Peek-a-boo fragile sites? Not really.
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Chromosome Fragile Sites↗
Biomedical subjects
G R Sutherland
Publications and source records attributed to G R Sutherland.
Cloning of the cDNA and localization of the gene encoding human NRBP, a ubiquitously expressed, multidomain putative adapter protein.
Adapter proteins modulate multiple signaling pathways by regulating the aggregation of other factors into signaling complexes. Here we have identified a novel human cDNA encoding NRBP, a multidomain putative adapter protein containing (i) two putative nuclear receptor binding motifs (LXXLL), (ii) a putative binding domain for Src homology-2 (SH2) domain containing proteins, (iii) a kinase-like domain, (iv) a bipartite nuclear localization signal, and (v) three sequences rich in glutamic acid, serine, proline, and threonine (PEST) residues. The NRBP mRNA transcript, of approximately 2.4 kb, was ubiquitously expressed in a wide range of normal human tissues and 15 human tumor cell lines. The NRBP cDNA is predicted to encode a polypeptide of 535 amino acids with a molecular mass of 59.8 kDa. Translation of NRBP mRNA in vitro reveals three translation products of 60, 51, and 43 kDa, suggesting that translation of NRBP may initiate at multiple sites. The NRBP gene was localized to human chromosome 2p23, near the location of the NCOA1 gene encoding the nuclear receptor coactivator, steroid receptor coactivator-1 (SRC-1). The features of NRBP predict a function as an adapter protein potentially linking signaling pathways involving nuclear receptors and SH2 domain containing proteins.
3' Untranslated Regions↗
Molecular cloning and characterisation of GPR74 a novel G-protein coupled receptor closest related to the Y-receptor family.
A novel gene product, GPR74, with homology to the seven transmembrane-domain receptor superfamily, has been cloned. GPR74 has been identified from the expressed sequence tags (EST) database. Subsequent PCR amplification of that sequence and screening of a human heart cDNA library led to the isolation of a 1.7-kb cDNA clone encoding a protein of 408 amino acids. GPR74 shows highest amino acid identity (33%) to the human neuropeptide Y-receptor subtype Y2. The human and mouse genes for GPR74 have been isolated and their exon-intron structures determined. In both species the gene consists of four exons spanning around 20 kb with the exon-intron borders being 100% conserved. Northern analysis of various human tissues reveals highest levels of mRNA expression in brain and heart. In situ hybridisation analysis of rat brain tissue confirms this result and identifies the hippocampus and amygdala nuclei as the brain areas with particular high expression of GPR74 mRNA. Fluorescence in situ hybridisation, PCR analysis on a radiation hybrid panel and interspecific mouse backcross mapping have localised the genes to human chromosome 4q21 and mouse chromosome 5. Expression of the human GPR74 cDNA as a GFP-fusion protein in various cell lines reveals the inability of the recombinant receptor protein to reach the cell surface. This is consistent with the lack of NPY specific binding in these cells and suggests that unknown factors are required for a full functional receptor complex.
Amino Acid Sequence↗
Y-receptor-like genes GPR72 and GPR73: molecular cloning, genomic organisation and assignment to human chromosome 11q21.1 and 2p14 and mouse chromosome 9 and 6.
Two novel G-protein-coupled receptors, one from human, GPR72, and one from mouse, GPR73 have been isolated, sequenced and their genomic organisation determined. Non-isotopic in situ hybridisation and radiation hybrid mapping have identified GPR72 to be localised on human chromosome 11q21.1, and GPR73 on human chromosome 2p14. Interspecific mouse backcross mapping has localised the genes to mouse chromosomes 9 and 6, respectively. Northern analysis reveals GPR72 mRNA expression only in brain tissue. However, GPR73 mRNA can be found in heart, skeletal muscle and pancreas. Both receptors are closely related with 36 and 33% overall amino acid identity, respectively, to the Y-receptor family. However, although successful cell surface expression in a heterologous expression system can be achieved no specific binding to this ligand family can be detected, indicating that perhaps additional factors are required for binding.
Animals↗
Maintenance of tricarboxylic acid cycle kinetics in Brown-Norway Fischer 344 rats may translate to longevity.
Glucose metabolism and tricarboxylic acid cycle (TCA) kinetics have been shown to decline in brain with age in various animal species. This study examined TCA cycle kinetics and age in Brown-Norway Fischer 344 rats. Using [1-(13)C]glucose infused over 10, 30, 60 or 100 min, and following the label through the TCA cycle using (1)H¿(13)C¿ spin-echo difference magnetic resonance spectroscopy, groups of 2 (n=18), 12 (n=16), and 24 (n=16) month old rats were evaluated. Unexpectedly, TCA cycle kinetics did not change with age. Observed decreases in glutamate, glutamine and N-acetyl aspartate levels are consistent with an age-related decrease in neuronal numbers. The possible link between this observation and increased longevity, together with a decreased incidence of neoplasia in the Brown-Norway Fischer 344 rat is discussed.
Aging↗
The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat.
The purpose of the study was to evaluate the effect of delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, on ischemic neuronal injury. A 12-min ischemic insult was induced by a reduction in systolic blood pressure to a mean of 50 mm Hg, followed by bilateral carotid artery occlusion at a middle ear temperature of 37.5 degrees C. THC at either a low (0.1 mg/kg; n=8) or high (10 mg/kg; n=8) dose was injected i.p. every 12 h for 7 days prior to ischemia. Non-treated ischemic (n=8) animals formed the control group. The animals were sacrificed 3 weeks post-ischemia for quantitative histopathology. THC at either dose did not significantly reduce ischemic neuronal damage in the hippocampus. The high dose THC-treated group showed significantly less neocortical injury, compared to either the control or low-dose THC groups (p<0.05). The striatum was markedly protected by both low and high dose THC (p<0.001). This regionally specific protection implies that either the hippocampus undergoes suprathreshold ischemic injury or that mechanisms of ischemic injury vary in different brain regions.
Animals↗
Fragile sites and minisatellite repeat instability.
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Amino Acid Sequence↗
Memory trace reactivation in hippocampal and neocortical neuronal ensembles.
During active behavior, patterns of hippocampal and neocortical neuronal activity reflect ongoing inputs and their contexts. Recent neurophysiological investigations have shown that during 'off-line' periods, traces of these experiences are spontaneously reactivated in both structures. Although the functional importance of this phenomenon remains to be demonstrated, it does provide clues about the nature and mechanisms of memory retrieval and consolidation.
Animals↗
The clinical significance of fragile sites on human chromosomes.
Fragile X syndrome is now a well established common clinical entity and most of those who are aware of the condition probably know that it takes its name from a rare fragile site (FRAXA) on the X chromosome. This is the best known fragile site and its clinical significance is clear. Similar, but a little less known is FRAXE, a fragile site close to that associated with fragile X syndrome, but in this case associated with a mild form of non-specific X-linked mental retardation. These are the only two fragile sites that are unequivocally of clinical significance. A fragile site within the CBL2 oncogene on chromosome 11 has been mapped very close to the deletion breakpoint in a handful of patients with Jacobsen syndrome. It is doubtful that parents with FRA11B are at increased risk of having children with Jacobsen syndrome, but this cannot be ruled out. The common fragile sites have been implicated in oncogenesis since shortly after their discovery in the early 1980s. While a couple of these are within genes that have been implicated in cancer it is unclear whether either the fragile sites, or the genes in which they are located are important in cancer. It may be that the common fragile sites are regions of genomic instability and that this instability is increased in malignant cells, analogous to the enhanced instability seen at microsatellite loci in a number of tumours. Since we all have the common fragile sites there is no suggestion that they give anyone an increased risk of developing malignant disease. In dealing with patients who are found to have fragile sites, other than FRAXA, FRAXE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites.
Chromosome Aberrations↗
Fc alpha/mu receptor mediates endocytosis of IgM-coated microbes.
IgM is the first antibody to be produced in a humoral immune response and plays an important role in the primary stages of immunity. Here we describe a mouse Fc receptor, designated Fc alpha/microR, and its human homolog, that bind both IgM and IgA with intermediate or high affinity. Fc alpha/microR is constitutively expressed on the majority of B lymphocytes and macrophages. Cross-linking Fc alpha/microR expressed on a pro-B cell line Ba/F3 transfectant with soluble IgM or IgM-coated microparticles induced internalization of the receptor. Fc alpha/microR also mediated primary B lymphocyte endocytosis of IgM-coated Staphylococcus aureus. Thus, Fc alpha/microR is involved in the primary stages of the immune response to microbes.
Amino Acid Sequence↗
Psychiatric epigenetics: a new focus for the new century.
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Animals↗
Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8.
Dipeptidyl peptidase (DPP) IV has roles in T-cell costimulation, chemokine biology, type-II diabetes and tumor biology. Fibroblast activation protein (FAP) has been implicated in tumor growth and cirrhosis. Here we describe DPP8, a novel human postproline dipeptidyl aminopeptidase that is homologous to DPPIV and FAP. Northern-blot hybridization showed that the tissue expression of DPP8 mRNA is ubiquitous, similar to that of DPPIV. The DPP8 gene was localized to chromosome 15q22, distinct from a closely related gene at 19p13.3 which we named DPP9. The full-length DPP8 cDNA codes for an 882-amino-acid protein that has about 27% identity and 51% similarity to DPPIV and FAP, but no transmembrane domain and no N-linked or O-linked glycosylation. Western blots and confocal microscopy of transfected COS-7 cells showed DPP8 to be a 100-kDa monomeric protein expressed in the cytoplasm. Purified recombinant DPP8 hydrolyzed the DPPIV substrates Ala-Pro, Arg-Pro and Gly-Pro. Thus recombinant DPP8 shares a postproline dipeptidyl aminopeptidase activity with DPPIV and FAP. DPP8 enzyme activity had a neutral pH optimum consistent with it being nonlysosomal. The similarities between DPP8 and DPPIV in tissue expression pattern and substrates suggests a potential role for DPP8 in T-cell activation and immune function.
Amino Acid Sequence↗
A comparison of regional myocardial velocity information derived by pulsed and color Doppler techniques: an in vitro and in vivo study.
The objective was to compare velocity information derived from either a tissue mimicking phantom or normal contracting myocardium by both pulsed wave and color Doppler myocardial imaging (PWDMI and CDMI). Both CDMI and PWDMI allow quantitative assessment of regional myocardial contraction and relaxation velocities, but their potential clinical applications have not yet been investigated. Moreover, no information is available as to whether they can be used interchangeably for regional velocity assessment. For the in vitro study, a rotating, circular-shaped, tissue-mimicking sponge driven by a motor at speeds of 15, 30, 60, 90 rpm was used to derive velocity data from the same eight points of interest by using PWDMI or CDMI techniques. For the in vivo study, 25 normal subjects were examined at rest using parasternal and apical approaches. Velocity profiles were derived from the same 26 areas of interest (18 left ventricular segments, 3 right ventricular segments, and 5 measurement points for the tricuspid and mitral annuli) for each technique. Peak maximal velocities were detected by PWDMI and peak mean velocities were measured using CDMI. The results of the in vitro study phantom showed excellent correlation (r = 0.99, P < 0. 001) and satisfactory agreement (0.04 cm/sec; 3.3 cm/sec) between both Doppler techniques. PWDMI velocities were higher than CDMI velocities by up to 20% and overestimated the real velocity value (0. 37 +/- 0.29 cm/sec) while CDMI underestimated predicted velocity by 1.35 +/- 0.36 cm/sec. Good correlation (r = 0.87, P < 0.001), but poor agreement (-2.1 cm/sec; 5.4 cm/sec) was shown in vivo for all segments with regard to peak systolic and diastolic velocities. Both Doppler techniques cannot be used interchangeably for comparing peak velocities in the clinical situation. However, with adequate temporal resolution, they can be used interchangeably for velocity profile recording and for timing of events.
Adolescent↗
The Grüntzig Lecture. Regional myocardial function — a new approach.
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Blood Flow Velocity↗
High frame rate myocardial integrated backscatter. Does this change our understanding of this acoustic parameter?
AIMS: Integrated backscatter (IB) and its cyclic variation (CV) derived from radio-frequency (RF) data have been used as parameters to attempt myocardial tissue characterization. Prior imaging systems used to measure IB and its CV typically acquired data at frame rates of 20-30 Hz and at a resolution of 6-8 bits. If changes in IB levels are in part related to specific short-lived events, occurring within the cardiac cycle, this frame rate and resolution could have been too low to resolve adequately what might be a more complex data set. METHODS AND RESULTS: To investigate this possibility, we acquired real time two-dimensional (2D) myocardial IQ data (the 'in-phase quadrature' sampled RF data) at high frame rate (> 100 Hz), high dynamic resolution (theoretical 19-bit) and a sector angle of 20 degrees. Several consecutive heart cycles of myocardial data were acquired from individual cardiac walls in five closed chest dogs and 10 healthy, young volunteers at normal heart rates. On the reconstructed RF data regions of interest were indicated, and IB and its CV were calculated. The extracted high frame rate curves showed that the CV of IB is not a smooth sinusoidal-like curve, but is made up of multiple reproducible peaks and troughs with local minima and maxima which are temporally related to active or passive mechanical events, i.e. systolic contraction, early ventricular relaxation and ventricular filling due to atrial contraction. CONCLUSIONS: This study shows that increasing the rate of real-time RF data acquisition results in a more complex, reproducible IB curve. The resolved maxima and minima in IB levels are related to specific phases of the myocardial contraction. Furthermore, spectral analysis showed that IB curves acquired at normal heart rates contain information up to 40 Hz. Hence, cardiac imaging data sets used to analyse regional myocardial function obtained at frequencies lower than 80 frames per second can contain aliased information.
Adult↗
Pulsed doppler myocardial imaging. A new approach to regional longitudinal function?
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Blood Flow Velocity↗
The effect of pacing-induced heart rate variation on longitudinal and circumferential regional myocardial function after acute beta-blockade--a cardiac ultrasound study.
AIMS: To evaluate the effect of acute beta-blockade in combination with differing heart rates on longitudinal and circumferential regional myocardial function using Doppler myocardial imaging and two-dimensional-echocardiography. METHODS AND RESULTS: In seven pigs the following echocardiographic indices were measured at baseline, after beta-blockade both without and with atrial pacing: wall thickening fraction, fractional shortening, myocardial peak systolic velocity, transmyocardial velocity gradient and systolic velocity time integral of the posterolateral wall in short-axis view; mitral valve plane excursion, myocardial peak systolic velocity and systolic velocity time integral of the posterolateral wall in an apical five-chamber view. Peak systolic velocities and velocity gradients decreased significantly following acute beta-blockade but no further decay occurred at high heart rate due to pacing. The velocity time integrals and mitral valve plane excursion showed a tendency to decrease following beta-blockade but only after pacing were they significantly reduced. The wall thickening fraction and fractional shortening showed a significant reduction after beta-blockade but no further decay after pacing. CONCLUSION: Changes in systolic velocities and velocity gradients were independent of heart rate reduction under high dosage beta-blockade, whereas wall thickening fraction, mitral valve plane excursion and velocity time integrals changed due to pacing.
Adrenergic beta-Antagonists↗
Regional strain and strain rate measurements by cardiac ultrasound: principles, implementation and limitations.
The non-invasive quantification of regional myocardial function is an important goal in clinical cardiology. Myocardial thickening/thinning indices is one method of attempting to define regional myocardial function. A new ultrasonic method of quantifying regional deformation has been introduced based on the principles of 'strain' and 'strain rate' imaging. These new imaging modes introduce concepts derived from mechanical engineering which most echocardiographers are not familiar with. In order to maximally exploit these new techniques, an understanding of what they measure is indispensable. This paper will define each of these modalities in terms of physical principles and will give an introduction to the principles of data acquisition and processing required to implement ultrasonic strain and strain rate imaging. In addition, the current status of development of the technique and its limitations will be discussed, together with examples of potential clinical applications.
Biomedical Engineering↗