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PubMed2002

Correlated perturbations from inflation and the cosmic microwave background.

We compare the latest cosmic microwave background data with theoretical predictions including correlated adiabatic and cold dark matter (CDM) isocurvature perturbations with a simple power-law dependence. We find that there is a degeneracy between the amplitude of correlated isocurvature perturbations and the spectral tilt. A negative (red) tilt is found to be compatible with a larger isocurvature contribution. Estimates of the baryon and CDM densities are found to be almost independent of the isocurvature amplitude. The main result is that current microwave background data do not exclude a dominant contribution from CDM isocurvature fluctuations on large scales.

Journal Article↗
PubMed1999

[The hypothesis of environmental causes of damage to the endocrine system: science of sensationalism?].

AN EMERGING TOPIC: It has been hypothesized that exposure to certain chemical compounds in the environment could lead to reproduction and development anomalies. VARIABLE MECHANISMS OF ACTION, SUSCEPTIBILITIES AND EFFECTS: The incriminated environmental agents could have several targets in the endocrine system. As hormones play a cardinal role in regulating differentiation during early stages of life, developing organisms would be particularly vulnerable. AN EVALUATION METHODOLOGY: Although the hypothesis of endocrine perturbation is theoretically plausible, solid scientific data is still lacking to conclude that environmental compounds have a deleterious effect in humans after low-dose exposure. The ubiquitous nature of the intermediary metabolism of these compounds, the existence of critical periods of life, the complexity of the cell processes involved, and the differed timing of the effects make it difficult to assess risk. Current research is being conducted to develop specific methodologies to better understand this risk. AN INTERNATIONAL EFFORT: Different international and national entities have organized scientific committees with the task of identifying chemical compounds susceptible of perturbing endocrine function. In 1998, an international convention set up regulatory control of sales of certain chemical compounds.

Endocrine System↗
PubMed1985

Long-term perturbation of hemopoiesis after moderate damage to stem cells.

Hematological indices of BDF1 mice characterizing regeneration in a complex fashion (peripheral cell counts, bone marrow CFU-S, GM-CFU, CFU-F, and the turnover state of bone marrow CFU-S) were followed periodically for 11-14 weeks after 0.5 Gy acute gamma irradiation in order to obtain detailed information about the nonsteady state of murine hemopoiesis after moderate damage to stem cells, demonstrated in our previous experiments. Virtually complete hematological regeneration was followed by long-term increase in the proliferation rate of CFU-S, oscillation in some parameters (granulocyte count, CFU-S level) or an overshooting, sometimes multiwavelike regeneration in others (reticulocyte count, thrombocyte count, and GM-CFU and CFU-F levels). These data suggest a long-term perturbation of hemopoiesis and its environment after moderate damage to the bone marrow.

Animals↗
PubMed1982

Ca2+-tolerant adult canine myocytes: preparation and response to anoxia/acidosis.

A procedure is described for the production of large numbers of Ca2+-tolerant adult canine ventricular myocytes. Gentle tissue dissociation is achieved in Spinner flasks using 320 mosM enzyme buffer containing collagenase hyaluronidase, and trypsin in the presence of millimolar levels of Ca2+. The technique allows for the complete removal of erythrocytes, the gentle removal of closely adhering nonmuscle cells (less than 3% contamination), and the selective removal of damaged from nondamaged myocytes. Total myocyte yields averaged 4-6 x 10(6)/g wet wt; 61.0 +/- 6.5% of the cells have rod-shaped morphology and are "viable" based on trypan blue exclusion. Only 3.9 +/- 1.1% of the rod-shaped cells beat spontaneously when challenged with 2 mM Ca2+. Exposure to 2 mM Ca2+ at 37 degrees C results in minimal loss of viability (2.1 +/- 1.3%/h) based on both trypan blue uptake and creatine kinase release. Simulation of cellular (i.e., membrane) injury in vitro is performed by the separate application of the perturbations of anoxia, acidosis, and low glucose to the canine myocyte suspensions; the data suggest that these myocytes are affected independently by these perturbations and are in good agreement with the results obtained by others using the isolated rat myocyte system.

Acidosis↗
PubMed2002

A new redundant variable pruning approach--minor latent variable perturbation-PLS used for QSAR studies on anti-HIV drugs.

A new approach for eliminating the redundant variables in the multivariable data matrix encountered in QSAR studies, minor latent variable perturbation (MLVP)-PLS method has been proposed. In the latent variable (LV) space, the minor latent variables (LVs) with small covariances are mainly formulated by linear combinations of the redundant variables including information-deficient and highly correlative ones, while the major LVs with large covariances are mainly contributed by the informative variables. Deleting a minor LV, which is equivalent to a perturbation for LV space, could make the redundant variables not well be represented in LV subspace, leading to strong variation of their PLS regression coefficients. The informative variables could still be normally represented in LV subspace with the PLS regression coefficients remaining relatively stable. MLVP-PLS utilizes this fact to discriminate the informative and redundant variables. It gradually identifies and eliminates the redundant variables according to the relative variation of PLS regression coefficients after perturbations are given. The elimination process is terminated according to some proposed criteria. Applying the method to the quantitative structure-activity relationship (QSAR) studies on TIBO derivatives as potential anti-HIV drugs has demonstrated the feasibility and robustness of the proposed approach. A deeper insight into the effect of different structural parameters on the bio-activity of TIBO derivatives has been reached.

Anti-HIV Agents↗
PubMed1992

Inhibition of murine leukemia viruses by nuclease-resistant alpha-oligonucleotides.

We studied the antiviral activity of nuclease-resistant alpha-anomeric oligonucleotides. An alpha-oligonucleotide (20-mer) targeted to the primer binding site (PBS) of murine retroviruses inhibited viral spreading. The inhibition only occurred when the cells had been electropermeabilized in the presence of the oligonucleotide. The PBS sequence is involved in reverse transcription and in translation. The data suggest that the oligonucleotide could perturb reverse transcription activity. Thus, either the oligonucleotide induced a decrease in initiation or it inhibited the extension of the minus or plus strands DNA during reverse transcription. These results show that reverse transcription may be an interesting target for antisense oligonucleotides.

3T3 Cells↗
PubMed2000

Membrane lipid composition of Bacillus stearothermophilus as affected by lipophilic environmental pollutants: an approach to membrane toxicity assessment.

The thermophilic eubacterium Bacillus stearothermophilus is used as a model to identify membrane perturbing effects of lipophilic compounds. A parallelism has been established between the toxicity of the organochlorine insecticide DDT and its metabolite, DDE, in bacterial growth and the effects on cell functions and physical perturbations induced at the membrane (Donato et al. 1997a, Arch Environ Contam Toxicol 33:109-116; Donato et al. 1997b, Appl Environ Microbiol 63:4948-495). In the present work, the use of B. stearothermophilus as a model of screening for chemical toxicity has been implemented. Because the regulation of the lipid composition of the membrane is a common strategy in response to adverse growth conditions, we studied the effects of DDE on the lipid composition and the consequent alterations of membrane physical properties in comparison to the parental compound DDT. As expected, different adaptation responses were induced by the compounds, being DDT more effective as compared with DDE. Collected data are consistent with the stronger perturbations induced by DDT on growth and membrane functions. It is concluded that the membrane lipid composition of the bacterium is a very sensitive criterium to detect membrane-mediated toxic effects at low concentrations of lipophilic xenobiotics.

Calorimetry, Differential Scanning↗
PubMed2001

A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda (SEDL) is a genetically heterogeneous disorder characterized by mild-to-moderate short stature and early-onset osteoarthritis. Both autosomal and X-linked forms have been described. Elsewhere, we have reported the identification of the gene for the X-linked recessive form, which maps to Xp22.2. We now report characterization of an exon-skipping mutation (IVS3+5G-->A at the intron 3 splice-donor site) in two unrelated families with SEDL. Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. The mutation was not detected in 120 control X chromosomes. Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER). RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae. The latter homologue, p20, has a putative role in vesicular transport from ER to Golgi complex. These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.

Adult↗
PubMed2006

Differential interactions between transforming growth factor-beta3/TbetaR1, TAB1, and CD2AP disrupt blood-testis barrier and Sertoli-germ cell adhesion.

The biochemical basis that regulates the timely and selective opening of the blood-testis barrier (BTB) to migrating preleptotene/leptotene spermatocytes at stage VIII of the epithelial cycle in adult rat testes is virtually unknown. Recent studies have shown that cytokines (e.g. transforming growth factor (TGF)-beta3) may play a crucial role in this event. However, much of this information relies on the use of toxicants (e.g. CdCl(2)), making it difficult to relay these findings to normal testicular physiology. Here we report that overexpression of TGF-beta3 in primary Sertoli cells cultured in vitro indeed perturbed the tight junction (TJ) barrier with a concomitant decline in the production of BTB constituent proteins as follows: occludin, N-cadherin, and ZO-1. Additionally, local administration of TGF-beta3 to testes in vivo was shown to reversibly perturb the BTB integrity and Sertoli-germ cell adhesion via the p38 MAPK and ERK signaling pathways. Most importantly, the simultaneous activation of p38 and ERK signaling pathways is dependent on the association of the TGF-beta3-TbetaR1 complex with adaptors TAB1 and CD2AP because if TbetaR1 was associated preferentially with CD2AP, only Sertoli-germ cell adhesion was perturbed without compromising the BTB. Collectively, these data illustrate that local production of TGF-beta3, and perhaps other TGF-betas and cytokines, by Sertoli and germ cells into the microenvironment at the BTB during spermatogenesis transiently perturbs the BTB and Sertoli-germ cell adhesion to facilitate germ cell migration when the activated TbetaRI interacts with adaptors TAB1 and CD2AP. However, TGF-beta3 selectively disrupts Sertoli-germ cell adhesion in the seminiferous epithelium to facilitate germ cell migration without compromising BTB when TbetaRI interacts only with adaptor CD2AP.

Activin Receptors, Type I↗
PubMed1992

Phase-dependent reversal of reflexly induced movements during human gait.

To investigate whether phase-dependent reversals in reflex responses on electromyography (EMG) are accompanied by movement reversals, a series of human volunteers were studied for their behavioural responses to sural nerve stimulation during running or walking on a treadmill. Low-intensity stimulation (less than 2.5 x perception threshold, T) of the sural nerve yielded facilitatory responses in the tibialis anterior muscle (TA), correlated with an induced ankle dorsiflexion (mean maximum 4 degrees) in early swing. The same stimuli yielded primarily TA suppression and weak ankle plantar flexion (mean maximum 1 degree) at end swing. The correlated induced knee angle changes did not precede the ankle changes, and they were relatively small. Mean maximum flexion in early swing was 6.2 degrees, while mean maximum extension was 3.7 degrees. High-intensity stimulation of the sural nerve (greater than 2.5 x T) always gave rise to suppression of the ongoing activity. This resulted in a second type of movement reversal. During late stance and early swing the responses in TA were suppressive (i.e. below background activity) and related to ankle plantar flexion. In contrast, the responses during early and middle stance consisted of suppression in extensor activity (gastrocnemius medialis and soleus) and ankle dorsiflexion. The data are discussed in terms of a new hypothesis, which states that the responses to electrical stimulation of cutaneous nerves during locomotion do not correspond directly to corrections for stumbling following mechanical perturbations during the step cycle. Instead, the data invite a reinterpretation in terms of the opening and closing of reflex pathways, presumably by a central pattern generator for locomotion.

Adult↗
PubMed2003

DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a.

The Rad23 family of proteins, including the human homologs hHR23a and hHR23b, stimulates nucleotide excision repair and has been shown to provide a novel link between proteasome-mediated protein degradation and DNA repair. In this work, we illustrate how the proteasomal subunit S5a regulates hHR23a protein structure. By using NMR spectroscopy, we have elucidated the structure and dynamic properties of the 40-kDa hHR23a protein and show it to contain four structured domains connected by flexible linker regions. In addition, we reveal that these domains interact in an intramolecular fashion, and by using residual dipolar coupling data in combination with chemical shift perturbation analysis, we present the hHR23a structure. By itself, hHR23a adopts a closed conformation defined by the interaction of an N-terminal ubiquitin-like domain with two ubiquitin-associated domains. Interestingly, binding of the proteasomal subunit S5a disrupts the hHR23a interdomain interactions and thereby causes it to adopt an opened conformation.

Amino Acid Sequence↗
PubMed1989

Evidence for ligand-induced conformational changes in proteins from phosphorescence spectroscopy.

Phosphorescence spectroscopy on mouse myeloma IgA J539 in rigid solution at 77K revealed the type of anomalous short-lived component in the tryptophan decay originally observed with lysozyme (Churchich, J.E., 1966. Biochim. Biophys. Acta. 120:406-412) and seen in a large number of Bence Jones proteins (Longworth, J.W., C.L. McLaughlin, and A. Solomon. 1976. Biochemistry. 15:2953-2958). The decay time of the anomalous component that results from the interaction between tryptophan side chains and disulfide linkages in proteins was observed to significantly lengthen in J539 in response to binding of a galactan antigen. With hen egg-white lysozyme in which the type of fluorescence enhancement on ligand binding seen with J539 has also been observed, phosphorescence measurements revealed a similar lengthening of the decay time of the disulfide-induced anomalous component in the tryptophan decay. These perturbations are interpreted as ligand-induced changes to the tryptophan-disulfide proximities that have been shown to exist in these structures. Given the short-range nature of the disulfide perturbation (see following article) the observations suggest, in particular when combined with x-ray crystallographic data, that phosphorescence decay-time measurements of disulfide perturbations can serve as a sensitive spectroscopic indicator of subtle conformational changes in immunoglobulins and other tryptophan-disulfide containing proteins.

Antigen-Antibody Complex↗
PubMed2002

Insertion of a small peptide of six amino acids into the beta7-beta8 loop of the p51 subunit of HIV-1 reverse transcriptase perturbs the heterodimer and affects its activities.

BACKGROUND: HIV-1 RT is a heterodimeric enzyme, comprising of the p66 and p51 subunits. Earlier, we have shown that the beta7-beta8 loop of p51 is a key structural element for RT dimerization (Pandey et al., Biochemistry 40: 9505, 2001). Deletion or alanine substitution of four amino acid residues of this loop in the p51 subunit severely impaired DNA binding and catalytic activities of the enzyme. To further examine the role of this loop in HIV-1 RT, we have increased its size such that the six amino acids loop sequences are repeated in tandem and examined its impact on the dimerization process and catalytic function of the enzyme. RESULTS: The polymerase and the RNase H activities of HIV-1 RT carrying insertion in the beta7-beta8 loop of both the subunits (p66INS/p51INS) were severely impaired with substantial loss of DNA binding ability. These enzymatic activities were restored when the mutant p66INS subunit was dimerized with the wild type p51. Glycerol gradient sedimentation analysis revealed that the mutant p51INS subunit was unable to form stable dimer either with the wild type p66 or mutant p66INS. Furthermore, the p66INS/p66INS mutant sedimented as a monomeric species, suggesting its inability to form stable homodimer. CONCLUSION: The data presented herein indicates that any perturbation in the beta7-beta8 loop of the p51 subunit of HIV-1 RT affects the dimerization process resulting in substantial loss of DNA binding ability and catalytic function of the enzyme.

Amino Acids↗
PubMed1978

Response to transient disturbances during intentional forearm flexion in man.

Steps of torque were applied to the human forearm during intentional flexion movements with peak velocities of 40-500 degrees/sec and during ballistically initiated flexion movements. The question asked was whether or not the motor ouput to both agonist and antagonist muscles is independent of sensory input data or is accessible and influenced by these inputs. The data obtained demonstrate unequivocally that the applied perturbation affects the motor output, irrespective of the speed of the movement. The time of onset of the reflex changes in motor output and their maxima are related to the movement's parameters. Data are presented which indicate that the source for the reflex changes observed are the muscle spindles.

Afferent Pathways↗
PubMed1999

A robust ensemble data method for identification of human joint mechanical properties during movement.

This paper describes a perturbation method for the identification of linear time-varying systems with an unknown input (voluntary joint input) using ensemble data. The method separates the unknown input and the perturbation through high-pass filtering and recasts the multi-input single-output system identification into single-input single-output system identification. The method is robust to intertrial variation, and can track changes of system dynamics up to 5 Hz. Analysis and simulation are given for the conditions similar to those for the human arm experiments. Experiments show that mechanical properties of the human elbow joint change with voluntary movement speed and that the mean stiffness with voluntary movement is in the range of the posture and is higher than reported before.

Adult↗
PubMed1995

Determination of haem electronic structure in His-Met cytochromes c by 13C-NMR. The effect of the axial ligands.

The assignment of 13C resonances of nuclei alpha to the haem in horse ferricytochrome c is completed and the Fermi contact shifts are evaluated at 30 degrees C and 50 degrees C using empirical magnetic susceptibility tensors to correct for dipolar interactions. The Fermi contact shifts are fitted to a model of molecular orbitals of eg symmetry, which are subject to a rhombic perturbation. A similar analysis is performed using published data for Pseudomonas aeruginosa cytochrome c551. The relationship between the orientation of the effective g tensor and that of the rhombic perturbation in these proteins is shown to agree with theoretical predictions. A comparison between the orientation of the rhombic perturbations and the crystal structures of horse cytochrome c and P. aeruginosa cytochrome c551 reveals that the orientation of the histidine and methionine axial ligands dominates the rhombic perturbation and that the two ligands have approximately equal influence. The magnitude of the perturbation shows that the orientation of the axial ligands has little effect on the haem redox potential. However, the relationship that is established between the magnetic susceptibility tensor, the partially filled haem molecular orbitals, and the orientation of the haem ligands offers a new source of precise structural information.

Animals↗
PubMed1998

Selective perturbation of apical membrane traffic by expression of influenza M2, an acid-activated ion channel, in polarized madin-darby canine kidney cells.

The function of acidification along the endocytic pathway is not well understood, in part because the perturbants used to modify compartmental pH have global effects and in some cases alter cytoplasmic pH. We have used a new approach to study the effect of pH perturbation on postendocytic traffic in polarized Madin-Darby canine kidney (MDCK) cells. Influenza M2 is a small membrane protein that functions as an acid-activated ion channel and can elevate the pH of the trans-Golgi network and endosomes. We used recombinant adenoviruses to express the M2 protein of influenza virus in polarized MDCK cells stably transfected with the polymeric immunoglobulin (Ig) receptor. Using indirect immunofluorescence and immunoelectron microscopy, M2 was found to be concentrated at the apical plasma membrane and in subapical vesicles; intracellular M2 colocalized partly with internalized IgA in apical recycling endosomes as well as with the trans-Golgi network marker TGN-38. Expression of M2 slowed the rate of IgA transcytosis across polarized MDCK monolayers. The delay in transport occurred after IgA reached the apical recycling endosome, consistent with the localization of intracellular M2. Apical recycling of IgA was also slowed in the presence of M2, whereas basolateral recycling of transferrin and degradation of IgA were unaffected. By contrast, ammonium chloride affected both apical IgA and basolateral transferrin release. Together, our data suggest that M2 expression selectively perturbs acidification in compartments involved in apical delivery without disrupting other postendocytic transport steps.

Animals↗
PubMed1985

Effect of streptococcal lipoteichoic acid on prolyl hydroxylase activity as related to collagen formation in mouse fibroblast monolayers.

Dried and wet mouse fibroblast monolayers with labeled collagenous substrate were used to study the effects of lipoteichoic acid (LTA) on cellular prolyl hydroxylase activity. LTA is a scavenger of cations, and Fe2+ is essential for prolyl hydroxylase activity. Surprisingly, addition of LTA to dried monolayers resulted in increased prolyl hydroxylase activity, whereas preincubation of Fe2+ with LTA only negated this increase. However, significant inhibition of enzyme activity by wet monolayers occurred whether LTA was added directly to the test system or whether it was used after preincubation with Fe2+. These data suggest that LTA causes membrane perturbations. Also, that the binding of LTA to the membrane of dried and wet monolayers appears to be decidedly different when based on the subsequent availability of Fe2+ for cellular prolyl hydroxylase activity. The ability of LTA to act as a cationic exchanger and the presence of intracellular Fe2+ inaccessible to LTA probably accounted for the lack of complete inhibition of prolyl hydroxylase activity by this amphiphile in the wet cell system. Considerably less iron was needed to negate the partial inhibition of prolyl hydroxylase activity by LTA in viable cells than was needed to restore the increased enzyme activity by this amphiphile in equivalent dried preparations. These and other results showed that, although LTA does not affect collagen polypeptide chain formation in wet monolayers, its involvement at the molecular level does result in a marked decrease in the hydroxylation of collagenous peptidyl prolyl residues through LTA interaction with Fe2+. This reduction in prolyl hydroxylase activity equaled the reduction in hydroxylation of collagenous protein in fibroblast monolayers caused by LTA reported earlier (O. Leon and C. Panos, Infect. Immun. 40:785-794, 1983). Therefore, these data suggest that partial inhibition of prolyl hydroxylase activity is directly related to the synthesis of defective collagen by wet fibroblast monolayers exposed to minute amounts of group A, type 12 streptococcal LTA. Use of LTA also showed that complete inhibition of hydroxyproline formation is not required for the continued formation and accumulation of defective collagenous protein by these monolayers.

Animals↗