Biomedical subjects
Publications and source records attributed to M Viau.
A series of N-arylsulfonyl S-alkyl homocysteine hydroxamic acids were synthesized with variations in three subsites corresponding to P(1), P(1)', and P(2)'. Enzyme assays with a variety of MMPs revealed activity at the low nanomolar level.
Various aspects of the immune response to HIV-1 infection remain unclear. While seropositive subjects generally mount a strong humoral response, the antibodies produced are not effective in halting disease progression. Molecular characterization of the antibody repertoire specific for HIV-1 antigens represents an approach to further our understanding of the mechanisms involved in mounting a humoral immunity in this infection. Recently, the content, structure, and organization of the human immunoglobulin-variable gene loci have been elucidated and a number of laboratories have characterized the variable gene elements of human anti-HIV-1 antibodies derived from infected persons by cell fusion or by Epstein-Barr virus transformation. The results show evidence for extensive somatic mutations that lead to preferential amino acid substitutions in the hypervariable regions, an indication of an antigen-driven process. Multiple other molecular events also are engaged in generating antibody diversity, including various types of fusions of variable genes, usage of inverted diversity genes, and addition of extragenomic nucleotides. Most importantly, there is a paucity of antibodies expressing the major V(H)3 gene family, which could result from the capacity of gp120 to act as superantigen for human B cells. This V(H)3+ antibody deficit also has been observed in B cells isolated ex vivo from the patients. Since V(H)3+ antibodies play an essential role in immune defense against infections, the abnormalities observed in HIV-1 infection may predispose to opportunistic infections and further compromise the immune defense mechanisms of the subjects.
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On a highly purified preparation, the structure of the carbohydrate chain of the human vitamin D-binding protein was investigated and two genetic forms of this protein were considered (Gc 2 and Gc 1 proteins). It was found that only the Gc 1 protein (Gc1a isoform) was glycosylated, the glycan moiety representing about 1% of the protein. The structure of this O-glycosidically linked glycan was determined to be: Neu Ac alpha (2 leads to 3) Gal beta (1 leads to 3) GaINAc alpha (1 leads to 0) Ser (or Thr). A tetrasaccharidic O-glycan with two N-acetylneuraminic residues was also characterized. The vitamin D-binding protein is a rare example of a serum protein O-glycosylated only on some genetic forms.
The mechanism of the interaction between two genetically determined serum vitamin D-binding protein forms and the muscle skeletal actin was investigated. Vitamin D-binding protein was isolated in a good yield from human serum, using immunoaffinity chromatography. 16 mg of pure vitamin D-binding protein were obtained from 100 ml of serum. The interaction between purified vitamin D-binding protein and skeletal muscle actin was studied by viscosity, delta A (232 nm) measurements and by electron microscopy. The effect of vitamin D-binding protein on actin polymerization is characterized by the decrease of the nucleation and elongation rates and by the decrease of the final concentration of polymerized actin in the steady state. The depolymerizing effect is not the result of direct action on vitamin D-binding protein on F-actin but rather of an increased concentration of the complex of the former protein with G-actin. The characteristics of the vitamin D-binding protein and profilin interactions with actin are similar. Both proteins seem to react only with G-actin.
The serum level of the 'vitamin D binding protein' (DBP) or Gc ('group-specific component'), its phenotype distribution and the quantitative estimation of the different electrophoretic isoforms were determined in a sample of healthy individuals (blood donors) and in patients with alcoholic hepatitis. It is shown that the serum DBP levels and the amount of the different electrophoretic isoforms are influenced by the protein phenotypes. In the patients an increased frequency of the Gc 1 allele is noticed. For the first time, an unusual form of the apo DBP protein was detected but only in the sera of the Gc 1 allele carriers. The protein form investigated by analytical procedures presents one more sialic acid residue than the usual Gc 1 protein. This unusual metabolic transformation of the DBP is mostly observed among male patients and is often associated with a deteriorating clinical outcome.
In this investigation, the authors developed two new procedures: a micromethod for haptoglobin purification and the isoelectric focusing electrophoresis on slab polyacrylamide gel for peptide subtyping. These technics are adapted to the study of large sample series for population genetic surveys. The improvements obtained enabled us to disclose in an easy and highly reproducible way the Hp alpha and alpha 2 peptide chains. Electrophoretic separation of the alpha 2 FS, SS, and FF chains were greatly improved. Their frequencies estimated in a sample already investigated by the conventional PAGE presented higher values than previously described. New Hp alpha and alpha 2 mutants were also detected. For the first time, isoelectric points of the Hp peptides were determined; the values obtained are discussed with regard to their known amino acid structure.
The indirect immunofluorescence method is used to study the binding of the serum vitamin D carrier protein (DBP) to lymphocytes. It is shown that in vitro this serum protein will bind to the lymphocyte cytoplasm and intact membrane. This result is in agreement with recent evidence of an actin-binding protein present in the serum. Besides, a difference in the binding to the lymphocyte membrane is observed between the holo forms of the DBP with the different vitamin D derivatives. These findings could be relevant in illuminating the possible role of the DBP in the cellular metabolism of the active metabolites of vitamin D and in the cellular mobility.
Protein polymorphism is studied in more than 900 serum samples during different investigations conducted in a Bi Aka Pygmy group. The Gc, Tf and alpha 1-antitrypsin subtype polymorphisms were determined after isoelectric focusing while the haptoglobins alpha and alpha 2-peptides were studied on PAGE. A high frequency of the Hp2 gene is noted while Hp1F and Hp1S gene frequencies are similar. According to the Gc1S and Gc2 gene frequencies this group falls within the cluster of the melanoderm populations such as the Sara, Bantu and Peulhs. The two subtypes of TfC1 and TfC2 are present in this sample. TfC3 is absent. The TfD1 variant frequency is one of the highest observed in African groups. The alpha 1-antitrypsin polymorphism corresponds to the presence of the three PiM subtypes. No other variants are observed, neither PiS nor PiZ. For the first time a highly significant association is described between the TfD1 and Gc1A1 (GcAb) genes. Family pedigrees do not permit the ascertainment of the linkage between the two loci.
The haptoglobin (Hp) polymorphism is investigated in 11 African groups living in an area from the Algerian Sahara to Central Africa. More than 4,000 samples were examined. In the Saharian samples, the Hp1 gene frequency is higher than in any other African group. From north to south, a decrease in the Hp1 gene frequency is observed; in the Pygmy sample only, this frequency is lower than the frequency of the Hp2 gene. By means of a sensitive radioimmunoelectrophoresis, the presence of a residual Hp in Hp O sera in which the Hp polymorphism can also be determined can be revealed. Absence of Hp 1-1 and significant excess of Hp 2-2 individuals were observed. More Hp 2-1M phenotypes were detected in the Hp O population than in the non-Hp O population examined. In the Hp O samples, the influence of the phenotype distribution on the Hp gene frequencies is discussed. The heavy polymers of the Hp related to the presence of the alpha 2 chain (Hp2 gene product) are involved only in the biological mechanisms responsible for the presence of Hp O and Hp 2-1 M phenotypes among African groups.
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Isoelectric focusing (IEF) is widely used for the determination of serum protein polymorphisms in forensic investigations. Because of non-genetic heterogeneity of some proteins and of protein-ligand dissociation observed after IEF standardization of procedures is necessary. In this article the authors point out the main difficulties encountered in studying the transferrin subtype polymorphism and describe a new and sensitive method. Two new Tf C subtypes were observed: Tf C4 in North American, Bolivian and Brazilian Indians, Tf C5 in Black Americans, both with polymorphic allele frequencies. In a Pyrenean population the allele frequencies for Tf C1, Tf C2 and Tf C3 were quite similar to those observed in a German population sample.
The authors studied Pi polymorphism using the Separator isofocusing method with slight modification. A new Pi allele was observed. Family pedigrees confirmed co-dominant inheritance with other Pi alleles. According to the electrophoretic mobility of its isoprotein bands, and to its frequency (0.04) this new allele is considered as a fourth Pi M subtype: Pi M4.
The authors describe the results obtained in an examination by isoelectrofocusing of more than 1,000 serum samples from various regions in France. The autochthonous populations of the north side of the Pyrénées are characterized by a high frequency of the gene Gc2 and a very low frequency of the Gc1F gene. This distinguishes them from the other groups studied (southwestern, northwestern and eastern France). The quantitative analysis of the data emphasizes the difference. These results can only be explained by the interdependance of the genetic and metabolic factors.
The authors confirm the analogy between Gc and DBP as a result of analytic studies by isoelectrofocusing and labeling of Gc with 3H vitamin D3. The presence of a relationship between Gc polymorphism and the amount of sunshine in a given region is discussed.
For the study of the group-specific component (Gc) system, serum samples were examined by polyacrylamide gel electrophoresis and by a newly developed immunofixation isoelectrofocusing procedure. Thereby, a greater extent of polymorphic variation was revealed than was known previously. The allele Gc1 could be subdivided into the alleles Gc1F and Gc1S. The distribution of Gc1 subtypes was very different in three populations (Pygmies, Amerindians, and Pyreneans) examined. New variants of the Gc1 and Gc2 genes were also described in the Amerindians and in the Pygmy population, respectively.
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In the course of a genetic investigation carried out in a Pyrenean population, a family with a new allele of the Gc system was found. Electrophoretic analysis revealed a faster migrating variant with a double band pattern. Presumably, this variant represents a mutant of the Gc1 allele. The variant is transmitted as an autosomal codominant trait. This additional allele at the Gc locus is named GcT (TcToulouse).