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The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition.

A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF-impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.

8-Hydroxy-2'-Deoxyguanosine↗

Reward expectation, orientation of attention and locus coeruleus-medial frontal cortex interplay during learning.

Regulation of attention and promotion of behavioural flexibility are functions attributed to both the noradrenergic nucleus locus coeruleus (LC) and the prefrontal cortex (PFC). The PFC receives a large innervation from LC and small changes in catecholaminergic activity in PFC profoundly affect cognitive function. It is crucial to the understanding of learning-related plasticity, that the cognitive context driving LC neurons be determined and the relation to activity in PFC be elucidated. To this end simultaneous recordings were made from LC and prelimbic cortex (PL) during an odour-reward association task in the rat. Neuronal activity related to orientation of attention, reward predictability, reward itself, and changes in stimulus reinforcement contingencies, was measured. All LC neurons and a significant proportion of PL neurons were engaged during several aspects of a Go/NoGo task, especially after the signal for trial onset and CS+ presentation. LC activation was, however, more tightly aligned to the behavioural response than to the CS+ 22% of PL neurons were activated during the response-reward delay. This suggests that the activity of both these structures is related to reward anticipation. Finally, LC neurons exhibited rapid plasticity when the reward-contingency was modified. Within-trial response latencies were always shorter in LC than in PL and between-trial response adaptation in LC preceded that in PL by many trials. Identifying such temporal relationships is an essential step toward understanding how neuromodulatory inputs to forebrain networks might promote or permit experience-dependent plasticity in behavioural situations.

Action Potentials↗

Personality reflected in a coherent idiosyncratic interplay of intra- and interpersonal self-regulatory processes.

This article discusses a framework that conceptualizes personality in terms of a unique pattern of interacting intra- and interpersonal self-regulatory mechanisms employed in the service of constructing and maintaining a desired self. These personal goals motivate the individuals' self-construction efforts and give direction, organization, and coherence to the self-regulatory dynamics--both within the person and in the social world in which they play out. The framework is illustrated through research on construct validation of the narcissistic personality type and extended by brief applications to dependency and rejection sensitivity to show how it may help us understand the complex signatures that are the expressions of a personality type. It offers a guide for where to look for and how to organize the unique features and idiosyncratic dynamics of different self-construction types and to make sense of their otherwise often seemingly paradoxical expressions. In so doing, the framework speaks to basic goals of personality psychology by providing an approach for capturing trait-like individual differences while simultaneously shedding light on the psychological mechanism that underlies them.

Humans↗

The interplay of central and peripheral factors in limiting maximal O2 consumption in man after prolonged bed rest.

1. The effects of bed rest on the cardiovascular and muscular parameters which affect maximal O2 consumption (VO2,max) were studied. The fractional limitation of VO2,max imposed by these parameters after bed rest was analysed. 2. The VO2,max, by standard procedure, and the maximal cardiac output (Qmax), by the pulse contour method, were measured during graded cyclo-ergometric exercise on seven subjects before and after a 42-day head-down tilt bed rest. Blood haemoglobin concentration ([Hb]) and arterialized blood gas analysis were determined at the highest work load. 3. Muscle fibre types, oxidative enzyme activities, and capillary and mitochondrial densities were measured on biopsy samples from the vastus lateralis muscle before and at the end of bed rest. The measure of muscle cross-sectional area (CSA) by NMR imaging at the level of biopsy site allowed computation of muscle oxidative capacity and capillary length. 4. The VO2,max was reduced after bed rest (-16.6%). The concomitant decreases in Qmax (-30.8%), essentially due to a change in stroke volume, and in [Hb] led to a huge decrease in O2 delivery (-39.7%). 5. Fibre type distribution was unaffected by bed rest. The decrease in fibre area corresponded to the significant reduction in muscle CSA (-17%). The volume density of mitochondria was reduced after bed rest (-16.6%), as were the oxidative enzyme activities (-11%). The total mitochondrial volume was reduced by 28.5%. Capillary density was unchanged. Total capillary length was 22.2% lower after bed rest, due to muscle atrophy. 6. The interaction between these muscular and cardiovascular changes led to a smaller reduction in VO2,max than in cardiovascular O2 transport. Yet the latter appears to play the greatest role in limiting VO2,max after bed rest (> 70% of overall limitation), the remaining fraction being shared between peripheral O2 diffusion and utilization.

Adult↗

Interplay between the NO pathway and elevated [Ca2+]i enhances ciliary activity in rabbit trachea.

1. Average intracellular calcium concentration ([Ca2+]i) and ciliary beat frequency (CBF) were simultaneously measured in rabbit airway ciliated cells in order to elucidate the molecular events that lead to ciliary activation by purinergic stimulation. 2. Extracellular ATP and extracellular UTP caused a rapid increase in both [Ca2+]i and CBF. These effects were practically abolished by a phospholipase C inhibitor (U-73122) or by suramin. 3. The effects of extracellular ATP were not altered: when protein kinase C (PKC) was inhibited by either GF 109203X or chelerythrine chloride, or when protein kinase A (PKA) was inhibited by RP-adenosine 3', 5'-cyclic monophosphothioate triethylamine (Rp-cAMPS). 4. Activation of PKC by phorbol 12-myristate, 13-acetate (TPA) had little effect on CBF or on [Ca2+]i, while activation of PKA by forskolin or by dibutyryl-cAMP led to a small rise in CBF without affecting [Ca2+]i. 5. Direct activation of protein kinase G (PKG) with dibutyryl-cGMP had a negligible effect on CBF when [Ca2+]i was at basal level. However, dibutyryl-cGMP strongly elevated CBF when [Ca2+]i was elevated either by extracellular ATP or by ionomycin. 6. The findings suggest that the initial rise in [Ca2+]i induced by extracellular ATP activates the NO pathway, thus leading to PKG activation. In the continuous presence of elevated [Ca2+]i the stimulated PKG then induces a robust enhancement in CBF. In parallel, activated PKG plays a central role in Ca2+ influx via a still unidentified mechanism, and thus, through positive feedback, maintains CBF close to its maximal level in the continuous presence of ATP.

Adenosine Triphosphate↗

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points.

Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 6 of the gene is an alternatively spliced cassette whose expression profile differs from that of the other tau regulated exons, implying the involvement of distinct regulatory factors. Previous work had established the existence and use of two additional 3' splice sites within exon 6 and the influence of splicing factors polypyrimidine binding protein (PTB) and U2AF on its splicing. The present work shows that exon 6 isoforms exist in distinct ratios in different compartments of the nervous system and that splicing of exon 6 is governed by multiple branch points, exonic cis elements and additional trans factors. Recent results show that tau exon 6 is specifically suppressed in the brains of people who suffer from myotonic dystrophy type 1. The understanding of how tau exon 6 splicing is regulated may give us insights into the disease.

Alternative Splicing↗

Autonomic interplay in VIP-induced tracheal smooth muscle relaxation.

VIP-induced inhibitory responses of the guinea-pig tracheal pouch, an in vivo preparation designed to demonstrate non-noradrenergic non-cholinergic innervation, where determined in chloraloseurethane anaesthetized animals under control conditions, or pretreated with atropine, propranolol, both atropine and propranolol or atropine-propranolol with indomethacin. Of the five groups, the control group showed a significantly greater cumulative dose-response relaxation to VIP than did the treatment groups. Among the treatment groups, the propranolol pretreated animals showed significantly greater relaxation than the remaining treatments. The group that received atropine alone and the combination of atropine and propranolol showed the least relaxation to VIP. The relaxations in these two groups did not differ significantly. The significantly greater relaxation of the pouch to VIP in the propranolol treated group suggested that the non-noradrenergic inhibitory mechanism for VIP is dependent upon the existing smooth muscle tone of the pouch. Pretreatment of the guinea-pigs with indomethacin did not cause a significant change in the relaxation of the pouch due to VIP suggesting that VIP caused airway smooth muscle relaxation by a mechanism other than that of the release of bronchodilator prostaglandins.

Adrenergic Fibers↗

The interplay between climate variability and density dependence in the population viability of Chinook salmon.

The viability of populations is influenced by driving forces such as density dependence and climate variability, but most population viability analyses (PVAs) ignore these factors because of data limitations. Additionally, simplified PVAs produce limited measures of population viability such as annual population growth rate (lamda) or extinction risk. Here we developed a "mechanistic" PVA of threatened Chinook salmon (Oncorhynchus tshawytscha) in which, based on 40 years of detailed data, we related freshwater recruitment of juveniles to density of spawners, and third-year survival in the ocean to monthly indices of broad-scale ocean and climate conditions. Including climate variability in the model produced important effects: estimated population viability was very sensitive to assumptions of future climate conditions and the autocorrelation contained in the climate signal increased mean population abundance while increasing probability of quasi extinction. Because of the presence of density dependence in the model, however we could not distinguish among alternative climate scenarios through mean lamda values, emphasizing the importance of considering multiple measures to elucidate population viability. Our sensitivity analyses demonstrated that the importance of particular parameters varied across models and depended on which viability measure was the response variable. The density-dependent parameter associated with freshwater recruitment was consistently the most important, regardless of viability measure, suggesting that increasing juvenile carrying capacity is important for recovery.

Animals↗

The interplay of science, values, and experiences among scientists asked to evaluate the hazards of dioxin, radon, and environmental tobacco smoke.

To investigate the extent to which personal values and experiences among scientists might affect their assessment of risks from dioxin, radon, and environmental tobacco smoke (ETS), we conducted an experiment through a telephone survey of 1461 epidemiologists, toxicologists, physicians, and general scientists. Each participant was read a vignette designed to reflect the mainstream scientific thinking on one of the three substances. For half of the participants (group A) the substance was named. For the other half (group B), the substance was not named but was identified only as Substance X, Y, or Z. Knowing the name of the substance had little effect on the scientists' evaluation of dioxin, although those who knew the substance to be dioxin were more likely to rate the substance as a serious environmental health hazard (51% vs. 42%, p = 0.062). For radon, those who knew the substance by name were significantly more likely to consider it an environmental health hazard than were those who knew it as substance Z (91% vs. 78%, p less than 0.001). Participants who knew they were being asked about ETS rather than substance X were significantly more likely to consider the substance an environmental health hazard (88% vs. 66%, p less than 0.001), to consider the substance a serious environmental health hazard (70% vs. 33%, p less than 0.001), to believe that background exposure required public health intervention (85% vs. 41%, p less than 0.001), and to believe that above-background exposure required public health intervention (90% vs. 74%, p less than 0.001). These findings suggest that values and experiences may be influencing health risk assessments for these substances, and indicate the need for more study of this phenomenon.

Data Collection↗

Modeling the dynamic interplay between general and specific change in children's conceptual understanding.

In introducing this chapter, I pointed out that traditional theories of learning and of cognitive development were in conflict with regard to the effects of specific learning. Developmental theorists saw general structures as influencing specific learning but not being affected by it, whereas learning theorists took the opposite view - that general structures (if they existed) were affected only by specific experiences. In the formulation of neo-Piagetian theory, both general and specific effects were acknowledged; however, general effects were assigned to mental capacity and specific ones to the child's schematic repertoire. Thus, the possibility of reciprocal influence did not emerge (or at least was not explored). In the present chapter, I have proposed the existence of such a reciprocal influence and explored its consequences. At a general level, the two consequences that follow are (1) that the overall pace of development is accelerated and (2) that the profile of development is evened out because benefits obtained from high-frequency learning experiences are passed on, via the mediation of the central conceptual structure, to low-frequency ones. These two effects were then advanced as one possible explanation for the difference in the data obtained between different cultures and different social classes. In the former case, the explanation utilized the notion that the benefits of high-frequency learning could be passed on to low-frequency situations via the mediation of general structures; in the latter case, the explanation drew on the notion that experiential loops can accelerate or decelerate development by magnifying experiential differences that are relatively small but that prevail across most of the tasks that a child encounters. The last half of the present chapter was devoted to specifying the dynamics of this sort of interaction in mathematical terms. The data that were obtained in Chapters III and V were extremely regular and showed an even pattern of development across different tasks; hence, they could conceivably be modeled with single curves or even straight lines. The mathematical model chosen to fit these findings was much more complex, however. Each growth curve was generated by an expression that contained a dynamic tension between two opposing categories of effect: those whose tendency is to make different developmental pathways disperse (different growth rates and the effect of compounding) and those whose tendency is to hold development to a single course (the constraints imposed by a growing carrying capacity and the "binding together" or "squeezing" effect generated by the reciprocal feedback loop). The disadvantage of this sort of modeling is clearly its complexity. An equally clear advantage, however, is that it allows one to provide a unified explanation for a set of data that might otherwise seem quite disparate and to express relations in quantitative rather than merely qualitative terms. This, in turn, permits one to check the entire set of proposed relations for their consistency, and to explore the dynamic pattern of their interaction, by conducting "intellectual experiments" and checking them against common sense and/or existing data sets. In the present chapter, this approach has been used for the effects of social class and of culture. In principle, however, it could potentially be used equally to explore the effects of other variables, such as those that underlie intellectual retardation and/or "giftedness". At least for the moment, then, the mathematical modeling approach looks promising.

Child↗

Interplay between the TCR/CD3 complex and CD4 or CD8 in the activation of cytotoxic T lymphocytes.

Interactions between CTL and target cells occur in the absence of specific antigen recognition and precede subsequent interaction of the TCR with its specific antigen. This antigen-independent adhesion progresses through two different pathways, one involving the interaction of CD2 with LFA-3 on the target cell, the second the interaction of LFA-1 with ICAM-1. Such antigen-independent adhesions are critical for the activation of T cells via the TCR. Also, CD4 and CD8 can serve as adhesion molecules by binding to monomorphic determinants expressed on class II and class I MHC antigens, respectively, on the target cells, but compared to LFA-1 and CD2 antigens their contribution to conjugate formation is minor. CD4 and CD8 are required for effective T-cell activation in situations where the intrinsic affinity of the TCR or antigen expression is low, suggesting that CD4 and CD8 enhance the avidity of T cells for target cells by binding to class II and class I antigen, respectively. However, CD4 and CD8 are also involved in post-binding events that lead to CTL activation and subsequent lysis of the target cells. On the other hand, blocking of anti-TCR/CD3 mAb-induced CTL reactivity by anti-CD4/CD8 mAbs does not necessarily involve an interference with the binding of CD4 and CD8 to their respective ligands and it has been proposed that the TCR and CD4 or CD8 form functional complexes that are required for optimal T-cell activation. It is still unclear whether blocking by anti-CD4/CD8 mAbs is based on the prevention of complex formation of the TCR with CD4 or CD8, since formation of such complexes has yet to be demonstrated. The alternative hypothesis, that anti-CD4/anti-CD8 mAbs can directly confer negative regulatory signals to the CTL is not supported by our studies with antibody-directed lysis mediated by a CD4+, CD8+ CTL clone. Anti-CD4/CD8 mAbs can also inhibit T-cell cytotoxicity induced by other T-cell surface activation antigens such as CD2 or Tp103. In these situations, the triggering may involve signals transferred via CD3 requiring functional CD3/CD8 or CD3/CD4 complexes. Although most studies investigating the sequence of events leading to T-cell activation are carried out with CTL, preliminary data indicate that the same mechanisms described here for CTL activation are probably also valid for the interactions of T-helper cells with APC or B cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Interplays between mouse mammary tumor virus and the cellular and humoral immune response.

Mouse mammary tumor virus has developed strategies to exploit the immune response. It requires vigorous immune stimulation to achieve efficient infection. The infected antigen-presenting cells present a viral superantigen on the cell surface which stimulates strong CD4-mediated T-cell help but CD8 T-cell responses are undetectable. Despite the high frequency of superantigen-reactive T cells, the superantigen-induced immune response is comparable to classical antigen responses in terms of T-cell priming, T-cell-B-cell collaboration as well as follicular and extra-follicular B-cell differentiation. Induction of systemic anergy is observed, similar to classical antigen responses where antigen is administered systemically but does not influence the role of the superantigen-reactive T cells in the maintenance of the chronic germinal center reaction. So far we have been unable to detect a cytotoxic T-cell response to mouse mammary tumor virus peptide antigens or to the superantigen. This might yet represent another step in the viral infection strategy.

Amino Acid Sequence↗

The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol.

Cyclopia, the paradigmatic "face [that] predicts the brain" in severe holoprosencephaly (HPE) (DeMyer et al., 1964), has been recognized since ancient times. Descriptive embryologists and pathologists have noted the continuum of defective separation of the forebrain and loss of central nervous system (CNS) midline structures for more than a century. It has been recognized more recently that inhibitors of cholesterol biosynthesis, whether consumed in native plants by range sheep, or experimentally applied to early embryos, could phenocopy the natural malformation, as could a variety of other teratogens (maternal diabetes, alcohol). Yet it has been less than a decade that the genomic knowledge base and powerful analytic methods have brought the sciences of descriptive, molecular, and genetic embryology within range of each other. In this review, we discuss the clinical presentations and pathogenesis of HPE. We will outline various genetic and teratogenic mechanisms leading to HPE. Lastly, we will attempt to examine the pivotal role of cholesterol and the Sonic Hedgehog (Shh) pathway in this disorder and in normal embryonic forebrain development.

Age Factors↗

Hepatocyte-specific interplay of transcription factors at the far-upstream enhancer of the carbamoylphosphate synthetase gene upon glucocorticoid induction.

Carbamoylphosphate synthetase-I is the flux-determining enzyme of the ornithine cycle, and neutralizes toxic ammonia by converting it to urea. An 80 bp glucocorticoid response unit located 6.3 kb upstream of the transcription start site mediates hormone responsiveness and liver-specific expression of carbamoylphosphate synthetase-I. The glucocorticoid response unit consists of response elements for the glucocorticoid receptor, forkhead box A, CCAAT/enhancer-binding protein, and an unidentified protein. With only four transcription factor response elements, the carbamoylphosphate synthetase-I glucocorticoid response unit is a relatively simple unit. The relationship between carbamoylphosphate synthetase-I expression and in vivo occupancy of the response elements was examined by comparing a carbamoylphosphate synthetase-I-expressing hepatoma cell line with a carbamoylphosphate synthetase-I-negative fibroblast cell line. DNaseI hypersensitivity assays revealed an open chromatin configuration of the carbamoylphosphate synthetase-I enhancer in hepatoma cells only. In vivo footprinting assays showed that the accessory transcription factors of the glucocorticoid response unit bound to their response elements in carbamoylphosphate synthetase-I-positive cells, irrespective of whether carbamoylphosphate synthetase-I expression was induced with hormones. In contrast, the binding of glucocorticoid receptor to the carbamoylphosphate synthetase-I glucocorticoid response unit was dependent on treatment of the cells with glucocorticoids. Only forkhead box A was exclusively present in hepatoma cells, and therefore appears to be an important determinant of the observed tissue specificity of carbamoylphosphate synthetase-I expression. As the glucocorticoid receptor is the only DNA-binding protein specifically recruited to the glucocorticoid response unit upon stimulation by glucocorticoids, it is likely to be directly responsible for the transcriptional activation mediated by the glucocorticoid response unit.

Animals↗