fluid immunoglobulin quotients, kappa/lambda ratios, and viral antibody titres in neurological disease.

A description has been given of cerebrospinal fluid (CSF) immunoglobulins in 355 patients with demyelinating, infectious, neuropathic, and other neurological disorders. An increase in the CSF IgG/albumin quotient was observed in 19/36 (53%) cases of definite multiple sclerosis (MS), in 13/47 (28%) cases of probable or possible MS, in 6/9 (67%) cases of proven herpes simplex viral encephalitis (HSVE), in 3/4 (75%) cases of neurosyphilis, in 1/1 case of subacute sclerosing panencephalitis (SSPE), in 2/9 )22%) cases of other central nervous system infections, and in 2/12 (17%) cases of polyneuritis when compared with a group of 236 patients having other neurological disorders. In constrast, a relative increase in the CSF IgA of IgM was seen only in some of the patients with central nervous system infections. It was also found that the quotient CSF/serum IgG, expressed as a percentage of the CSF/serum albumin, was better in distinguishing patients with definite or suspected MS from those with other neurological disorders than the quotients IgG/albumin or IgG/total protein. The CSF K/lambda ratio and the CSF and serum complement-fixing antibody titre to measles and herpes simplex virus were measured in many of the patients. In general, abnormalities of these measurements were associated with raised IgG/albumin quotients. However, in eight patients with definite or suspected MS, a normal IgG/albumin quotient was found with abnormal CSF K/lambda ratios (6 cases) or abnormal CSF titres of measles antibody (7 cases). In addition, two patients, with HSVE had normal IgG/albumin ratios but detectable herpes antibody in the CSF. These findings suggest that the measurement of the relative concentration of CSF immunoglobulin in combination with the K/lambda ratio and antibody titre to various viruses may supplement each other in the endeavour to detect central nervous system immunglobulin sysnthesis in neurological diseases.

Antibodies, Viral↗
PubMed1976

Mental change as an early feature of multiple sclerosis.

Five patients with mental change as a prominent and early feature of an illness which appeared to be multiple sclerosis are reported. All the patients had in addition clinical signs of predominant brain stem involvement and the cerebrospinal fluid findings were similar. It is emphasised that mental change may be an early feature of multiple sclerosis even in those patients in whom the onset of the disease is insidious.

Adult↗
PubMed1976

Terminal nitrogen rise.

Eighteen-breath nitrogen washouts were performed on eight subjects. Each washout could be simulated by a four-compartment model, each compartment with a different ventilation-to-volume ratio and a variable contribution to expiratory flow. In large breaths initiated near residual volume, a terminal nitrogen rise (TNR) was seen. To account for the TNR with this model, there were relatively small changes in flow from compartments with markedly different nitrogen concentration. Reasons are given for believing these compartments could not be the upper and lower lung. Three of these subjects were studied in the supine, seated, and head-down positions. The TNR was seen at the same lung volume in all positions. At routine bronchospirometry in a second group of subjects, sampling with small catheters during a nitrogen washout showed a TNR in the expirate of lungs, lobes, segments, and subsegments in the upright and supine positions. Apparently a large vertical hydrostatic gradient is unnecessary to produce a TNR. Finally, the TNR was shown to occur at that lung volume where transpulmonary pressure is very small and changing rapidly with volume. This TNR was often followed by a terminal nitrogen fall while the lung was continuing to empty. The TNR occurs when flow from a large poorly ventilated compartment increases relative to the flow from other compartments. A model of lung in which the poorly ventilated compartment develops high specific compliance at low lung volume explains these data.

Adult↗
PubMed1975

Postoperative management after thymectomy.

This paper reports a retrospective study of the preoperative and postoperative management of 28 patients who underwent thymectomy between 1956 and 1973. Patients who received postoperative artificial ventilation were compared with the group who did not with respect to sex, age, severity of disease, preoperative vital capacity, and thymic histology. Evidence is presented that postoperative artificial ventilation is required when the preoperative vital capacity with the patient on optimum anticholinesterase treatment is less than 2 litres. Additional features associated with a probable need for artificial ventilation were the presence of a thymoma, bulbar symptoms, especially dysphagia, and age over 50 years. These should be taken into account in any patient whose vital capacity is close to the critical level of 2 litres. When postoperative ventilation was required it was usually necessary for 12 days or more, and tracheostomy should therefore be done at or before thymectomy. Most patients in this series received the same dose of anticholinesterases after operation as before it and no evidence was found of a sudden decrease in requirements for anticholinesterase therapy. Two patients did not, and in them a myasthenic crisis was precipitated. We propose that the preoperative drug regimen can be continued in the immediate postthymectomy period, allowing selection of patients for tracheostomy and artificial ventilation primarily on the basis of the preoperative vital capacity.

Adolescent↗