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Biomedical subjects

M Fox

Publications and source records attributed to M Fox.

At least 73 records · Page 4Linked to original sources
PubMed1996

Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain.

Proteolytic cleavage of beta-amyloid precursor protein (beta APP) by alpha-secretase results in release of one secreted form (sAPP) of APP (sAPP alpha), whereas cleavage by beta-secretase releases a C-terminally truncated sAPP (sAPP beta) plus amyloid beta-peptide (A beta). beta APP mutations linked to some inherited forms of Alzheimer's disease may alter its processing such that levels of sAPP alpha are reduced and levels of sAPP beta increased. sAPP alpha s may play important roles in neuronal plasticity and survival, whereas A beta can be neurotoxic. sAPP alpha was approximately 100-fold more potent than sAPP beta in protecting hippocampal neurons against excitotoxicity, A beta toxicity, and glucose deprivation. Whole-cell patch clamp and calcium imaging analyses showed that sAPP beta was less effective than sAPP alpha in suppressing synaptic activity, activating K+ channels, and attenuating calcium responses to glutamate. Using various truncated sAPP alpha and sAPP beta APP695 products generated by eukaryotic and prokaryotic expression systems, and synthetic sAPP peptides, the activity of sAPP alpha was localized to amino acids 591-612 at the C-terminus. Heparinases greatly reduced the actions of sAPP alpha s, indicating a role for a heparin-binding domain at the C-terminus of sAPP alpha in receptor activation. These findings indicate that alternative processing of beta APP has profound effects on the bioactivity of the resultant sAPP products and suggest that reduced levels of sAPP alpha could contribute to neuronal degeneration in Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27.

We have cloned the human gene encoding the transcription factor T. T protein is vital for the formation of posterior mesoderm and axial development in all vertebrates. Brachyury mutant mice, which lack T protein, die in utero with abnormal notochord, posterior somites, and allantois. We have identified human T genomic clones and derived the mRNA sequence and gene structure. There is 91% amino acid identity between human and mouse T proteins overall and complete identity across 77 amino acids of the T-box motif within the DNA-binding domain. Human T expression is very similar to that found for T in other vertebrate species and is confined to cells derived from the notochord. The human T gene maps to chromosome 6q27 and is only the second human member of the T-box gene family to be described.

Amino Acid Sequence↗
PubMed1995

A novel human phosphoglucomutase (PGM5) maps to the centromeric region of chromosome 9.

The phosphoglucomutases (PGM1-3) in humans are encoded by three genes, PGM1, PGM2, and PGM3. These enzymes are central to carbohydrate metabolism. All three isozymes show genetic variation, and PGM1 has achieved prominence as a key marker in genetic linkage mapping and in forensic science. The human PGM genes are assumed to have arisen by gene duplication since their products are broadly similar in structure and function; however, direct proof of their evolutionary relationship is not available because only PGM1 has been cloned. During a search for other members of the PGM family, a novel sequence with homology to PGM1 was identified. Mapping using fluorescence in situ hybridization and somatic cell hybrids locates this gene to the centromeric region of chromosome 9. RT-PCR and Northern analysis indicate that this is an expressed PGM gene with widespread distribution in adult and fetal tissues. We propose that this gene be designated PGM5 and that it represents a novel member of the PGM family.

Adult↗
PubMed1995

The effects of anaemia on heart, placenta and body weight, and blood pressure in fetal and neonatal rats.

1. Reports that maternal anaemia in pregnancy is associated with a greater placental: birth weight ratio, which predisposes towards high postnatal blood pressure in the human, led us to examine the effects of maternal anaemia during pregnancy on placental size, fetal and neonatal growth, and blood pressure development in the rat. 2. Nutritional anaemia was induced in female rats prior to mating and maintained throughout pregnancy and up until weaning of the pups. Fetuses were studied at 20 days of gestation (E20). Pups were studied on postnatal days 20 (P20) and 40 (P40), having been weaned onto normal rat chow at 21 days. 3. In the anaemic group placental: fetal body weight ratios were lower compared with controls. Body weights at all ages were lower in the anaemic group than in controls, despite a greater rate of growth in the anaemic group between P20 and P40. 4. At P20 heart weights of the anaemic group were almost twice that of controls, suggesting an alteration in their cardiovascular development. However, paradoxically, the systolic blood pressure of the anaemic group was lower than that of controls. 5. By P40 the systolic blood pressure of the anaemic group (136 +/- 3 mmHg) had increased and was greater than that in control pups (126 +/- 3 mmHg). 6. In conclusion, we have shown that there is a pronounced postnatal rise in systolic blood pressure associated with maternal anaemia during pregnancy, which is not related to a greater placental: birth weight ratio. Before weaning, anaemic pups have a lower systolic blood pressure than controls and there is an important association between the rate of postnatal growth and blood pressure.

Anemia↗
PubMed1995

Characterization of a mucin cDNA clone isolated from HT-29 mucus-secreting cells. The 3' end of MUC5AC?

HT-29 cells resistant to 10(-6) M methotrexate (HT29-MTX) secrete mucins with gastric immunoreactivity (Lesuffleur, T., Barbat, A., Dussaulx, E., and Zweibaum, A. (1990) Cancer Res. 50, 6334-6343). A 3310-base pair mucin cDNA clone (L31) was isolated from an HT29-MTX expression library using a polyclonal serum specific for normal gastric mucosa. It shows a high level of identity (98.6%) to clone NP3a isolated from a nasal polyp cDNA library (Meerzaman, D., Charles, P., Daskal, E., Polymeropoulos, M. H., Martin, B. M., and Rose, M. C. (1994) J. Biol. Chem. 269, 12932-12939). However, as a result of changes in reading frame, the 1042-amino acid deduced peptide contains four regions of a low similarity to the NP3a peptide. The amino acid sequence shows 36.3% similarity to part of the carboxyl-terminal sequence of MUC2 including the so-called D4 domain and 21.3% to the pro von Willebrand factor. A short amino acid sequence is similar to cysteine-rich sequences repeated in tracheobronchial, gastric, and colonic mucin cDNAs. The gene corresponding to L31 is located in the mucin gene cluster on chromosome 11p15.5. The patterns of mRNA expression were indistinguishable from those revealed with the JER58 probe (MUC5AC). Southern blot analysis indicates that the L31 and JER 58 sequences are within 20 kilobase pairs of each other. Together, these results suggest that L31 clone is the 3' end of MUC5AC.

Adult↗
PubMed1995

A radiation hybrid panel for human chromosome 6q.

A panel of 63 radiation-reduced hybrids has been derived from a mouse cell line containing a neo-marked human Chromosome (Chr) 6, primarily to provide a resource for higher resolution localization of new markers. Hybrids were generated with radiation doses of 40-400 Gy, selected in G418, and were shown by PCR to contain the neo gene. PCR was also used to score the retention of 15 loci that map from 6q13 to q25.2 of the current consensus map, plus six other loci assigned to 6q26-q27. An average retention frequency of 27.8% was observed, with the highest frequencies at D6S313 and D6S280 (63.5%) located near the centromere at 6q13, and at D6S283 (68.5%) at 6q16.3-q21, presumably close to the neo integration site. Lowest frequencies (4.8%) were observed for telomeric markers. All markers segregated independently except D6S297 and D6S193. Agreement and some improvement to the current consensus map of 6q was made by mapping 12 loci by the non-parametric statistical method of Falk. In addition, deletion mapping with informative hybrids allowed the ordering of six loci from 6q26 to q27 and permitted some integration of maps of this region.

Animals↗
PubMed1995

Gene expression in response to retinoic acid in novel human chromosome 21 monochromosomal cell hybrids.

To access a wide a variety of expressed sequence from human chromosome 21 we have placed this chromosome into undifferentiated P19 mouse embryonic carcinoma cells. Cell lines resulting from these experiments have a range of morphologies and a wide variety of karyotypes. We have studied the retinoic acid response of five cell lines, compared to P19 cells, by observing three markers of retinoic acid induced P19 differentiation--cell morphology, RAR alpha and Wnt1 transcription. We see an 'early' retinoic acid response effect, however this response breaks down by the time the 'late' gene. Wnt1 would be transcribed in P19 cells. A highly responsive cell line will be useful for cloning expressed sequences from human chromosome 21 which are produced by early genes in retinoic acid inducible pathways, such as those involved in neurogenesis.

Animals↗
PubMed1995

Correlation of loss of heterozygosity with cytogenetic analysis using G-banding and fluorescence in situ hybridization in aneuploid cultures from two human testicular germ-cell tumors.

A detailed karyotype analysis using fluorescence in situ hybridization (FISH), with 24 chromosome-specific paint probes has been carried out on newly established cell lines from two testicular tumors, an i(12p)-positive teratoma, and an i(12p)-negative combined seminoma/teratoma. This has been correlated with loss of heterozygosity (LOH) and allelic imbalance, using DNA RFLP analysis to clarify the genetic changes and to identify any common regions of deletion or rearrangement. With G-banding alone, a total of 11 breakpoints were recognized. After FISH, the position of seven required revision, and 21 new ones were identified. The chromosomes involved most frequently in both tumors were numbers 1, 12, and 18. Breakpoints in 11q and 16q were also seen in both, and seven or more copies of 12p per cell were found in all clones. LOH was found for 18q in both tumors, and overall was much more frequent in underrepresented regions (one or two copies). On the whole, there was good agreement between the cytogenetic and DNA RFLP data; loci showing allelic imbalance generally had an odd number of copies of the chromosome region in which they were known to be located. Combined data on the chromosome 1 translocations in both tumors suggested that rearrangements were more complicated than cytogenetics alone had predicted.

Alleles↗
PubMed1995

Chemotherapeutic tumour targeting using clostridial spores.

The toxicity associated with conventional cancer chemotherapy is primarily due to a lack of specificity for tumour cells. In contrast, intravenously injected clostridial spores exhibit a remarkable specificity for tumours. This is because, following their administration, clostridial spores become exclusively localised to, and germinate in, the hypoxic/necrotic tissue of tumours. This unique property could be exploited to deliver therapeutic agents to tumours. In particular, genetic engineering could be used to endow a suitable clostridial host with the capacity to produce an enzyme within the tumour which can metabolise a systemically introduced, non-toxic prodrug into a toxic metabolite. The feasibility of this strategy (clostridial-directed enzyme prodrug therapy, CDEPT) has been demonstrated by cloning the Escherichia coli B gene encoding nitroreductase (an enzyme which converts the prodrug CB1954 to a highly toxic bifunctional alkylating agent) into a clostridial expression vector and introducing the resultant plasmid into Clostridium beijerinckii (formerly C. acetobutylicum) NCIMB 8052. The gene was efficiently expressed, with recombinant nitroreductase representing 8% of the cell soluble protein. Following the intravenous injection of the recombinant spores into mice, tumour lysates have been shown, by Western blots, to contain the E. coli-derived enzyme.

Animals↗
PubMed1995

Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure.

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than either treatment alone. We investigated whether BMS-182657 (BMS), which bears inhibitory activities against both NEP and ACE, elicited similar enhanced effects. BMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the pressor response to Ang I in rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP inhibition but not to ACE inhibition, BMS at 100 mumol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In sodium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mumol/kg p.o. lowered MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 mumol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28603; or BMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. BMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P < .05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowering of MAP by 21 +/- 3 mm Hg at 60 min (P < .05 vs. each other group). There were no significant differences in the changes in heart rate or left ventricular stroke work index among the four groups. Hence, BMS-182657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespective of the activity of the renin-angiotensin system and has acute hemodynamic effects in hamsters with heart failure greater than those produced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of BMS-182657 act synergistically and mimic the interaction resulting from combining selective inhibitors of these enzymes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure.

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1994

Identification of YAC and cosmid clones encompassing the ZFX-POLA region using irradiation hybrid cell lines.

The human Xp21.3-p22.1 region is poorly mapped relative to other X chromosome regions. To target cosmid and YAC clones specifically from Xp21.3-p22.1 for rapid contig construction, a hybridization-based screening approach using irradiation hybrids has been used. Alu-PCR products generated from hybrid lines containing small overlapping fragments from Xp21-p22 were hybridized to an X chromosome cosmid library, and cosmids predicted by their hybridization pattern to map to the region of interest were analyzed by fluorescence in situ hybridization (FISH). Hybridization of the cosmids in pools to gridded YAC libraries identified 15 YACs, which were verified and tested for chimerism by FISH. Cosmid content analysis of the YACs defined two contigs, one with 12 YACs covering about 1.5 Mb and one with 3 YACs. Five YACs from the 12-YAC cluster had been previously recognized by DNA polymerase alpha (POLA). ZFX identified a single YAC; hence, the physical linkage of ZFX and POLA was demonstrated within the contig. Four YACs had been isolated previously with ZFX and these extend the contig to 2 Mb. Restriction mapping of several YACs demonstrates that ZFX and POLA are about 700 kb apart, a distance similar to that reported in the mouse between Zfx and Pola. The order of these two loci and two additional loci identified by homologous mouse linking clones was found to be conserved between human and mouse: tel-ZFX-DXCrc57-DXCrc140-POLA-cen. We have shown that YAC contigs can be rapidly constructed from targeted regions without the need for time-consuming YAC end rescue and chromosomal walking.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Regional localization of DPP4 (alias CD26 and ADCP2) to chromosome 2q24.

A panel of microcell hybrids containing fragments of chromosome 2 was analyzed for the presence of human DPP4, the gene that codes for dipeptidyl peptidase IV (or CD26), by specific PCR amplification of a fragment of the 3' untranslated region of the gene. This analysis placed DPP4 between LCT and GAD in bands q21 to q31. The localization was confirmed by in situ hybridization using two genomic probes that each revealed a hybridization signal in band q24. We also use the recent identification of the ADA binding protein as DPPIV to propose that the gene ADCP2 should be renamed DPP4.

Animals↗