Biomedical subjects

E Lazar

Publications and source records attributed to E Lazar.

At least 37 records · Page 2Linked to original sources

PubMed1988

Transforming growth factor alpha: mutation of aspartic acid 47 and leucine 48 results in different biological activities.

To study the relationship between the primary structure of transforming growth factor alpha (TGF-alpha) and some of its functional properties (competition with epidermal growth factor (EGF) for binding to the EGF receptor and induction of anchorage-independent growth), we introduced single amino acid mutations into the sequence for the fully processed, 50-amino-acid human TGF-alpha. The wild-type and mutant proteins were expressed in a vector by using a yeast alpha mating pheromone promoter. Mutations of two amino acids that are conserved in the family of the EGF-like peptides and are located in the carboxy-terminal part of TGF-alpha resulted in different biological effects. When aspartic acid 47 was mutated to alanine or asparagine, biological activity was retained; in contrast, substitutions of this residue with serine or glutamic acid generated mutants with reduced binding and colony-forming capacities. When leucine 48 was mutated to alanine, a complete loss of binding and colony-forming abilities resulted; mutation of leucine 48 to isoleucine or methionine resulted in very low activities. Our data suggest that these two adjacent conserved amino acids in positions 47 and 48 play different roles in defining the structure and/or biological activity of TGF-alpha and that the carboxy terminus of TGF-alpha is involved in interactions with cellular TGF-alpha receptors. The side chain of leucine 48 appears to be crucial either indirectly in determining the biologically active conformation of TGF-alpha or directly in the molecular recognition of TGF-alpha by its receptor.

Amino Acid Sequence↗

PubMed1988

Respiratory muscle dysfunction in hereditary motor sensory neuropathy, type I.

Pulmonary function tests were performed on ten patients who were shown to have hereditary motor sensory neuropathy, type I. Mean values for spirometry, static lung volumes, and diffusion capacity were all greater than 80% of the predicted normal values for the group. In contrast, both inspiratory and expiratory muscle testing showed substantial reductions in function for the group. These abnormalities have not previously been reported, and they may be important in the management of these patients and in patients with other neuromuscular diseases.

Adolescent↗

PubMed1987

Transformation of normal rat kidney (NRK) cells by an infectious retrovirus carrying a synthetic rat type alpha transforming growth factor gene.

We synthesized a gene for rat type alpha transforming growth factor (TGF-alpha) consisting of the leader sequence and the sequence coding for the mature 50-amino acid peptide without the C-terminal processed region. This gene was inserted into the retrovirus vector pSW272, which is derived from spleen necrosis virus, to obtain an infectious recombinant virus carrying the rat TGF-alpha gene. This recombinant virus can infect normal rat kidney (NRK) cells and allow these cells to grow in soft agar in the presence of TGF-beta. Transformed cells isolated from colonies grown in soft agar contain an integrated form of the recombinant virus and secrete biologically active TGF-alpha into their medium. These results show that a biologically active TGF-alpha can be produced by a gene synthesized from only part of the coding region and that the infectious retrovirus carrying the TGF-alpha gene (SW355) can function as a transforming agent in NRK cells in the presence of TGF-beta.

Animals↗

PubMed1986

Endocarditis of a tricuspid prosthesis causing valvular stenosis and shunting through a patent foramen ovale.

A young intravenous drug user presented with Staphylococcus aureus endocarditis involving the tricuspid valve, which was replaced with a Hancock bioprosthesis. She presented again with fever and dyspnea five months later and was found to be cyanotic. Recurrent endocarditis involving the prosthesis with right-to-left shunting through a patent foramen ovale was documented by echo and confirmed at autopsy.

Adult↗

PubMed1986

Twice-daily nicardipine in the treatment of essential hypertension.

The antihypertensive effect of twice-daily nicardipine, an investigational calcium-channel blocker, was evaluated in a placebo-controlled, single-blind trial in 18 adult patients with essential hypertension (supine diastolic blood pressure [BP] of greater than or equal to 95 and less than or equal to 120 mmHg). Following a 4-week run-in period in which patients received placebo for the final 2 weeks, nicardipine was administered for 12 weeks with a treatment goal of a supine diastolic BP of less than 90 mmHg at 12 hours postdosing or to a maximum dose of 60 mg twice daily. Supine and standing BPs and heart rates were determined at 1 hour and 12 hours postdosing. At all dose levels, supine and standing BPs were reduced at 1 hour after dosing, with partial loss of efficacy seen at 12 hours. Increases in heart rate seen at 1 hour were not significant at 12 hours. Eight patients withdrew from the study for minor, although troublesome, side effects, such as palpitations and headaches. These data suggest that nicardipine monotherapy given in a twice-daily dosing regimen has only a limited role to play in the chronic treatment of patients with essential hypertension.

Adult↗

PubMed1985

Vein valve transplantation.

The vein valve transplantation has, in our experience, subjectively relieved symptoms in the majority of patients. More importantly, elevated venous pressure has been decreased in most patients. Thus, patients exhibiting signs of venous insufficiency syndrome as well as elevated venous pressure and proved valvular incompetence should be considered candidates for vein valve transplantation after an unsuccessful trial of medical management.

Follow-Up Studies↗

PubMed1985

Continuous ambulatory venous pressure for diagnosis of venous insufficiency. Preliminary report.

We have found that the venous pressure slope during minimal exercise is a sensitive measurement of venous disease. This parameter differed greatly in our two study populations. Due to increased venous pressure, venous insufficiency syndrome patients have a greater volume of pooled blood, which results in smaller pressure changes with each muscle contraction. In patients with incompetent valves, blood flows in a retrograde fashion in the vein, which leads to a higher steady state minimal pressure and notably to a decreased venous pressure slope. Venous pressure slope is a particularly sensitive measurement and a good prognosticator of venous insufficiency syndrome before symptoms become disabling to the patient. Our data indicate a strong correlation between venous pressure slope and venographic results. In fact, patients with abnormal venographic results invariably have demonstrated venous pressure slopes in the abnormal range.

Ambulatory Care↗

PubMed1984

A family of small nucleoplasmic RNAs with common structural features.

The four small nucleoplasmic RNAs designated as U1, U2, U4 and U5 RNA have a common structural domain or domain A. It is characterized by the presence of consensus sequence Pu-A-(U)5-G-Pup in a free single-stranded region and of the sequence Py-N-Py-Gp in the top loop of a hairpin located at the 3' end of the free region. Domain A is likely to be involved in a function common to the four small RNAs. Other domains possibly involved in the specific function of U1 and U5 RNAs are also presented. Several molecular forms of a same U RNA may be found in a same cellular type. These variant U RNAs are particularly numerous for U5 RNA. The possible origin of such new molecular forms is discussed in relation to multigene families for U RNAs. U1, U2, U4 and U5 RNAs are capped (with trimethylguanosine) and the consensus sequence for their 6 first nucleotides is A-(Py)5p. Thus, their 5' end resembles that of premessenger RNA, also capped (with monomethylguanosine) and bearing A-(Py)5p. Both classes of RNA are synthesized by RNA polymerase B, but the presence of a "TATA box" upstream of the capsite has not yet been demonstrated for U RNA genes. U1, U2, U4 and U5 RNAs bear a sequence C-Py-Pu at their 3' end or very close to it. This trinucleotide might be part of a site of post-transcriptional cleavage of U RNA precursors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

High evolutionary conservation of the secondary structure and of certain nucleotide sequences of U5 RNA.

The nucleotide sequence of chicken, pheasant, duck and Tetrahymena pyriformis U5 RNAs as well as that of new mammalian variant U5 RNAs was determined and compared to that of rat and HeLa cells U5 RNAs. Primary structure conservation is about 95% between rat and human cells, 82% between mammals and birds and 57% between the Protozoan and mammals. The same model of secondary structure, a free single-stranded region flanked by two hairpins can be constructed from all RNAs and is identical to the model previously proposed for mammalian U5 RNA on an experimental basis (1). Thus, this model is confirmed and is likely to be that of an ancestor U5 RNA. The 3' region of the U5 RNA molecule constitutes domain A, and is common to U1, U2, U4 and U5 RNAs (2). The characteristic nucleotide sequences of domain A are highly conserved throughout the phylogenetic evolution of U5 RNA suggesting that they are important elements in the function of the four small RNAs. Another region of high evolutionary conservation is the top part of the 5' side hairpin whose conserved sequence is specific to U5 RNA. It might participate in the particular function of U5 RNA.

Animals↗

PubMed1983

Two 5S genes are expressed in chicken somatic cells.

Two 5S RNA species were detected in chicken cells. 5S I RNA has the nucleotide sequence of chicken 5S RNA previously published by Brownlee et al. (1) and 5S II RNA differs from it by 10 mutations. The secondary structure of both species is compatible with that proposed for other eukaryotic 5S RNAs. 5S II RNA represents 50-60% of 5S I RNA. Both species were found in total chicken liver and brain and were present in polysomes in the same relative proportions. Only one 5S RNA species could be detected in rat liver and HeLa cells. Chicken is the first vertebrate described so far in which two 5S RNA genes are expressed in somatic cells.

Animals↗

PubMed1982

Accessibility of U1 RNA to base pairing with a single-stranded DNA fragment mimicking the intron extremities at the splice junction.

A DNA fragment containing a 16 nucleotide sequence mimicking the intron extremities of premessenger RNA aligned as proposed previously (1,2) in a model of splicing mechanism was prepared and used as a probe for accessibility of the 5' extremity of U1 RNA. Hybridization of U1 RNA to the probe under non denaturing conditions and digestion of the hybrid with RNase H revealed that the sequence of U1 RNA which is complementary to the extremities of introns is accessible to hybridization and to enzymes. Therefore, the configuration of isolated U1 RNA satisfies the criteria required for the alignment of introns and further enzymatic reactions of splicing.

Base Composition↗

PubMed1982

U2 RNA shares a structural domain with U1, U4, and U5 RNAs.

We previously reported common structural features within the 3'-terminal regions of U1, U4, and U5 RNAs. To check whether these features also exist in U2 RNA, the primary and secondary structures of the 3'-terminal regions of chicken, pheasant, and rat U2 RNAs were examined. Whereas no difference was observed between pheasant and chicken, the chicken and rat sequences were only 82.5% homologous. Such divergence allowed us to propose a unique model of secondary structure based on maximum base-pairing and secondary structure conservation. The same model was obtained from the results of limited digestion of U2 RNA with various nucleases. Comparison of this structure with those of U1, U4, and U5 RNAs shows that the four RNAs share a common structure designated as domain A, and consisting of a free single-stranded region with the sequence Pu-A-(U)n-G-Pup flanked by two hairpins. The hairpin on the 3' side is very stable and has the sequence Py-N-Py-Gp in the loop. The presence of this common domain is discussed in connection with relationships among U RNAs and common protein binding sites.

Animals↗

PubMed1981

Primary and secondary structures of chicken, rat and man nuclear U4 RNAs. Homologies with U1 and U5 RNAs.

U4 RNA from chicken, rat and man was examined for nucleotide sequence and secondary structure. Three molecular species, U4A, U4B and U4C were detected in the three animal species. U4A is 146 nucleotide long and U4B RNA only lacks the 3' terminal G. four nucleotides are missing at the 3'-end of U4C RNA which, in addition, differs from U4A and U4B RNAs at two internal positions. Thus, U4C RNA is encoded by another gene as U4A and U4B RNAs. Only one nucleotide substitution occurred between chicken and man showing that U4A, U4B and U4C RNAs have been extremely conserved throughout evolution. The three molecular species are capped, they contain three psi, a 2'-P methyl A and a m6A. An additional post-transcriptional modification close to the cap structure is observed in man. On the basis on an experimental study, two models of secondary structure may be proposed for U4 RNA. The 3'domain is the same in both models and is homologous to that of U1 and U5 RNAs. It consists of a single-stranded region, containing the sequence Py-(A)2-(U)n-Gp flanked by two stable hairpins probably involved in tertiary interactions. The 5' domain is less stable than the 3' domain and its structure is different in the two models. However, a long single-stranded pyrimidine region containing modified nucleotides is found in both models as in U1 and U5 RNAs. Several other nucleotide sequence homologies related to specific features of secondary structure suggest that U1, U4 and U5 RNAs derive from a common ancestor and may have common function.

Animals↗

PubMed1981

Small RNAs in HnRNP fibrils and their possible function in splicing.

Several arguments are in favor of a function of snRNA in the processing of premessenger RNA. A large fraction of snRNA is localized in hnRNP which are assumed to be the site of processing. The different snRNA species are not bound to hnRNP in a unique manner but are associated with both proteins and hnRNA which suggests the possibility of metabolic exchanges in the course of processing. There is approximately 1-2 molecules of snRNA per individual hnRNP. We reexamined the possibility that U1A RNA might serve for the alignment of the extremities of the intron sequences of premessenger RNA insuring correct condition for cutting and splicing. We found that only a UCCA (3' leads to 5') sequence at position 8-11 of U1A RNA was complementary to an AG-GU (5' leads to 3') around a putative splice point for 69 different introns sequenced so far. On the basis of secondary structure of U1A RNA, the UCCA sequence would be available for hybridization. The UCCA sequence is also present in U2 RNA and 4.5 S RNAI. It might associate with AG-GU in a manner similar to that of codon-anticodon, the stability of the complex being insured by the configuration of hnRNP. The possible formation of larger hybrids stable by themselves is unlikely upon examination of the nucleotide sequence of various introns adjacent to the splice point. As there is no direct experimental evidence for the function of snRNA in splicing, there considerations are speculative at the present time. The possibility that adenovirus encoded VA RNA would play a role in splicing was also examined. Various arguments suggest that this possibility is rather remote.

Adenoviridae↗

PubMed1981

The nuclear 5S RNAs from chicken, rat and man. U5 RNAs are encoded by multiple genes.

Preparations of chicken, rat and human nuclear 5S RNA contain two sets of molecules. The set with the lowest electrophoretic mobility (5Sa) contains RNAs identical or closely related to ribosomal 5S RNA from the corresponding animal species. In HeLa cells and rat brain, we only detected an RNA identical to the ribosomal 5S RNA. In hen brain and liver, we found other species differing by a limited number of substitutions. The results suggest that mutated 5S genes may be expressed differently according to the cell type. The set with the highest mobility corresponds to U5 RNA. In both rat brain and HeLa cells, U5 RNA was found to be composed of 4 and 5 different molecules respectively (U5A, U5B1-4) differing by a small number of substitutions or insertions. In hen brain, no U5B was detected but U5A' differing from U5A by the absence of the 3'-terminal adenosine. All the U5 RNAs contain the same set of modified nucleotides. They also have the same secondary structure which consists of two hairpins joined together by a 17 nucleotide long single-stranded region. The 3' half of the molecule has a compact conformation. Together, the results suggest that U5 RNAs are transcribed from a multigene family and that mutated genes may be expressed as far as secondary structure is conserved. The conformation of U5 RNA is likely to be related to its function and it is of interest to mention that several similarities of structure are found between U5 and U1A RNA.

Animals↗

PubMed1981

The conformation of chicken, rat and human U1A RNAs in solution.

Chicken, rat and human U1A RNAs in solution, were examined for secondary structure, using several methods including hydrolysis by various nucleases, hybridization to DNA oligomers and analysis of fragment interactions. The experimental results showed that the three U1A RNAs have the same structure, stable over a wide range of pH and ionic conditions. They allowed the selection of one out of several possible models constructed from the data of primary structure. This model is characterized by 4 hairpins and two single-stranded regions, the two hairpins from the 3' part of the molecule bearing very stable stems. In addition, the experimental results showed that in contrast to the 5' half of the molecule, the 3' half has a compact conformation probably stabilized by tertiary interactions. The 5' end of U1A RNA is accessible and free of base-pairing so that it might base-pair with regions of other RNA molecules, for instance, with the extremities of introns as has been recently proposed in a model of splicing.

Animals↗

PubMed1981

Sudden disappearance and reappearance of the pathologic Q waves after successive myocardial necrosis: electrocardiographic and pathologic correlations.

A case with sudden disappearance of the pathologic Q waves of an old posterior myocardial infarction after a superimposed acute anterior infarction is reported. This phenomena probably is due to the loss of the opposing electromotive forces in the anterior myocardial wall after acute anterior myocardial necrosis. When a third acute lateral myocardial infarction occurred, new Q waves in the corresponding leads could be observed. Pathologic examinations documented three temporally and spaciously separate infarctions. Such correlations allow a better understanding of the electrocardiographic changes in patients with successive myocardial infarctions.

Electrocardiography↗

PubMed1980

Nucleotide sequences of nuclear U1A RNAs from chicken, rat and man.

The methods of enzymatic and chemical treatment of end-labeled RNA were applied to the determination of the nucleotide sequence of chicken and man U1A RNA and to the reexamination of that of rat U1A RNA. The chemical method allowed the easy demonstration of the cap structure. All three RNA were 165 nucleotide long. Two hitherto non described modified pyrimidines were detected close to the 5' end. Only 9 base substitutions were observed from chicken to man indicating high degree of conservation of U1A RNA through evolution.

Animals↗