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PubMed1997

Glucagon-like peptide-1 structure, function and potential use for NIDDM.

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon. This precursor is processed by tissue-specific proteolysis to produce glucagon in pancreatic alpha-cells and a glucagon-like peptide-1 (GLP-1) in the intestine. GLP-1 is a hormone that is released by intestinal cells into the circulation in response to food intake. GLP-1 and gastric inhibitory peptide (GIP) which has also been termed glucose-dependent insulinotropic peptide appear to account for most of the incretin effect in the augmentation of glucose-stimulated insulin secretion. These two hormones have specific beta-cell receptors that are coupled to GTP binding proteins to induce production of cyclic AMP and activation of cyclic AMP-dependent protein kinase. It is proposed that at least one factor contributing to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is desensitization of the GLP-1 receptor on beta-cells. At pharmacological doses, infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin response in NIDDM patients. Agonists of GLP-1 receptor have been proposed as new potential therapeutic agents in NIDDM patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of NIDDM.

Diabetes Mellitus, Type 2↗
PubMed1993

Simulation of the kinetics of ligand binding to a protein by molecular dynamics: geminate rebinding of nitric oxide to myoglobin.

We have begun to use molecular dynamics to simulate the kinetics of nitric oxide rebinding to myoglobin after photodissociation. Rebinding was simulated using a potential function that switches smoothly between a nonbinding potential and a binding potential as a function of the position and orientation of the ligand, with no barrier arising from the crossing of potential surfaces of different electron spin. In 96 of 100 trajectories, the ligand rebound in < 15 ps. The kinetic progress curve was obtained by determining the time in each trajectory at which the ligand rebound and then calculating the fraction of unbound ligands as a function of time. The curve can be well reproduced by a simple model based on the dynamics of a Langevin particle moving on a one-dimensional potential of mean force calculated from nonreactive protein trajectories. The rate of escape from the energy well adjacent to the heme is in good agreement with the value calculated from experimental data, suggesting that a multiple-well model provides a plausible explanation for the nonexponential rebinding kinetics. A transition-state analysis suggests that protein conformational relaxation coupled to the displacement of the iron from the heme plane is an unlikely cause for the nonexponential rebinding of nitric oxide.

Computer Simulation↗
PubMed2006

Functional consequences of mitochondrial proteome heterogeneity.

Potential functional consequences of the differences in protein distribution between the mitochondria of the rat liver, heart, brain, and kidney, as determined in the companion paper in this issue (Johnson DT, French S, Blair PV, You JS, Bemis KG, Wang M, Harris RA, and Balaban RS. The tissue heterogeneity of the mammalian mitochondrial proteome. Am J Physiol Cell Physiol292: C689-C697, 2006), were analyzed using a canonical metabolic pathway approach as well as a functional domain homology analysis. These data were inserted into the Kyoto Encyclopedia of Genes and Genomes pathway framework to give global and metabolic pathway-specific information on the impact of the differential protein distribution on mitochondrial function. Custom pathway analysis was also performed using pathways limited to the mitochondrion. With the use of this approach, several well-known functional differences between these mitochondrial populations were confirmed. These included GABA metabolism in the brain, urea synthesis in the liver, and the domination of oxidative phosphorylation in the heart. By comparing relative protein amounts of mitochondria across tissues, a greater understanding of functional emphasis is possible as well as the nuclear "programming" required to enhance a given function within the mitochondria. For proteins determined to be mitochondrial and lacking a defined role functional domain BLAST analyses were performed. Several proteins associated with DNA structural modification and a novel CoA transferase were identified. A protein was also identified capable of catalyzing the first three steps of de novo pyrimidine synthesis. This analysis demonstrates that the distribution of nuclear encoded proteins significantly modifies the overall functional emphasis of the mitochondria to meet tissue-specific needs. These studies demonstrate the existence of mitochondrial biochemical functions that at present are poorly defined.

Animals↗
PubMed2006

An algorithm for the uniform sampling of iso-energy surfaces and for the calculation of microcanonical averages.

In this article an algorithm is proposed to efficiently perform the uniform sampling of an iso-energy surface corresponding to a fixed potential energy U of a molecular system, and for calculating averages of certain quantities over microstates having this energy (microcanonical averages). The developed sampling technique is based upon the combination of a recently proposed method for performing constant potential energy molecular dynamics simulations [Rapallo, A. J Chem Phys 2004, 121, 4033] with well-established thermostatting techniques used in the framework of standard molecular dynamics simulations, such as the Andersen thermostat, and the Nose-Hoover chain thermostat. The proposed strategy leads to very accurate and drift-free potential energy conservation during the whole sampling process, and, very important, specially when dealing with high-dimensional or complicated potential functions, it does not require the calculation of the potential energy function hessian. The technique proved to be very reliable for sampling both low- and high-dimensional surfaces.

Algorithms↗
PubMed2004

Brain potentials index executive functions during random number generation.

The generation of random sequences is considered to tax different executive functions. To explore the involvement of these functions further, brain potentials were recorded in 16 healthy young adults while either engaging in random number generation (RNG) by pressing the number keys on a computer keyboard in a random sequence or in ordered number generation (ONG) necessitating key presses in the canonical order. Key presses were paced by an external auditory stimulus to yield either fast (1 press/800 ms) or slow (1 press/1300 ms) sequences in separate runs. Attentional demands of random and ordered tasks were assessed by the introduction of a secondary task (key-press to a target tone). The P3 amplitude to the target tone of this secondary task was reduced during RNG, reflecting the greater consumption of attentional resources during RNG. Moreover, RNG led to a left frontal negativity peaking 140 ms after the onset of the pacing stimulus, whenever the subjects produced a true random response. This negativity could be attributed to the left dorsolateral prefrontal cortex and was absent when numbers were repeated. This negativity was interpreted as an index for the inhibition of habitual responses. Finally, in response locked ERPs a negative component was apparent peaking about 50 ms after the key-press that was more prominent during RNG. Source localization suggested a medial frontal source. This effect was tentatively interpreted as a reflection of the greater monitoring demands during random sequence generation.

Adult↗
PubMed2003

Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo.

OBJECTIVE: To characterize the morphologic and immunologic features of adherent synovial fluid cells derived from patients with rheumatoid arthritis (RA), and to explore their potential function in vitro and in vivo by focusing on cartilage destruction. METHODS: Synovial fluid adherent cells obtained from patients with RA and from control subjects were characterized by immunohistochemistry, flow cytometry, and electron microscopy. In vitro, these cells were cultured in the presence of cartilage particles. Cartilage destruction was monitored by the release of sulfated glycosaminoglycans (sGAG) into the medium, and the level of matrix metalloproteinase 1 (MMP-1) in the cell culture supernatant was measured by enzyme-linked immunosorbent assay. To inhibit cartilage destruction in vitro, the MMP inhibitor marimastat was tested in this system. In vivo, in the SCID mouse coimplantation model, RA synovial fluid adherent cells and RA synovial fibroblasts (as positive controls) were coimplanted with human cartilage under the kidney capsule and maintained there for 60 days. RESULTS: In vitro, the synovial fluid adherent cells consisted of 2 subpopulations, large round-shaped macrophage-like cells (CD68+) and spindle-shaped fibroblast-like cells (Thy-1+). When passaged, the latter cells proliferated and organized themselves into 3-dimensional formations. This allowed them to reach collagen particles fixed with agarose. Fibroblasts derived from synovial tissues could not be used in this assay because they grew only in monolayers and not on agarose. The majority (>90%) of passaged RA synovial fluid adherent cells expressed the Thy-1+,CD45-,CD68-,CD86- phenotype. Electron microscopy did not reveal important morphologic differences between the 2 types of fibroblasts, those from synovial tissue or those from synovial fluid. However, synovial fluid adherent cells expressed lower levels of adhesion molecules, including CD54 and galectin 3, as well as the complement-regulatory molecule CD55. The in vitro release of sGAG associated with cell activity was 2.5-fold higher from RA synovial fluid adherent cells in comparison with that from negative control cells. The release of sGAG correlated with the concentration of MMP-1 and was inhibited by the broad-range MMP inhibitor marimastat in a dose-dependent manner. RA synovial fluid adherent cells coimplanted with cartilage in SCID mice showed the same invasive behavior as that displayed by tissue-derived RA synovial fibroblasts. CONCLUSION: Similar to tissue-derived RA synovial fibroblasts, RA synovial fluid adherent cells, which contain "floating" anchorage-independent fibroblast-like cells, mediate cartilage destruction independent of the hyperplastic synovial tissue.

Adult↗
PubMed2001

Human herpesvirus-8 and Kaposi's sarcoma: relationship with the multistep concept of tumorigenesis.

Kaposi's sarcoma (KS) develops through discrete inflammatory-angiogenic stages of polyclonal nature (early-stage lesions) to monomorphic nodules of spindle-shaped cells that can be clonal (late-stage lesions) and resemble true sarcomas. Molecular and epidemiological studies indicate that development of KS is tightly associated with infection by the human herpesvirus-8 (HHV-8). However, only individuals with specific conditions of immunodysregulation develop KS. In these individuals the systemic and tissue increase of Th-1-type cytokines (IC) reactivate HHV-8 infection, leading to increased viral load, antibody titers, and an expanded cell tropism that precedes the clinical appearance of KS. Recruitment of the virus into tissues by infected monocytes and other cell types is facilitated by the endothelial cell activation due to IC. In clinical lesions, HHV-8 infection increases with lesion stage and in late-stage lesions most of the spindle cells are latently infected, whereas only few lyrically infected cells are present, suggesting that latent genes may have a role in the transformation of the early inflammatory-hyperplastic lesion into a real sarcoma. The development of tumors, however, is regulated through a multistep process based on the acquisition by cells of several different capabilities leading to malignant growth. Here we review the available data on the expression of HHV-8-encoded genes in primary KS lesions and, in view of their biological activity, analyze their potential function in different steps of tumorigenesis. By this pragmatic approach interesting insights into potential key functions of HHV-8-encoded genes are found and steps of potential cooperativity with other viral factors (HIV-1-Tat) in the pathogenesis of KS are identified.

Gene Expression Regulation, Neoplastic↗
PubMed2006

Routine screening for the functional asymmetry of potential kidney donors.

The functional capacity of each kidney of a healthy donor may change under the influence of genetic and environmental factors. An assumption that the donor kidneys show equal function is not always true. As part of the pre-nephrectomy evaluation of potential donors, radioisotope renal scintigraphy using technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) was routinely included to evaluate renal functional asymmetry of undetermined etiology. The functional ratios of each kidney using 99mTcDTPA as well as serum creatinine (Scr) and creatinine clearance (Ccr) in a 24-hour urine were measured and calculated from a hundred donors. The left kidneys showed greater function (51.67%-53.35% under 95% confidence interval [CI]) and the average left versus right ratio was 52.5 versus 47.5. The average fraction of Ccr of left kidneys was 57.8 mL/min/1.73 m +/- 10.99 compared with right kidneys at 52.6 mL/min/1.73 m +/- 11.63. Seventy-three healthy volunteers donated their left kidneys, and 27, their right kidney. The average fraction of Ccr of the donated kidneys was 55.9 mL/min/1.73 m +/- 11.78 compared with that of the remnant kidneys (54.5 mL/min/1.73 m +/- 11.39). After kidney donation, the Scr of the donors increased from 0.85 mg/dL +/- 0.17 to 1.33 mg/dL +/- 0.27. The average postnephrectomy Ccr was 68.0 mL/min/1.73 m +/- 14.29. Even though the Ccr after kidney donation was higher than that of the remnant kidney estimated before the donation, one must pay attention to possible functional kidney asymmetry to select the nephrectomy site.

Humans↗
PubMed2001

Influence of rotational energy barriers to the conformational search of protein loops in molecular dynamics and ranking the conformations.

An adjustable-barrier dihedral angle potential was added as an extension to a novel, previously presented soft-core potential to study its contribution to the efficacy of the search of the conformational space in molecular dynamics. As opposed to the conventional soft-core potential functions, the leading principle in the design of the new soft-core potential, as well as of its extension, the soft-core and adjustable-barrier dihedral angle (SCADA) potential (referred as the SCADA potential), was to maintain the main equilibrium properties of the original force field. This qualifies the methods for a variety of a priori modeling problems without need for additional restraints typically required with the conventional soft-core potentials. In the present study, the different potential energy functions are applied to the problem of predicting loop conformations in proteins. Comparison of the performance of the soft-core and SCADA potential showed that the main hurdles for the efficient sampling of the conformational space of (loops in) proteins are related to the high-energy barriers caused by the Lennard-Jones and Coulombic energy terms, and not to the rotational barriers, although the conformational search can be further enhanced by lowering the rotational barriers of the dihedral angles. Finally, different evaluation methods were studied and a few promising criteria found to distinguish the near-native loop conformations from the wrong ones.

Computational Biology↗
PubMed1987

Potentiation of right ventricular function at a reduced workload: a potential pitfall in assessing right ventricular function by exercise radionuclide ventriculography.

Right ventricular ejection fraction (RVEF) determinations at rest (R) and exercise (E) are a means of demonstrating exercise-induced RV dysfunction. Not all patients are able to maintain peak (P) cardiac workloads during a gated RVEF study or, if a first-pass study is performed, for multiple acquisitions. Reductions from P cardiac workloads have been shown to potentiate LV function; however, the effect on RVEF has not been studied. Supine exercise radionuclide ventriculography was performed on 26 patients: nine normal subjects and 17 patients with coronary artery disease (CAD) (greater than 50% stenosis of one or more coronary artery). Gated RVEF's were obtained from sequential left anterior oblique views obtained at R, P, and at a workload reduced approximately 40% from P work levels postpeak (PP). In normals, RVEFs were at R, P, and PP 27, 38 and 44. In CAD patient RVEFs were 31, 35 and 39, at R, P, and PP, respectively. The conclusions are that RVEF improves from rest to PP exercise levels in normal subjects and in CAD patients and from P to PP levels in normal subjects. This improvement must be considered in interpreting exercise RV studies to aid in the detection of patients with CAD.

Adult↗
PubMed2006

5-ht5A receptors as a therapeutic target.

The 5-ht5A receptor is enigmatic among 5-HT receptors since, although the human receptor was cloned in 1994, until recently, very little has been learnt about the function of the receptor in native tissues. Findings from 5-ht5A receptor mRNA localisation and immunolabelling studies have revealed widespread expression in the CNS, and have provided pointers to the potential functional role(s) of the receptor. The expression of the 5-ht5A receptor in raphe nuclei and in higher brain areas, such as the cerebral cortex and hippocampus, suggests a potential autoreceptor function whilst localisation in the suprachiasmatic nucleus (SCN) suggests a role in circadian rhythm control. Additionally, 5-ht5A receptor knockout mouse phenotyping studies support a role in the control of exploratory behaviour. The lack of understanding of the role of the receptor has been, in part, due to the lack of available selective 5-ht5A receptor ligands. However, a selective 5-ht5A receptor antagonist, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride (SB-699551-A), has recently been identified which appears to be a useful tool with which to elucidate the physiological function of the receptor. Brain localisation and functional studies to date potentially implicate the receptor in the control of circadian rhythms, mood and cognitive function, whilst gene association studies implicate the receptor in the aetiology of schizophrenia. Although much is still to be learnt about the function of the 5-ht5A receptor, on the basis of these findings, it can be speculated that 5-ht5A receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.

Animals↗
PubMed1986

Organization of atriopeptin-like immunoreactive neurons in the central nervous system of the rat.

The atrial natriuretic peptide, atriopeptin, is a circulating hormone that plays an important role in the regulation of fluid and electrolyte homeostasis. Several recent studies have shown that atriopeptin-like immunoreactivity is present within the central nervous system as well as peripheral tissues. In the present report, we describe in detail the organization of atriopeptin-like immunoreactive (APir) perikarya and fibers in the central nervous system of the rat. The most prominent collection of APir perikarya was found in the hypothalamus, adjacent to the anteroventral tip of the third ventricle. Additional groups of APir perikarya were observed along the wall of the third ventricle and in the paraventricular and arcuate nuclei. Separate, smaller groups with distinctive morphology were seen in the lateral hypothalamic area, in the supra-mammillary, medial, and lateral mammillary nuclei, medial habenular nucleus, bed nucleus of the stria terminalis, and the central nucleus of the amygdala. In the pons and brain-stem, APir neurons were observed in the pedunculopontine and laterodorsal tegmental nuclei, as well as in the ventral tegmental area, Barrington's nucleus, the parabrachial nucleus, and the nucleus of the solitary tract. The densest terminal fields of APir fibers were found in the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, the median eminence, and the interpeduncular nucleus. The presence of atriopeptin immunoreactivity within the central nervous system suggests that atriopeptin may function as a central neuromediator. Potential functions of this candidate neuromediator deduced from its anatomical distribution are discussed, including the possibility that atriopeptin may function as both a central neuromediator and a systemic hormone in the regulation of the cardiovascular system.

Animals↗
PubMed2007

The oncogenic roles of p53 mutants in mouse models.

Tumors associated with p53 usually contain missense mutations in the p53 tumor suppressor gene rather than deletions of p53, suggesting a growth advantage for cells with missense mutations. The oncogenic roles of p53 mutants have been examined extensively in cell lines. Mouse models that inherit p53 mutations expressed at physiological levels have now been generated to examine the activities of mutant p53 upon tumorigenesis in vivo. Mice with p53 mutations develop tumor spectrums and metastatic phenotypes different from those of mice with a p53-null allele. Embryo fibroblasts with mutant p53 also show increased proliferative and transformation properties. One mechanism for this gain-of-function potential is the inhibition of function of the p53 family members p63 and p73.

Animals↗