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PubMed2006

Genes and the environment in neurodegeneration.

Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.) and discuss possible links of gene-environment interplay including, where implicated, mitochondrial genes.

Alzheimer Disease↗

PubMed1995

Role of selectins in myocardial ischemia-reperfusion injury.

During reperfusion of ischemic myocardium, there is a well-orchestrated interplay between the coronary vascular endothelium and the circulating neutrophils. This interplay involves the initial slowing or "rolling" of neutrophils along the endothelium during the early moments of reperfusion, followed by firm attachment and amplification of the neutrophil response, and culminating with the diapedesis of neutrophils into the myocardial parenchyma where neutrophil-myocyte interaction contributes to the necrotic process. The selectins are glycoproteins that play a key role in the early phases of neutrophil adherence and activation. There are three members of the selectin family: P-selectin on endothelial cells and platelets, L-selectin on neutrophils, and E-selectin on endothelium. Monoclonal antibodies directed specifically toward these selectins and their associated ligands (eg, Sialyl Lewisx) not only substantiate their role in the dynamic process of neutrophil-mediated reperfusion injury but also offer a unique therapeutic opportunity to interfere with this cascade of inflammatory events.

Cell Adhesion↗

PubMed1981

The influence of dietary unsaturated cis and trans and saturated fatty acids on tissue lipids of swine.

A feeding trial was conducted to evaluate the effects of dietary trans unsaturated fatty acids (trans fat) and of the interplay of dietary saturated fatty acids (saturated fat), cis unsaturated fatty acids, (cis fat) and trans fat on tissue lipids, particularly those effects suggestive of angiotoxicity. Swine were fed for 10 months a diet containing 17% added fat. Seven blends of varying proportions of the 3 fat components provided sufficient sample points to permit an examination of the interplay. Parameters under study included weight gain, serum cholesterol and triglyceride concentrations, lipoprotein lipid profile, total lipid and cholesterol concentrations of liver, heart and aorta, fatty acid composition of liver and aorta lipids and hepatic fatty acid synthesis and cholesterol synthesis and oxidation. Fat blends containing disproportionately high levels of saturated or cis fat generally elicited responses consistent with results reported by others. The notable exception was the serum cholesterol concentration. Throughout the study, the swine were hypercholesterolemic. Swine fed the high saturated fat blend had serum cholesterol levels equal to those swine fed the high cis fat blend. Serum cholesterol levels in the swine fed the other fat blends were more elevated. Another apparent anomaly was the lower concentration of lipid in the aortas of swine fed the high-saturated fat diet. The impact of the trans fat was modulated by the relative proportions of saturated and cis fat in the diet. The impact of trans fat was of greater magnitude for most parameters when the fat blend was low in saturated fat. The sole parameter suggestive of trans fat-mediated angiotoxicity was the distribution of lipids in lipoprotein fractions. Swine fed diets containing trans fat had lower relative proportions of the alpha-lipoprotein lipids. Although hypercholesterolemic, the high fat diets were not overtly angiotoxic except when fed to swine that carried a specific immunogenetically-defined low density lipoprotein.

Acetyl-CoA Carboxylase↗

PubMed1986

The role of intersegmental dynamics during rapid limb oscillations.

The interactive dynamic effects of muscular, inertial and gravitational moments on rapid, multi-segmented limb oscillations were studied. Using three-segment, rigid-body equations of motion, hip, knee and ankle intersegmental dynamics were calculated for the steady-state cycles of the paw-shake response in adult spinal cats. Hindlimb trajectories were filmed to obtain segmental kinematics, and myopotentials of flexors and extensors at each of the three joints were recorded synchronously with the ciné film. The segmental oscillations that emerged during the paw-shake response were a consequence of an interplay between active and passive musculotendinous forces, inertial forces, and gravity. During steady-state oscillations, the amplitudes of joint excursions, peak angular velocities, and peak angular accelerations increased monotonically and significantly in magnitude from the proximal joint (hip) to the most distal joint (ankle). In contrast to these kinematic relationships, the maximal values of net moments at the hip and knee were equal in magnitude, but of significantly lower magnitude than the large net moment at the ankle joint. At both the ankle and the knee, the flexor and extensor muscle moments were equal, but at the hip the magnitude of the peak flexor muscle moment was significantly greater than the extensor muscle moment. Muscle moments at the hip not only acted to counterbalance accelerations of the more distal segments, but also acted to maintain the postural orientation of the hindlimb. Large muscle moments at the knee functioned to counterbalance the large inertial moments generated by the large angular accelerations of the paw. At the ankle, the muscle moments dominated the generation of the paw accelerations. At the ankle and the knee, muscle moments controlled limb dynamics by slowing and reversing joint motions, and the active muscle forces contributing to ankle and knee moments were derived from lengthening of active musculotendinous units. In contrast to the more distal joints, the active muscles crossing the hip predominantly shortened as a result of the interplay among inertial forces and gravitational moments. The muscle function and kinetic data explain key features of the complex interactions that occur between central control mechanisms and multi-segmented, oscillating limb segments during the paw-shake response.

Animals↗

PubMed1986

Peptide-steroid interactions in brain regulation of pulsatile gonadotropin secretion.

Reproductive function is regulated by an intricate system of peptide, steroid and amine factors interacting within the brain, pituitary and gonads. At no point is the complexity of the reproductive system better exemplified than in the exquisite interplay of factors required to produce and modulate pulsatile gonadotropin secretion. By extension, analysis of the pulsatile secretory pattern of the gonadotropins, as a means of assessing the contribution of these various factors, can reveal interactions too subtle to be detected by the conventional examination of mean gonadotropin concentration. Analysis of the pulsatile secretory patterns of both LH and FSH reveals striking differences between the two gonadotropins in their response to inhibitory, gonadal peptide and steroid factors, suggesting divergent paths of brain-pituitary regulation. Further studies to clarify this disparity in regulation have demonstrated that neutralization of endogenous LHRH completely abolishes pulsatile LH secretion without affecting pulsatile FSH secretion, suggesting the existence of another, as of yet unknown, brain factor which regulates FSH secretion. The feedback signals provided by gonadal steroids can induce both inhibition and facilitation of LHRH and LH secretion. Neurons of the central opiatergic system exert a tonic inhibitory influence on the catecholaminergic neurons regulating LHRH secretion, and are believed to mediate the inhibitory actions of the gonadal steroids on the LHRH system. Withdrawal of the gonadal steroids has been reported to cause a rapid loss of the tonic inhibitory control of the opiate system on LHRH secretion as revealed by a lack of response to naloxone. Reassessment of this system by analyzing the pulsatile pattern of LH secretion, however, reveals that the loss of naloxone effect after gonadectomy occurs very gradually and that an effect can still be obtained up to 2 weeks after the removal of gonadal steroids. These studies provide excellent examples of the complex interplay observed just between selected factors regulating pulsatile gonadotropin secretion. The use of pulsatile gonadotropin analysis is a powerful model, not only for providing greater clarity of known regulatory interactions, but also for revealing new and more subtle levels of control in the brain-pituitary-axis.

Animals↗

PubMed1983

Effects of naloxone on the secretion of prolactin and corticosterone induced by 5-hydroxytryptophan and a serotonergic agonist, mCPP.

The effects of naloxone, an opiate "pure" receptor antagonist, on the release of prolactin and corticosterone in the rat were studied following the administration of the serotonin precursor 5-hydroxytryptophan or the serotonin receptor agonist (-) -m-chlorophenylpiperazine. Naloxone clearly antagonizes the release of prolactin induced by 5-hydroxytryptophan administered alone at a dosage of 50 mg/Kg/b.wt. or at dosage of 30 mg/Kg/b.wt. preceded 60 minutes before injection by the administration of the serotonin uptake blocker fluoxetine. The opiate antagonist does not modify the increase in blood level of prolactin induced by (-) -m-chlorophenylpiperazine. Naloxone itself does not reduce the increase in plasma level of corticosterone induced by 5-hydroxytryptophan, 5-hydroxytryptophan+fluoxetine or (-)-m-chlorophenylpiperazine. The results suggest that endogenous opioids may be involved in the increase in serum level of prolactin induced by 5-hydroxytryptophan and also indicate the existence of different serotonergic neurotransmitter circuits capable of modulating the release of prolactin and corticosterone. A mutual interplay between serotonergic and opiate neurons may be involved in controlling the release of prolactin, but such an interplay does not seem to occur in the secretion of corticotrophin-releasing hormone.

5-Hydroxytryptophan↗

PubMed1985

The vasculature and limb development.

The developing vascular pattern of the embryonic chick limb results from a combination of two properties: the intrinsic self-assembly and branching properties of the vascular cells and the extrinsic information associated with the expanding mitotic population of mesenchymal cells; and the inhibitory factors which restrict the entrance of vessels into particular domains and/or decrease the branching frequency of such vessels. It is hypothesized that an important component of limb pattern formation is the interplay between the dividing population of mesenchymal cells and the intrinsic properties of the vascular cells. It is further asserted that the presence of particular vascular elements may, indeed, be 'positional information'. Two examples are cited involving aspects of limb duplication to support this possibility; it is suggested that vascular vessel size of a host limb may dictate the polarity of duplication events. The presented hypothesis emphasizes that the interplay between the intrinsic properties of self-assembly into tissues and extrinsic factors which establish boundaries and morphologies is involved in both vascular and limb pattern formation.

Animals↗

PubMed1995

Characterization of the interactions of NADH with the dimeric and tetrameric states of methaemoglobin.

The binding of NADH to the dimeric (alpha beta) and tetrameric (alpha 2 beta 2) states of human aquomethaemoglobin has been characterized by sedimentation equilibrium studies of the effect of the concentration of free ligand on the macromolecular state of the haemoprotein. Both macromolecular states of aquomethaemoglobin exhibit a single binding site for NADH, which interacts approximately tenfold more strongly (6000 cf. 700 M-1) with the tetramer under the conditions studied (pH 6.0, I 0.10). Because the structure of aquomethaemoglobin resembles that of the deoxy state of haemoglobin, there is a high probability that organic phosphates also bind to dimeric deoxyhaemoglobin, a phenomenon which is not considered in thermodynamic treatments of the interplay between oxygen binding and its allosteric inhibition by 2,3-bisphosphoglycerate. Fortunately, the equilibrium constant for deoxyhaemoglobin self-association is so large that neglect of the interaction between allosteric inhibitor and dimeric haemoglobin is an oversight that should have no deleterious implications in the resultant thermodynamic analysis of the interplay between the preferential interactions of oxygen and organic phosphate with the various macromolecular states of deoxyhaemoglobin.

Binding Sites↗

PubMedDate not supplied

Medical, social and psychological factors as predictors of survival - a follow-up from 67 to 87 years of age.

All pensioners in a primary care district (n=142) participating in a multi-disciplinary population study were followed from 67 years of age to the age of 87 with regard to survival. A multivariate survival analysis of psychological and social factors and medical symptoms at 67 years of age was used to test the relationship between such data and survival. Out of the 23 original medical, social and psychological factors/variables, the successive ranking risk factors for men were: positive attitudes to old-age homes, high social class, many reported disease at age 67, low degree of need satisfaction, and many reported earlier disease. For women the ranking of risk factors for early death were: early death age of mother, low degree of social rigidity, smoking, field-dependency and need of social help. The results reflect the interplay between hereditary, medical, social and psychological factors in predicting survival and how this interplay differs between males and females.

Journal Article↗

PubMedDate not supplied

Transgenic mice expressing APP-C100 in the brain.

The classic hallmarks of Alzheimer's disease are the deposition of amyloid in plaques and in the cerebrovasculature, and the emergence of neurofibrillary tangles in neurons. The interplay between these two pathologic processes, on the one hand, and the degeneration of neurons and loss of cognitive functions on the other, remains incompletely understood. We have proposed that one crucial component of this interplay is a fragment of the Alzheimer amyloid protein precursor (APP) comprising the carboxyterminal 100 amino acids of this molecule, which we term APP-C100 (or, more simply, C100). This fragment, which comprises the 42-amino acid amyloid protein (A beta) and an additional 58 amino acids carboxyterminal to it, was found to be toxic specifically to nerve cells in vitro. We developed transgenic mouse models to test the hypothesis that APP-C100 causes Alzheimer's disease neuropathology. APP-C100 was delivered to the mouse brain via a transgene expressing C100 under the control of the dystrophin brain promoter. These transgenic animal models for the action of APP-C100 in the brain exhibited some of the neuropathological features characteristic of Alzheimer disease brain. The animal models that we have created can be used to test hypotheses concerning the mechanism by which C100 interacts with a neuronal receptor to kill neurons.

Alzheimer Disease↗

PubMed1993

A novel role for calcium and membrane-binding proteins in regulation of respiratory burst in Ehrlich ascites tumour cells.

The effect of the signals, dexamethasone and phorbol-ester (TPA) and their interplay on the respiratory burst in Ehrlich ascites tumour (EAT) cells and the effect of this interplay has on the phosphorylation state and thus function of EAT cell cytosolic calcium and membrane-binding proteins (CaMBPs) was studied. Dexamethasone (1 mg/kg body weight) inhibited basal and TPA-activated EAT cell respiratory burst. CaMBPs isolated from EAT cells under the influence of either or both signals by a membrane-affinity binding technique showed similar profiles on SDS-PAGE. Autoradiography showed that only an 11,000 M(r) protein is subject to phosphorylation and that dexamethasone brings down the extent of phosphorylation of CaMBPs isolated from control and TPA-treated EAT cells. Phosphorylated CaMBPs from control and TPA-treated cells could activate the respiratory burst in Triton-permeabilized EAT cells in a dose-dependent manner (four- and six-fold activations, respectively, at 16 micrograms protein concentration) when included in the assay, whereas dephosphorylated CaMBPs from EAT cells from mice treated with dexamethasone alone, or later activated with TPA, could not. A phosphatase activity was detected in EAT cell cytosol receiving the dual-signal, dexamethasone and TPA.

Animals↗

PubMed1996

Regulation of corticosteroid-binding globulin synthesis by 1alpha,25-dihyroxy-vitamin D3 (calcitriol), 9-cis-retinoic acid and triiodothyronine in cultured rat fetal hepatocytes.

Evidence regarding the nature of the regulatory factors which directly act upon liver cells and extra-hepatic tissues to alter CBG synthesis is scarce. The present study used cultured rat fetal hepatocytes to investigate the involvement and possible interplay in this process of several members of the nuclear receptors superfamily: vitamin D (VDR), retinoic acids (RAR/RXR) and thyroid hormones (TR). Treatment of cells with 1alpha,25-(OH)2D3 (1,25-D) elicited a dose-dependent inhibition of basal CBG concentration in culture medium. Maximum inhibition to about 15% of control level was achieved with 0.1-1.0 nM, with an IC50 of 3.8 x 10(-12) M and with no significant change in binding affinity. Differential activation of RAR and RXR with either 9-cis-retinoic acid (9-cis-RA) or the RAR-selective synthetic retinoid TTNPB revealed that high doses of both drugs diminished CBG expression, though the former proved about 10-times more potent than the latter in this regard. Amplification by triiodothyronine (T3) of CBG synthesis failed to block the inhibitory effects of either 1,25-D or retinoids, as revealed by both binding capacity and mRNA measurements. Relative to CBG, 1,25-D similarly depressed the synthesis of alpha-fetoprotein (AFP), while on the contrary, retinoids and T3 were shown to cause opposite effects, as 9-cis-RA and TTNPB elevated and T3 decreased AFP expression. The present findings identify for the first time ligands of VDR and RAR/RXR as powerful negative regulators of both basal and T3-stimulated CBG biosynthesis in fetal hepatocytes and suggest lack of a functional interplay between TR and VR or RAR/RXR in these processes.

Animals↗

PubMedDate not supplied

Lingering biologic dilemmas about the status of the progenitor cells in myelodysplasia.

Myelodysplastic syndromes (MDS) are considered to be stem cell disorders. High incidence of intramedullary apoptosis has been associated with the peripheral cytopenia and refractory anemia in these disorders. The investigations on the cell of origin in the bone marrow have invariably been hampered by a poor yield of CD34+ cells from these marrows. Interestingly, even though limited in number, these studies raised more questions and dilemmas than providing answers. While the enigma surrounding the clonality of these marrows continues, the controversies regarding incidence of apoptosis, proliferation, and potential of clonogenic expansion may be closer to a settlement. The present review proposes a model depicting interplay between extraneous apoptogenic factors and intracellular apoptosis-susceptibility determinants that contributes significantly toward the progression of MDS and how a shift in dynamics of this interplay may provide grounds to accumulate additional mutations with a probable block in differentiation eventually leading to a leukemic transformation.

Antigens, CD34↗

PubMed2004

Higher order chromatin architecture in the cell nucleus: on the way from structure to function.

The cell nucleus is a highly compartmentalized structure. In this review we describe controversial views on higher order chromatin organization from the level of higher order chromatin domains built up from folded chromatin fibers to the level of chromosome territories and the interchromatin compartment (IC), which harbors non-chromatin nuclear domains, such as interchromatin granule clusters (IGCs visualized in the electron microscope) or splicing factor-containing speckles (visualized by fluorescence microscopy). Emphasis is laid on the definition and functional importance of a nuclear compartment located at the periphery of chromatin domains in direct contact with the IC, termed the perichromatin region (PR). Ongoing experiments to elucidate the topological relationships between PR and IC have provided new insights into the functional interplay between transcription and splicing. As an example, we discuss the structure and nuclear topology of perichromatin fibrils (FPs) contained in the PR and their functional interplay with IGCs/speckles. In addition we discuss the advantages and drawbacks of experimental approaches currently used to study nuclear architecture and function in fixed and living cells.

Animals↗

PubMed2005

The influence of GFP-actin expression on the adhesion dynamics of HepG2 cells on a model extracellular matrix.

Integrins belong to a family of important cell surface receptors which mediate the adhesion of most anchorage-dependent cells to nature extracellular matrix (ECM) and biomaterials. It is known that the binding of integrin with ECM proteins triggers mechanochemical responses of cytoskeleton. To date, the intricate interplay between integrin-ECM interaction and cytoskeleton dynamics leading to the regulation of cell morphogenesis on biomaterials remains largely unknown. In this study, green fluorescence protein (GFP)-actins were expressed in HepG2 cells for the temporal visualization of cytoskeletal structure of adherent cells on naturally derived materials. By combining confocal reflectance contrast microscopy and fluorescence microscopy, the adhesion contact dynamics, cytoskeleton remodeling and two-dimensional spreading of intact and GFP-actin expressing HepG2 cells on collagen and fibronectin-coated substrates are simultaneously probed during the initial cell seeding. First of all, our results show that the evolution of adhesion contact of HepG2 cells upon integrin-collagen or integrin-fibronectin interaction is impaired by GFP-actin expression. Also, the initial rate of cell deformation is reduced by 70% and 43% on fibronectin and collagen, respectively, upon GFP-actin expression. Interestingly, the steady-state adhesion energy of HepG2 cells remains unchanged and increases on fibronectin- and collagen-coated substrate, respectively, upon GFP-actin expression. Our highly integrated biophysical approach demonstrates that GFP-actins diffusively concentrate in the cytoplasmic cortex during initial cell seeding while adhesion contact evolves and cell spreads. Kinetics analysis on the adhesion contact formation demonstrates the intricate interplay between cytoskeleton property and ECM proteins in cell adhesion.

Actins↗

PubMed2006

Dietary intake of B-vitamins, polymorphisms in thymidylate synthase and serine hydroxymethyltransferase 1, and colorectal adenoma risk: a Dutch case-control study.

Thymidylate synthase and serine hydroxymethyltransferase are involved in folate metabolism. In a case-control study, including 768 cases and 709 controls, we investigated the associations between colorectal adenomas and TS tandem repeat and SHMT1 C1420T polymorphisms, and the interplay with B-vitamins. The polymorphisms were not associated with adenomas, but there was a borderline significant interaction between TS genotype and vitamin B6: the association between vitamin B6 and adenomas seemed positive in TS 3R/3R individuals, but inverse in TS 2R/2R individuals. This study does not provide evidence for a role of SHMT1 genotype in adenoma occurrence. Future research has to indicate whether the TS-B6 interplay is a real effect or a chance finding.

Adenoma↗

PubMed2004

Cytokine flow cytometry: a multiparametric approach for assessing cellular immune responses to viral antigens.

Considerable attention has been focused on CD8 and CD4 T cell responses as a major element of the cellular immune response to viral infections including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, increasing evidence based on the recent introduction of more quantitative assays for measuring antigen-specific T cells has suggested that the role of these cells in the development of a protective immune response to a particular viral pathogen may be determined by a complex interplay of multiple virologic and cellular factors. Thus, measurements of only the frequencies of the T cell subsets participating in the response to viral pathogens may be an incomplete reflection of efficacy. In this review, we suggest that some measurable factors may influence the role of T cell immunity in conferring protection, including functional avidity, epitope breadth and specificity, proliferative capacity, cytokine repertoire, degree of anergy, and differentiation phenotype, as well as magnitude, of viral-specific CD4 and CD8 T cells. We suggest that automated cytokine flow cytometry (CFC) is an efficient approach to the measurement of the complex interplay of multiple immune parameters involved in immune protection. These ideas are discussed in the context of new developments in sample preparation and analysis automation.

Animals↗

PubMed2005

The oscillatory network of simple repetitive bimanual movements.

Bimanual synchronization relies on the precisely coordinated interplay of both hands. It is assumed that during temporal bimanual coordination, timing signals controlling each hand might be integrated. Although a specific role of the cerebellum for this integration process has been suggested, its neural foundations are still poorly understood. Since dynamic interactions between spatially distributed neural activity are reflected in oscillatory neural coupling, the aim of the present study was to characterize the dynamic interplay between participating brain structures. More specifically, the study aimed at investigating whether any evidence for the integration of bilateral cerebellar hemispheres could be found. Seven right-handed subjects synchronized bimanual index finger-taps to a regular pacing signal. We recorded continuous neuromagnetic activity using a 122-channel whole-head neuromagnetometer and surface EMGs of the first dorsal interosseus (FDI) muscle of both hands. Coherence analysis revealed that an oscillatory network coupling at 8-12 Hz subserves task execution. The constituents are bilateral primary sensorimotor and premotor areas, posterior-parietal and primary auditory cortex, thalamus and cerebellum. Coupling occurred at different cortical and subcortical levels within and between both hemispheres. Coupling between primary sensorimotor and premotor areas was observed directly and indirectly via the thalamus. Coupling direction suggests that information was integrated within the left premotor cortex corroborating a specific role of the left premotor cortex for motor control in right-handers. Most importantly, our data indicate strong coupling between both cerebellar hemispheres substantiating the hypothesis that cerebellar signals might be integrated during task execution.

Adult↗