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Results for “Functional perturbation”

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PubMed1998

Adhesion of mature polyploid megakaryocytes to fibronectin is mediated by beta 1 integrins and leads to cell damage.

Human CD34+ bone marrow cells were committed to the megakaryocytic lineage in serum-free liquid cultures by the following cytokines: thrombopoietin, erythropoietin, and IL-6. Megakaryocyte maturation has been described as being regulated by the extracellular matrix. These cells express receptors for laminin, collagen, and vitronectin, but they selectively adhere to and spread on fibronectin, a major component of the bone marrow environment. Function-perturbing antibodies against beta 1 integrins totally abolished the adhesion of megakaryocytes on fibronectin, whereas antibodies to beta 3 did not, suggesting that beta 1 integrins were responsible for the adhesive phenotype of these polyploid cells. beta 1-positive clusters were visualized in close contact with the extremities of stress fibers at the cell surface. In the course of cell spreading, we observed morphological modifications such as the disorganization of the compact nuclei structure and the appearance of holes in the cytoplasm leading to the release of alpha IIb beta 3-positive cellular fragments. This process appeared to be a specific feature of megakaryocytes and is correlated neither to apoptosis nor to integrin signaling.

Actin Cytoskeleton↗

PubMed2000

Hydrogen bonding effects on the (15)N and (1)H shielding tensors in nucleic acid base pairs.

The results of systematic ab initio calculations of (15)N and (1)H chemical shielding tensors in the GC base pair as a function of hydrogen bond length are presented for the first time. The hydrogen bond length characterized by the distance r(N...N) between purine N1 and pyrimidine N3 was varied between 2.57 and 3.50 A and the chemical shift tensors were calculated by the sum-over-states density functional perturbation theory. It is shown that the hydrogen bond length has a strong effect on the chemical shielding tensor of both imino proton and nitrogen, on their orientation, and, as a consequence, on the relaxation properties of both nuclei. For a nitrogen nucleus not involved in hydrogen bonding, the shielding tensor is nearly axially symmetric and almost collinear with the bond vector. As the length of the hydrogen bond decreases, the least shielding component sigma(11) deflects from the N-H vector and the shielding tensor becomes increasingly asymmetric. The significance of the presented results for the analysis of relaxation data and the efficiency of TROSY effects together with a summary of the relevant shielding parameters are presented and discussed.

Base Pairing↗

PubMed2000

Experimental and theoretical 31P and 77Se nuclear magnetic shielding tensors for bis(dineopentoxyphosphorothioyl) diselenide.

An intergrown crystal of two phases of bis(dineopentoxyphosphorothioyl) diselenide 1 was investigated by goniometer 31P NMR. From the angular dependence of the chemical shift, the tensors of a triclinic and a monoclinic phase were determined. The principal values sigma11, sigma22, and sigma33, of the absolute nuclear magnetic shielding tensors for the triclinic phase are 134.1, 227.2, and 375.5 ppm and for the monoclinic phase are 132.4, 227.8, and 374.2 ppm, respectively. In both cases, the principal axis 3 of the 31P tensor is directed nearly along the P=S bond and the principal axis 2 is nearly perpendicular to the S=P-Se plane. Calculations of the 31P and 77Se nuclear magnetic shielding tensors were performed for molecules of both phases of 1 and for model compounds by the sum-over-states density functional perturbation theory IGLO method. The rms distances between calculated and experimental 31P NMR icosahedral tensor values sigma(j) (j = 1, ..., 6) amount to 17-21 ppm. The calculated and experimental orientations of the 31P principal axes show a maximum difference of 5 degrees and rms distances of 3.2 and 3.3 degrees. For the principal value sigma33 of the selenium shielding tensor the agreement between calculated and experimental values is satisfactory, but the calculated values sigma11 and sigma22 are distinctly too small. Calculations for a model compound in which the methyl groups of the neopentoxy residue are substituted by protons lead practically to the same results.

Crystallization↗

PubMed1992

Lung transplantation: pulmonary cell lysis mediated by alveolar mononuclear cells.

Methods were developed to monitor graft rejection in a porcine model of unilateral lung transplantation. The ability of peripheral blood mononuclear cells and lavage-derived mononuclear cells to lyse donor pulmonary tissue was determined by standard chromium release assays at various times after transplantation. Effective antigraft activity was observed in the local environment of a rejecting graft, but not in the periphery. Since transplant rejection is a reversible process, with the administration of suitable immunosuppressive regimes frequently restoring graft function, it was reasoned that immunological assays based on the lysis of individual cells may not be relevant to the in vivo situation. We therefore describe an assay of the lung barrier function; perturbations of the tight intraepithelial junctions which compose the air-blood barrier can be determined in vitro by the measurement of transmonolayer resistance values.

Animals↗

PubMed2000

Endothelial function and hemostasis.

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.

Arteriosclerosis↗

PubMed2000

A road to kidney tubules via the Wnt pathway.

Classical in vitro studies indicate that tubule induction in the kidney mesenchyme is mediated by cell-cell contacts between the inducer tissue and the metanephric mesenchyme. Induction is completed within the first 24 h, after which tubules will form because of stimulated cell proliferation, migration, and cell adhesion. Recent evidence has revealed an essential role for the secreted signals from the Wnt gene family. Of these, Wnt-4 is expressed in developing tubules and knocking out its function perturbed kidney development. More detailed studies demonstrated normal condensation, but tubules were missing. Subsequent experiments indicated that Wnt-4 is also a sufficient signal to trigger tubulogenesis. Cells that were engineered to express Wnt-4 not only induced tubulogenesis in the kidney mesenchyme of Wnt-4 mutant embryos, but also induced tubules in the wild type mesenchyme. With the transfilter induction assay, Wnt-4-mediated induction was completed within the first 24 h, depending on the presence of proteoglycans and cell-cell contacts between the interactants. In addition, Wnt-4 autoinduced expression of its own gene and a panel of other components of the Wnt signalling pathway, such as frizzleds and a candidate Wnt antagonist from the secreted frizzled-related protein family. Taken together, the data provide evidence of an essential role for Wnt signal transmission and transduction pathways in the induction of kidney tubules, and the findings have paved the way for detailed molecular studies.

Animals↗

PubMed1977

Hemoglobin Djelfa beta98 (FG 5) Val leads to Ala: isolation and functional properties of the heme saturated form.

Hemoglobin Djelfa beta98 (FG 5) Val leads to Ala is a neutrally substituted unstable hemoglobin, exhibiting the same gross features as hemoglobin Köln beta98 (FG 5) Val leads to Met. In addition to the presence of a deheminized fraction, a heme saturated abnormal hemoglobin was visualized and isolated by high resolution electrofocusing. By functional studies of the fully heminized form, a slightly increased oxygen affinity, an impairment of heme-heme interaction and a decreased response to organic phosphates were demonstrated. These functional perturbations point out the importance of the beta98 invariant valyl residue, in the quaternary contacts. They can account for the poor oxygen delivery of erythrocytes.

Alanine↗

PubMed1994

Lead perturbs 1,25 dihydroxyvitamin D3 modulation of intracellular calcium metabolism in clonal rat osteoblastic (ROS 17/2.8) cells.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is known to modulate Ca2+ metabolism in several cell types. 1,25(OH)2D3 causes an increase in Ca2+ influx and probably exerts many of its effects via the Ca2+ messenger system. Lead (Pb2+) interacts with and perturbs normal Ca2+ signalling pathways; hence, the purpose of this work was to determine if Pb2+ perturbs 1,25(OH)2D3 modulation of Ca2+ metabolism in ROS 17/2.8 cells, which express receptors for and respond to 1,25(OH)2D3, and to determine the effect of 1,25(OH)2D3 on Pb2+ metabolism in these cells. In both cases three kinetic compartments described the intracellular metabolism of the isotope. These data show that 1 microM Pb2+ inhibits 1,25(OH)2D3 modulated increases in Ca2+ flux, whereas 5 microM Pb2+ increases membrane fluxes, all intracellular Ca2+ pools, and total cell Ca2+. In the Pb2+ metabolism studies it was found that 10 nM 1,25(OH)2D3 increases intracellular Pb2+. Pb2+ appears to disrupt the modulation of intracellular steady-state Ca2+ homeostasis by 1,25(OH)2D3 in a complex, biphasic manner and may therefore perturb functions that are modulated by 1,25(OH)2D3 via the Ca2+ messenger system.

Animals↗

PubMedDate not supplied

Type II diabetic nephropathy in perspective.

The magnitude of type II diabetic nephropathy dilemma is observable in the growing number of diabetic patients with end-stage renal lesion receiving various modalities of treatment. Progressive glomerulopathy associated with proteinuria and hypertension is strongly causative of renal failure and mortality in diabetic patients. Besides hypertension, diabetes exceeds all other glomerulopathies in causing end-stage renal failure. Alterations in glomerular structure and function observed in diabetic patients are implicated in the development and progression of renal derangement. Diabetic glomerulosclerosis, an aggregate of structural and functional perturbations of the kidney, is indicated by alterations in the accumulation of extracellular matrix components, The pathology, epidemiology, risk factors, and other dependent variables may throw some light in the pathogenetic mechanisms and the prevention, treatment, and management modalities of type II diabetic nephropathy.

Blood Glucose↗

PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗

PubMed2005

Impact of lowering dialysate calcium concentration on serum bone turnover markers in hemodialysis patients.

Loss of renal function perturbs bone metabolism because kidney is a vital organ maintaining homeostasis of calcium and phosphate. In hemodialysis patients, bone diseases are serious complications resulting in fractures and extraosseous calcification. The latest clinical practice guidelines by the National Kidney Foundation (New York, US) recommend a dialysate calcium concentration (D-Ca) of 2.5 mEq/L rather than 3.0 mEq/L to avoid excess calcium load and to prevent subsequent vascular calcification. However, there is no perfect agreement yet about which concentration should be chosen because lowering D-Ca might enhance uncoupled bone resorption. Here, we studied effects of lowering D-Ca from 3.0 to 2.5 mEq/L on bone metabolism in 67 patients. Doses of vitamin D and phosphate binders were kept constant for a 2-month period beginning 1 month before the change in D-Ca, and were adjusted thereafter. In group A [intact parathyroid hormone (iPTH) < 100 pg/ml before the study], serum cross-linked N-terminal telopeptide of type I collagen (NTx) increased immediately after lowering D-Ca and then remained stable. Intact osteocalcin (iOC) increased later along with iPTH, suggesting the improvement of adynamic bone disease which shows a marked decrease in bone turnover without osteoid accumulation. Vitamin D was not dosed up in this group. In group B (100 < or = iPTH < 300), serum NTx increased transiently, which is followed by an increase of iOC but not by a change of iPTH. In group C (300 < or = iPTH), lowering D-Ca allowed us to increase the dose of vitamin D without hypercalcemia, leading to a significant decrease in NTx and iPTH. Overall, serum phosphate increased from 5.4 +/- 1.6 to 6.1 +/- 1.6 mg/dL (P < 0.0001) and serum NTx increased by 1.5-fold (P < 0.0001) 1 month after lowering D-Ca. Over a 3-month period after that, serum phosphate and serum NTx decreased to their basal levels. These indicate that bone resorption predominated over formation for only a short period. In conclusion, a D-Ca of 2.5 mEq/L with adjustment of vitamin D ameliorates metabolic abnormalities of bone which develop under 3.0 mEq/L.

Aged↗

PubMed2005

The coupling mechanism of P-glycoprotein involves residue L339 in the sixth membrane spanning segment.

The transmembrane (TM) domains in P-glycoprotein (P-gp) contain the drug binding sites and undergo conformational changes driven by nucleotide catalysis to effect translocation. However, our understanding of exactly which regions are involved in such events remains unclear. A site-directed labelling approach was used to attach thiol-reactive probes to cysteines introduced into transmembrane segment 6 (TM6) in order to perturb function and infer involvement of specific residues in drug binding and/or interdomain communication. Covalent attachment of coumarin-maleimide at residue 339C within TM6 resulted in impaired ATP hydrolysis by P-gp. The nature of the effect was to reduce the characteristic modulation of basal activity caused by transported substrates, modulators and the potent inhibitor XR9576. Photoaffinity labelling of P-gp with [(3)H]-azidopine indicated that residue 339C does not alter drug binding per se. However, covalent modification of this residue appears to prevent conformational changes that lead to drug stimulation of ATP hydrolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Simple b ions have cyclic oxazolone structures. A neutralization-reionization mass spectrometric and computational study of oxazolone radicals.

The 2-methyloxazol-5-on-2-yl radical (3) and its deuterium labeled analogs were generated in the gas-phase by femtosecond electron-transfer and studied by neutralization-reionization mass spectrometry and quantum chemical calculations. Radical 3 undergoes fast dissociation by ring opening and elimination of CO and CH(3)CO. Loss of hydrogen is less abundant and involves hydrogen atoms from both the ring and side-chain positions. The experimental results are corroborated by the analysis of the potential energy surface of the ground electronic state in 3 using density functional, perturbational, and coupled-cluster theories up to CCSD(T) and extrapolated to the 6-311 ++ G(3df,2p) basis set. RRKM calculations of radical dissociations gave branching ratios for loss of CO and H that were k(CO)/k(H) > 10 over an 80-300 kJ mol(-1) range of internal energies. The driving force for the dissociations of 3 is provided by large Franck-Condon effects on vertical neutralization and possibly from involvement of excited electronic states. Calculations also provided the adiabatic ionization energy of 3, IE(adiab) = 5.48 eV and vertical recombination energy of cation 3(+), RE(vert) = 4.70 eV. The present results strongly indicate that oxazolone structures can explain fragmentations of b-type peptide ions upon electron capture, contrary to previous speculations.

Computer Simulation↗

PubMed2005

Extending the simple weighted density approximation for a hard-sphere fluid to a Lennard-Jones fluid II. Application.

A simple weighted density approximation (SWDA) was extended to nonuniform Lennard-Jones fluids by following the spirit of a partitioned density function theory [S. Zhou, Phys. Rev. E 68 (2003) 061201] and mapping the hard-core part onto an effective hard-sphere fluid whose higher order terms beyond the second order of the functional perturbation expansion are treated by the SWDA. The resultant DFT formalism performs well for Lennard-Jones fluids under the influence of diverse external fields. With the present DFT formalism, we investigate in detail the structure and adsorption properties of a low-density LJ gas in a spherical cavity with a wall consisting of hard-sphere or LJ particles. It was found that when the cavity wall exerts an attractive external potential on the LJ particles in the cavity, the excess adsorption decreases as the temperature increases, while when the cavity wall exerts a hard repulsive external potential on the LJ particles in the cavity, the excess adsorption increases as the temperature increases.

Journal Article↗

PubMed2005

The negative cell cycle regulator, Tob (transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory.

Tob (transducer of ErbB2) is a negative cell cycle regulator with anti-proliferative activity in the periphery. Using a behavioral screening paradigm to look for novel gene functions in the brain, we identified Tob as a brain-expressed protein involved in learning and memory. Behavioral training of fear-conditioning triggered a transient elevation of Tob protein, which preceded the formation of long-term memory. Functional perturbation of Tob by intra-CA1 infusion of antisense oligonucleotides in rats impaired spatial learning and memory in the Morris water maze and long-term memory for contextual fear conditioning, two behavioral paradigms that require the hippocampus. Furthermore, long-term potentiation was suppressed by Tob antisense infusion into the CA1 region. Together, these results indicate that the negative cell cycle regulator Tob is a multifunctional protein involved in hippocampus-dependent learning and memory.

Amino Acid Sequence↗

PubMed2003

Phosphorus magnetic resonance spectroscopy: its utility in examining the membrane hypothesis of schizophrenia.

A novel approach to understanding the pathophysiology of schizophrenia has been the investigation of membrane composition and functional perturbations, referred to as the "Membrane Hypothesis of Schizophrenia." The evidence in support of this hypothesis has been accumulating in findings in patients with schizophrenia of reductions in phospholipids and essential fatty acids various peripheral tissues. Postmortem studies indicate similar reductions in essential fatty acids in the brain. However, the use of magnetic resonance spectroscopy (MRS) has provided an opportunity to examine aspects of membrane biochemistry in vivo in the living brain. MRS is a powerful, albeit complex, noninvasive quantitative imaging tool that offers several advantages over other methods of in vivo biochemical investigations. It has been used extensively in investigating brain biochemistry in schizophrenia. Phosphorus MRS (31P MRS) can provide important information about neuronal membranes, such as levels of phosphomonoesters that reflect the building blocks of neuronal membranes and phosphodiesters that reflect breakdown products. 31P MRS can also provide information about bioenergetics. Studies in patients with chronic schizophrenia as well as at first episode prior to treatment show a variety of alterations in neuronal membrane biochemistry, supportive of the membrane hypothesis of schizophrenia. Below, we will briefly review the principles underlying 31P MRS and findings to date. Magnetic resonance spectroscopy (MRS) is a powerful, albeit complex, imaging tool that permits investigation of brain biochemistry in vivo. It utilizes the magnetic resonance imaging hardware. It offers several advantages over other methods of in vivo biochemical investigations. MRS is noninvasive, there is no radiation exposure, does not require the use of tracer ligands or contrast media. Because of it is relatively benign, repeated measures are possible. It has been used extensively in investigating brain biochemistry in schizophrenia.

Brain↗

PubMed2006

A role for the L-selectin adhesion system in mediating cytotrophoblast emigration from the placenta.

Cytotrophoblast (CTB) aggregates that bridge the gap between the placenta and the uterus are suspended as cell columns in the intervillous space, where they experience significant amounts of shear stress generated by maternal blood flow. The proper formation of these structures is crucial to pregnancy outcome as they play a vital role in anchoring the embryo/fetus to the decidua. At the same time, they provide a route by which CTBs enter the uterine wall. The mechanism by which the integrity of the columns is maintained while allowing cell movement is unknown. Here, we present evidence that the interactions of L-selectin with its carbohydrate ligands, a specialized adhesion system that is activated by shear stress, play an important role. CTBs in cell columns, particularly near the distal ends, stained brightly for L-selectin and with the TRA-1-81 antibody, which recognizes carbohydrate epitopes that support binding of L-selectin chimeras in vitro. Function-perturbing antibodies that inhibited either receptor or ligand activity also inhibited formation of cell columns in vitro. Together, these results suggest an autocrine role for the CTB L-selectin adhesion system in forming and maintaining cell columns during the early stages of placental development, when the architecture of the basal plate region is established. This type of adhesion may also facilitate CTB exit from cell columns, a prerequisite for uterine invasion.

Antibodies, Monoclonal↗

PubMed2002

The Role of E-cadherin in the Motility and Invasion of Implantation Site Intermediate Trophoblast.

During early pregnancy, intermediate (extravillous) trophoblast infiltrates the basal plate and invades the spiral arteries, a physiological process required to establish the maternal-fetal circulation. Immunostaining studies have shown that differentiation of trophoblast into this invasive subpopulation is associated with down-regulation of E-cadherin expression. To study the function of E-cadherin in trophoblast in vitro, we restored E-cadherin expression in an E-cadherin negative human implantation site intermediate trophoblastic cell line, IST-1, using a recombinant adenovirus, E-cad/Ad5 which constitutively expresses E-cadherin. In contrast to the control IST-1 cells which were individual and pleomorphic in shape, E-cad/Ad5 transduced cells were cohesive, uniform, and round. The motility and invasiveness of E-cad/Ad5 transduced IST-1 cells, as compared with the control cells, was significantly reduced. These effects were contact-dependent and were attenuated by a function-perturbing anti-E-cadherin antibody. In conclusion, our results indicate that expression of E-cadherin in IST-1 cells results in a contact-mediated inhibition of motility and invasion and suggest an important role for E-cadherin down-regulation in the intermediate trophoblast during implantation.

Adenoviridae↗