Biomedical subjects

A Khachatryan

Publications and source records attributed to A Khachatryan.

4 recordsLinked to original sources

PubMed2001

Structure of Thermotoga maritima stationary phase survival protein SurE: a novel acid phosphatase.

BACKGROUND: The rpoS, nlpD, pcm, and surE genes are among many whose expression is induced during the stationary phase of bacterial growth. rpoS codes for the stationary-phase RNA polymerase sigma subunit, and nlpD codes for a lipoprotein. The pcm gene product repairs damaged proteins by converting the atypical isoaspartyl residues back to L-aspartyls. The physiological and biochemical functions of surE are unknown, but its importance in stress is supported by the duplication of the surE gene in E. coli subjected to high-temperature growth. The pcm and surE genes are highly conserved in bacteria, archaea, and plants. RESULTS: The structure of SurE from Thermotoga maritima was determined at 2.0 A. The SurE monomer is composed of two domains; a conserved N-terminal domain, a Rossman fold, and a C-terminal oligomerization domain, a new fold. Monomers form a dimer that assembles into a tetramer. Biochemical analysis suggests that SurE is an acid phosphatase, with an optimum pH of 5.5-6.2. The active site was identified in the N-terminal domain through analysis of conserved residues. Structure-based site-directed point mutations abolished phosphatase activity. T. maritima SurE intra- and intersubunit salt bridges were identified that may explain the SurE thermostability. CONCLUSIONS: The structure of SurE provided information about the protein's fold, oligomeric state, and active site. The protein possessed magnesium-dependent acid phosphatase activity, but the physiologically relevant substrate(s) remains to be identified. The importance of three of the assigned active site residues in catalysis was confirmed by site-directed mutagenesis.

Amino Acid Sequence↗

PubMed1999

Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice.

The neuropeptide calcitonin gene-related peptide (CGRP) is concentrated in fine sensory nerve endings innervating all tissues, including bone. CGRP inhibits osteoclasts, stimulates insulin-like growth factor I and inhibits tumor necrosis factor alpha production by osteoblasts in vitro. To investigate the role of CGRP in bone in vivo, mice were engineered to express CGRP in osteoblasts by placing the human CGRP gene under the control of the rat osteocalcin promoter (Ost-CGRP tg+ mice). Calvaria cultures from transgene positive (tg+), but not tg- mice, produced bioactive CGRP. Trabecular bone density and bone volume, determined by peripheral quantitative computed tomography and bone histomorphometry, respectively, were higher in tg+ than tg- littermates. This increase in bone volume was associated with an increased bone formation rate. Trabecular bone density decreased in tg+ mice as a result of ovariectomy, but remained higher than in sham tg- mice. Targeting CGRP to osteoblasts appears to favor the establishment of a higher trabecular bone mass in mice.

Animals↗

PubMed1997

Stabilizing function of trunk flexor-extensor muscles around a neutral spine posture.

STUDY DESIGN: This study examined the coactivation of trunk flexor and extensor muscles in healthy individuals. The experimental electromyographic data and the theoretical calculations were analyzed in the context of mechanical stability of the lumbar spine. OBJECTIVES: To test a set of hypotheses pertaining to healthy individuals: 1) that the trunk flexor-extensor muscle coactivation is present around a neutral spine posture, 2) that the coactivation is increased when the subject carries a load; and 3) that the coactivation provides the needed mechanical stability to the lumbar spine. SUMMARY OF BACKGROUND DATA: Theoretically, antagonistic trunk muscle coactivation is necessary to provide mechanical stability to the human lumbar spine around its neutral posture. No experimental evidence exists, however, to support this hypothesis. METHODS: Ten individuals executed slow trunk flexion-extension tasks, while six muscles on the right side were monitored with surface electromyography: external oblique, internal oblique, rectus abdominis, multifidus, lumbar erector spinae, and thoracic erector spinae. Simple, but realistic, calculations of spine stability also were performed and compared with experimental results. RESULTS: Average antagonistic flexor-extensor muscle coactivation levels around the neutral spine posture as detected with electromyography were 1.7 +/- 0.8% of maximum voluntary contraction for no external load trials and 2.9 +/- 1.4% of maximum voluntary contraction for the trials with added 32-kg mass to the torso. The inverted pendulum model based on static moment equilibrium criteria predicted no antagonistic coactivation. The same model based on the mechanical stability criteria predicted 1.0% of maximum voluntary contraction coactivation of flexors and extensors with zero load and 3.1% of maximum voluntary contraction with a 32-kg mass. The stability model also was run with zero passive spine stiffness to simulate an injury. Under such conditions, the model predicted 3.4% and 5.5% of maximum voluntary contraction of antagonistic muscle coactivation for no extra load and the added 32 kg, respectively. CONCLUSIONS: This study demonstrated that antagonistic trunk flexor-extensor muscle coactivation was present around the neutral spine posture in healthy individuals. This coactivation increased with added mass to the torso. Using a biomechanical model, the coactivation was explained entirely on the basis of the need for the neuromuscular system to provide the mechanical stability to the lumbar spine.

Adult↗

PubMed1997

Targeted expression of the neuropeptide calcitonin gene-related peptide to beta cells prevents diabetes in NOD mice.

To investigate whether the immunosuppressive neuropeptide calcitonin gene-related peptide (CGRP) was a potential candidate for tissue-specific gene therapy, we engineered nonobese diabetic (NOD) mice to produce CGRP in beta cells by placing the modified calcitonin gene under the control of the rat insulin promoter. CGRP inhibits CD4 T cell production of the cytokines that have been implicated in the pathogeny of type I diabetes. Three transgene-positive mouse lines were obtained, two of which expressed immunoreactive CGRP in beta cells (NOD-CGRP mice). Isolated islets from one of these two transgene-positive founders produced active CGRP, whereas islets from transgene-negative littermates did not. The production of CGRP by beta cells prevented insulin-dependent diabetes mellitus in male and reduced its incidence by 63% in female mice. This prevention was due to a local immunosuppressive effect of CGRP as no difference was detected between NOD-CGRP and NOD littermate lymph node, spleen, and thymus cells by either FACS analysis or proliferative response to stimulation by Ag, alloantigen or anti-CD3. These data suggest that CGRP is a potential therapeutic molecule to prevent or treat diabetes and possibly other diseases and conditions in which immune cells are involved. These data also suggest that endogenous CGRP concentrated in sensory nerve endings may regulate locally the immune response, further strengthening the importance of the functional neuroimmune link.

Animals↗