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Pathogenic neisseriae: complexity of pathogen-host cell interplay.

Recent studies have provided insight into the function of important neisserial adhesins (pili and Opa) and their interaction with cellular receptors, including members of heparan sulfate proteoglycan, CD66, and integrin receptor families. These interactions not only allow colonization of the human mucosa but also stimulate cellular signaling cascades involving phosphatidylcholine-dependent phospholipase C, acidic sphingomyelinase and protein kinase C in epithelial cells, and Src-related kinases, Rac1, p21-activated kinase, and Jun N-terminal kinase in phagocytic cells. Activation of these pathways is essential for cellular entry and intracellular accommodation of the pathogens but also leads to early induction of cytokine release, thus priming the immune response. Detailed knowledge of the cellular signaling cascades that are activated by infection will aid us in applying both current and novel interfering drugs (in addition to classical antibiotic therapy) as therapy and prophylaxis for persistent or otherwise difficult-to-treat bacterial infections, including periodontal infections.

Antigens, Bacterial↗

NF-kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression.

Oxidative processes are considered to play a crucial role in the induction of cell adhesion molecules, a key event in inflammatory processes. We recently reported on an unexpected unidirectional effect of an overexpressed antioxidant [phospholipid hydroperoxide glutathione peroxidase (PHGPx)] and an oxidant [15-lipoxygenase (15-LOX)] enzyme on the basal and interleukin-1 induced vascular cell adhesion molecule-1 (VCAM-1) expression in vascular smooth muscle cells (SMC). Both enzymes inhibited VCAM-1 expression and reduced the cellular protein thiol content, thus, both exerting an oxidant effect. We now investigated whether transcription factors known to be regulated by oxidation, i.e., the nuclear factor-kappaB and the Keap1/Nrf2 system, were affected in our set of cells: SMC, SMC(PHGPx), and SMC(LOX), as well as ECV and ECV(PHGPx). PHGPx and 15-LOX inhibited nuclear factor-kappaB activation most efficiently at a step downstream of DNA binding, which explains their inhibitory effect on VCAM-1 expression. Both enzymes up-regulated endogenous heme oxygenase-1 most probably via activation of Nrf2. Transfected Nrf2 strongly inhibited VCAM-1 promoter activity, which could be reversed by cotransfection with Keap1. The key player in this complex cross-talk obviously is heme oxygenase-1, which is known to be induced by oxidant-activated Nrf2. The moderate oxidative stress initiated by enhanced PHGPx or 15-LOX activity appears to induce a defense system that diminishes the response to further proinflammatory stimuli.

Active Transport, Cell Nucleus↗

Sexual self-disclosure in Cyberspace among Taiwanese adolescents: gender differences and the interplay of Cyberspace and real life.

This study explored adolescents' sexual self-disclosure in real life and cyberspace, as well as gender differences of sexual self-disclosure in cyberspace. There were 115 male and 92 female adolescents who participated in this pretest and posttest survey. In general, the depth of sexual self-disclosure in real life was greater than in cyberspace, but the breadth of sexual selfdisclosure in both real life and cyberspace was equivalent. The cross-lagged panel analysis indicated that adolescents who were willing to self-disclose sexual topics in real life also selfdisclosed them more in cyberspace, and vice versa. Furthermore, sexual self-disclosure in both disclosing environments was mutually predicted by each other. The findings also indicated that cyberspace might not be a substitute channel of compensatory gratification for sexual self-disclosure in real life. As for gender differences, the breadth and depth of sexual self-disclosure in male adolescents were greater than in female adolescents, in both real life and cyberspace. Male adolescents tend to be more active in Internet sexuality than females. However, female adolescents' sexual emancipation in cyberspace is not evident in Taiwan. Possible reasons, implications, and limitations of the findings are discussed.

Adolescent↗

Molecular interplay of murein synthases and murein hydrolases in Escherichia coli.

Affinity chromatography using different lytic transglycosylases as a specific ligand revealed an interaction of both murein hydrolases and murein synthases. This interaction is taken as evidence for the assemblage into a multienzyme complex that could function as a murein replicase precisely copying the given three-dimensional structure of the murein sacculus. The sacculus of the mother cell would function as a template, which is identically replicated by copying the lengths of the existing glycan strands and the pattern of crosslinkages. A hypothetical enzyme complex specifically involved in cell division and a complex specifically involved in cell elongation are presented. It is postulated that PBPs 1a and/or 1b are present in both complexes, whereas the presence of PBP2 or PBP3 defines the specificity of the murein-synthesizing machinery as being involved in either cell elongation or septation. Moreover, the proposed "holoenzyme" suprastructure could explain why the specific inhibition of PBPs 1a/1b results in bacteriolysis and why inhibition of PBP2 and PBP3 causes the well-known morphological alterations, spherical growth, and filamentation, respectively.

Escherichia coli↗

Coxsackievirus myocarditis: interplay between virus and host in the pathogenesis of heart disease.

Coxsackievirus (CVB) infection is a significant cause of myocarditis and dilated cardiomyopathy (DCM). Heart disease may be caused by direct cytopathic effects of the virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. CVB interacts with its host at multiple stages during disease development. Signaling through viral receptors may alter the intracellular environment in addition to facilitating virus entry. Viral genetic determinants that encode cardiovirulence have been mapped and may change depending on the nutritional status of the host. Virus persistence is directly associated with pathology, and recent work demonstrates that CVB evolves into a slowly replicating form capable of establishing a low-grade infection in the heart. The innate immune response to CVB has taken on increasing importance because of its role in shaping the development of the adaptive immune response that is responsible for cardiac pathology. Studies of T cell responsiveness and the development of autoimmunity at the molecular level are beginning to clarify the mechanisms through which CVB infection causes inflammatory heart disease.

Animals↗

Interplay of signal mediators of decapentaplegic (Dpp): molecular characterization of mothers against dpp, Medea, and daughters against dpp.

Decapentaplegic (Dpp) plays an essential role in Drosophila development, and analyses of the Dpp signaling pathway have contributed greatly to understanding of the actions of the TGF-beta superfamily. Intracellular signaling of the TGF-beta superfamily is mediated by Smad proteins, which are now grouped into three classes. Two Smads have been identified in Drosophila. Mothers against dpp (Mad) is a pathway-specific Smad, whereas Daughters against dpp (Dad) is an inhibitory Smad genetically shown to antagonize Dpp signaling. Here we report the identification of a common mediator Smad in Drosophila, which is closely related to human Smad4. Mad forms a heteromeric complex with Drosophila Smad4 (Medea) upon phosphorylation by Thick veins (Tkv), a type I receptor for Dpp. Dad stably associates with Tkv and thereby inhibits Tkv-induced Mad phosphorylation. Dad also blocks hetero-oligomerization and nuclear translocation of Mad. We also show that Mad exists as a monomer in the absence of Tkv stimulation. Tkv induces homo-oligomerization of Mad, and Dad inhibits this step. Finally, we propose a model for Dpp signaling by Drosophila Smad proteins.

Amino Acid Sequence↗

The interplay between folding-facilitating mechanisms in Trypanosoma cruzi endoplasmic reticulum.

Lectin (calreticulin [CRT])-N-glycan-mediated quality control of glycoprotein folding is operative in trypanosomatid protozoa but protein-linked monoglucosylated N-glycans are exclusively formed in these microorganisms by UDP-Glc:glycoprotein glucosyltransferase (GT)-dependent glucosylation. The gene coding for this enzyme in the human pathogen Trypanosoma cruzi was identified and sequenced. Even though several of this parasite glycoproteins have been identified as essential components of differentiation and mammalian cell invasion processes, disruption of both GT-encoding alleles did not affect cell growth rate of epimastigote form parasites and only partially affected differentiation and mammalian cell invasion. The cellular content of one of the already identified T. cruzi glycoprotein virulence factors (cruzipain, a lysosomal proteinase) only showed a partial (5-20%) decrease in GT null mutants in spite of the fact that >90% of all cruzipain molecules interacted with CRT during their folding process in wild-type cells. Although extremely mild cell lysis and immunoprecipitation procedures were used, no CRT-cruzipain interaction was detected in GT null mutants but secretion of the proteinase was nevertheless delayed because of a lengthened interaction with Grp78/BiP probably caused by the detected induction of this chaperone in GT null mutants. This result provides a rationale for the absence of a more drastic consequence of GT absence. It was concluded that T. cruzi endoplasmic reticulum folding machinery presents an exquisite plasticity that allows the parasite to surmount the absence of the glycoprotein-specific folding facilitation mechanism.

Animals↗

The complex interplay between the neck and hinge domains in kinesin-1 dimerization and motor activity.

Kinesin-1 dimerizes via the coiled-coil neck domain. In contrast to animal kinesins, neck dimerization of the fungal kinesin-1 NcKin requires additional residues from the hinge. Using chimeric constructs containing or lacking fungal-specific elements, the proximal part of the hinge was shown to stabilize the neck coiled-coil conformation in a complex manner. The conserved fungal kinesin hinge residue W384 caused neck coiled-coil formation in a chimeric NcKin construct, including parts of the human kinesin-1 stalk. The stabilizing effect was retained in a NcKinW384F mutant, suggesting important pi-stacking interactions. Without the stalk, W384 was not sufficient to induce coiled-coil formation, indicating that W384 is part of a cluster of several residues required for neck coiled-coil folding. A W384-less chimera of NcKin and human kinesin possessed a non-coiled-coil neck conformation and showed inhibited activity that could be reactivated when artificial interstrand disulfide bonds were used to stabilize the neck coiled-coil conformation. On the basis of yeast two-hybrid data, we propose that the proximal hinge can bind kinesin's cargo-free tail domain and causes inactivation of kinesin by disrupting the neck coiled-coil conformation.

Amino Acid Sequence↗

Determination of peak trabecular bone density: interplay of dietary fiber, carbohydrate, and androgens.

To elucidate mechanisms linking nutrition and sex hormones to magnitude of peak trabecular bone density, we studied 11 normal women aged 19-21 y. Trabecular bone density was related inversely to dietary fiber (r = -0.69, p = 0.02) and carbohydrate (r = -0.70, p = 0.02) and directly to serum free-and-albumin-bound testosterone (fab T) (r = -0.70, p = 0.02) and total testosterone (total T) (r = 0.66, p = 0.03). Dietary fiber was correlated negatively with fab T (r = -0.74, p = 0.009), total T (r = -0.70, p = 0.02), and androstenedione (Adione) (r = -0.72, p = 0.01). Controlling for the effect of fab T or Adione weakened the relationship between dietary fiber and bone density and the relationship was no longer statistically significant. Conversely, controlling for sex hormones did not abolish the effect of carbohydrate on bone density. The contributions of fab T and carbohydrate to bone density were independent. These results suggest that dietary fiber may depress serum androgens which in turn decrease trabecular bone density. Carbohydrate may also depress bone density but independently of sex steroid hormones.

Adult↗

Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption.

Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.

Adenoma↗

Interplay between adrenaline and interbeat interval on ventricular repolarisation in intact heart in vivo.

STUDY OBJECTIVE: The aim was to examine the hypothesis that an interaction between adrenaline and change in heart rate may alter the normal time sequence of ventricular repolarisation (and hence refractoriness) in a manner that (1) may favour arrhythmia formation, (2) may partly explain conflicting reports of the effect of adrenaline, ie, there are two opposing effects on action potential duration, and (3) be relevant to T wave abnormalities that sometimes occur in normal people. DESIGN: As a measure of the time course of repolarisation, monophasic action potentials were recorded simultaneously from three epicardial sites in the porcine heart (left ventricular apex, left ventricular base, and mid right ventricle). During steady state pacing, test pulse intervals were interposed at progressively shorter intervals in order to construct restitution curves. MEASUREMENTS AND MAIN RESULTS: Adrenaline infusion (0.4-1.5 micrograms.kg-1.min-1) resulted in earlier repolarisation in the beats after shorter interbeat intervals, and delayed repolarisation after longer interbeat intervals, tending to turn the restitution curve anticlockwise (ie, there were two opposing effects on action potential duration). The effects were not homogeneous between regions. To show this inhomogeneity, pairs of monophasic action potentials from different regions were subtracted using a differential input amplifier to produce an ECG like waveform at the amplifier output. The resulting T wave was thereby a measure of the time difference in repolarisation between the monophasic action potentials from which it was derived. The inhomogeneity of repolarisation induced by adrenaline and rate change was reflected in the morphology of this derived T wave, particularly at early (premature) beats. These T wave changes correlated closely with the true T wave changes in bipolar electrograms recorded between the same recording sites (R = 0.89; p less than 0.0001). CONCLUSIONS: These results show that adrenaline altered the normal relationship between interbeat interval and the timing of repolarisation. The effect was not homogeneous and when regional differences were observed they were reflected in changes in T wave morphology. These were marked at short intervals. It is possible that in addition to increased excitability observed with adrenaline, a combination of raised sympathetic activity and early beats predisposes to arrhythmias by exaggerating dispersion of repolarisation.

Action Potentials↗

Interplay of two uridylate-specific RNA binding sites in the translocation of poly(A) polymerase from vaccinia virus.

The VP55 (catalytic) subunit of vaccinia virus heterodimeric poly(A) polymerase (PAP) contacts 31-40 nucleotide segments of RNA in a uridylate-dependent manner, and effects the rapid, processive addition of a 30 nt oligo(A) tail. Here, the minimum size of uridylate-containing RNA required for stable VP55 interaction was refined to 33-34 nt. VP55 binding experiments using a set of sixteen 34 nt DNA-RNA chimeras, each containing a differently positioned tetra-uridylate cluster within an oligo(dC) background, indicated that the protein contacts uridylates at two positions within the oligonucleotide. Combination of two optimally positioned tetra-uridylate clusters into a single oligonucleotide fully restored the properties of an optimal substrate, rU34, in VP55 binding and salt-resistant polyadenylylation. The positions of the two uridylate interaction sites, approximately 10 and approximately 25 nt from the oligonucleotide 3' OH, were confirmed using a selection scheme employing dC-rU oligonucleotide chimera pools. These and additional data suggest a mechanism for polymerase translocation with respect to RNA comparable with inchworming models of transcriptional elongation. In selection experiments incorporating the PAP-associated processivity factor VP39, the latter was shown to replace the 3' OH-distal uridylate contact site with one approximately 10 nt further upstream.

Binding Sites↗

Termination of translation: interplay of mRNA, rRNAs and release factors?

Termination of translation in eukaryotes has focused recently on functional anatomy of polypeptide chain release factor, eRF1, by using a variety of different approaches. The tight correlation between the domain structure and different functions of eRF1 has been revealed. Independently, the role of prokaryotic RF1/2 in GTPase activity of RF3 has been deciphered, as well as RF3 function itself.

Amino Acid Sequence↗

The interplay of work and caregiving: relationships between role satisfaction, role involvement, and caregivers' well-being.

This study applied theory from the general work and family literature to the dual roles of work and caregiving, in order to examine whether level of satisfaction and time involvement in each of these roles moderate the effects of stress in the other role on well-being. Respondents were 118 employed women who were providing care to an impaired parent or parent-in-law. As predicted, greater time involvement in work was found to buffer women from the negative effects of caregiving stress. Satisfaction with caregiving and satisfaction with work were directly associated with better well-being, beyond the effects of stress in both roles. However, women who experienced high levels of caregiving stress and who were highly satisfied with work were especially vulnerable to depression. These findings illustrate the importance of examining the effects of caregiving stress on well-being in the context of work-related experiences.

Adult↗

Receiving help at home: the interplay of human and technological assistance.

OBJECTIVES: This research investigated use of mobility equipment as a substitute for human assistance and also examined whether use of mobility equipment results in out-of-pocket cost savings associated with formal home care services. METHODS: The authors analyzed data collected from 9,230 respondents to the Adult Followback Survey of the Disability Supplement to the 1994 and 1995 National Health Interview Survey (NHIS-D) who reported both mobility and limitations in daily living activities to test study hypotheses, using regression analyses to control for selection effects in mobility equipment use. RESULTS: Use of canes and crutches (but not walkers and wheelchairs) reduced both formal and informal hours of care received per week by sample members; there was also evidence of substitution on the individual activities of daily living task level. Use of canes and crutches was also associated with lower out-of-pocket costs for formal helping services. DISCUSSION: Findings suggest that canes and crutches are effective and efficient home care resources that have the potential to increase the autonomy of adults with disabilities and to facilitate chronic condition self-management.

Activities of Daily Living↗

The interplay between life stressors and depressive symptoms among older adults.

This study examined mutual predictive associations between life stressors and depressive symptoms in later life. A sample of late-middle-aged and older adults (N = 1,291) was surveyed at baseline and 1 year, 4 years, and 10 years later. At each contact point, participants completed an inventory that assessed chronic and acute life stressors and depressive symptoms. Over the 10-year interval, there was evidence of both social causation and social selection processes: More life stressors were associated with subsequent increases in depressive symptoms (social causation), and more depressive symptoms were associated with subsequent increases in stressors (social selection or stress generation). These findings reflect a mutual influence process in which life stressors and depressive symptoms can alter each other.

Activities of Daily Living↗