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Robert Millar

Publications and source records attributed to Robert Millar.

6 recordsLinked to original sources
PubMed2025

The mhqPOD gene cluster in lignin-degrading Paenibacillus sp. B2 encodes a pathway for the degradation of lignin-derived 5,5'-di(dehydrovanillic acid) (DDVA).

Lignin-degrading bacteria Paenibacillus sp. B2, Agrobacterium sp. B1, and Ochrobactrum sp. each contain mhqO genes encoding ring cleavage dioxygenase enzymes whose biochemical function is unknown. Each of these strains was found to degrade the biphenyl-containing lignin fragment 5,5'-di(dehydrovanillic acid) (DDVA) on solid media. An operon of five mhq genes in Paenibacillus sp. B2 was analysed via gene expression using quantitative PCR, and all five genes were highly induced (400-1000-fold overexpression) by the presence of DDVA. Recombinant azoreductase MhqP was found to demethylate DDVA to its monodemethylated derivative. Hence, these genes are proposed to be responsible for DDVA degradation, via a pathway involving the same biochemical steps as that studied in Sphingobium lignivorans SYK-6, but using several unrelated genes. Decarboxylation of later pathway intermediate 5-carboxyvanillic acid in Paenibacillus sp. B2 is proposed to be catalysed by decarboxylase UbiD, whose gene is also upregulated in the presence of DDVA. Degradation of the other fragment 4-carboxy-2-hydroxypentadienoic acid is proposed to occur via hydratase UxuA, whose gene is also upregulated by DDVA, and 4-hydroxy-4-methyl-2-oxoglutarate aldolase.

Paenibacillus↗
PubMed2005

[Recent data on GnRH receptors].

The main intracellular pathway activated by stimulation of GnRH receptors is related to Gq protein which induces a cytoplasmic metabolic cascade responsible for activation of genes producing gonadotrophins and regulating their secretion. Two other activation pathways were identified, a Gs protein-mediated pathway involved in pulsatile secretion of GnRH and a Gi protein-mediated pathway with an inhibitory and apototic effect on tumor cells. Finally, GnRH receptors may directly interact with membrane integrins and generate other cytoplasmic signals. Hence, GnRH receptors are not only involved in pituitary secretion but also in tumoral disease. The inhibitory effect of GnRH analogs on the secretion of sex steroids is responsible for the indirect anti-tumoral action already used in routine practice for the treatment of hormone-dependent cancer. However, the presence of GnRH receptors in tumor tissues suggests that they are directly involved in cancerous disease. The conformational variability of these receptors permits certain ligands to stabilize them in a form privileging various intracellular signals with activation of metabolic pathways involving protein kinase systems and generating a direct antitumoral effect by inhibition of cell growth and\or apotosis. The absence of an intracytoplasmic C-terminal tail in the structure of these receptors is an essential condition for the anti-proliferative effect of various ligands, agonists or antagonists, with an anti-tumoral activity varying according to their specificity. This will make it possible in the future to establish a new classification of GnRH analogs. The discovery of this direct antitumoral effect has therefore opened up a new therapeutic approach for hormone-independant cancers with GnRH receptors and the direct cytotoxic effect reinforces the hormonal action in hormone-dependant cancers.

Antineoplastic Agents↗
PubMed2004

The long-term effects of DDT exposure on semen, fertility, and sexual function of malaria vector-control workers in Limpopo Province, South Africa.

Hormonally active chemicals in the environment such as DDT have been associated with declining male reproductive health, especially semen quality. A cross-sectional study of 60 workers was performed near the Malaria Control Center (MCC) in Tzaneen, Limpopo Province, South Africa. Tests included a questionnaire (sexual function, fertility, and job history), a physical examination of the reproductive system, and semen analysis (produced via coitus interruptus or masturbation). Sperm count, density, and motility using the World Health Organization criteria and morphology using the strict Tygerberg criteria were determined. Serum o'p' and p'p' isomers of DDE, DDT, and DDD were measured. Forty-eight (81.0%) participants produced a semen sample, while all completed the questionnaires and physical examination. The mean sperm count was 93.8+/-130.3 million, and sperm density was 74.6+/-85.1 million/mL. The mean normal morphology score was 2.5+/-1.8% of subjects. Eighty-four percent of morphology scores were below either the WHO or the Tygerberg criteria, with the highest individual score being 6%. Self-perceived current problems with sexual function ranged between 10% and 20%. The most prevalent genital abnormality was abnormal testis disposition at 71%. There were few significant associations between DDT exposure measures (measured as years worked at MCC and serum DDT) and reproductive outcomes. p'p'-DDT was negatively associated with semen count (beta=-3.7+/-1.7; P=0.04; R2=0.05 adjusted for age, abstinence, physical abnormality, and fever in last 2 months). While the semen quality in the study was less than normal, no strong evidence for a DDT effect was found.

Animals↗
PubMed2002

Secondary structure of the third extracellular loop responsible for ligand selectivity of a mammalian gonadotropin-releasing hormone receptor.

The extracellular loop 3 (ECL3) of the mammalian gonadotropin-releasing hormone receptor (GnRH-R) contains an acidic amino acid (Glu(301) in the mouse GnRH-R) that confers agonist selectivity for Arg(8) in mammalian GnRH. It is proposed that a specific conformation of ECL3 is necessary to orientate the carboxyl side chain of the acidic residue for interaction with Arg(8) of GnRH, which is supported by decreased affinity for Arg(8) GnRH but not Gln(8) GnRH when an adjacent Pro is mutated to Ala. To probe the structural contribution of the loop domain to the proposed presentation of the carboxyl side chain, we synthesized a model peptide (CGPEMLNRVSEPGC) representing residues 293-302 of mouse ECL3, where Cys and Gly residues are added symmetrically at the N and C termini, respectively, allowing the introduction of a disulfide bridge to simulate the distances at which the ECL3 is tethered to the transmembrane domains 6 and 7 of the receptor. The ability of the ECL3 peptide to bind GnRH with low affinity was demonstrated by its inhibition of GnRH stimulation of inositol phosphate production in cells expressing the GnRH-R. The CD bands of the ECL3 peptides exhibited a superposition of predominantly unordered structure and partial contributions from beta-sheet structure. Likewise, the analysis of the amide I and amide III bands from micro-Raman and FT Raman experiments revealed mainly unordered conformations of the cyclic and of the linear peptide. NMR data demonstrated the presence of a beta-hairpin among an ensemble of largely disordered structures in the cyclic peptide. The location of the turn linking the two strands of the hairpin was assigned to the three central residues L(296), N(297), and R(298). A small population of structured species among an ensemble of predominantly random coil conformation suggests that the unliganded receptor represents a variety of structural conformers, some of which have the potential to make contacts with the ligand. We propose a mechanism of receptor activation whereby binding of the agonist to the inactive receptor state induces and stabilizes a particular structural state of the loop domain, leading to further conformational rearrangements across the transmembrane domain and signal propagating interaction with G proteins. Interaction of the Glu(301) of the receptor with Arg(8) of GnRH induces a folded configuration of the ligand. Our proposal thus suggests that conformational changes of both ligand and receptor result from this interaction.

Amino Acid Sequence↗