Multifaceted Physiological Response Allows Yeast to Adapt to the Loss of the Signal Recognition Particle-dependent Protein-targeting PathwayD⃞

Translational control has recently been recognized as an important facet of adaptive responses to various stress conditions. We describe the adaptation response of the yeast Saccharomyces cerevisiae to the loss of one of two mechanisms to target proteins to the secretory pathway. Using inducible mutants that block the signal recognition particle (SRP) pathway, we find that cells demonstrate a physiological response to the loss of the SRP pathway that includes specific changes in global gene expression. Upon inducing the loss of the SRP pathway, SRP-dependent protein translocation is initially blocked, and cell growth is considerably slowed. Concomitantly, gene expression changes include the induction of heat shock genes and the repression of protein synthesis genes. Remarkably, within hours, the efficiency of protein sorting improves while cell growth remains slow in agreement with the persistent repression of protein synthesis genes. Our results suggest that heat shock gene induction serves to protect cells from mislocalized precursor proteins in the cytosol, whereas reduced protein synthesis helps to regain efficiency in protein sorting by reducing the load on the protein translocation apparatus. Thus, we suggest that cells trade speed in cell growth for fidelity in protein sorting to adjust to life without SRP.

The ethylene hormone response in Arabidopsis: a eukaryotic two-component signaling system.

The simple gas ethylene affects numerous physiological processes in the growth and development of higher plants. With the use of molecular genetic approaches, we are beginning to learn how plants perceive ethylene and how this signal is transduced. Components of ethylene signal transduction are defined by ethylene response mutants in Arabidopsis thaliana. The genes corresponding to two of these mutants, etr1 and etr1, have been cloned. The ETR1 gene encodes a homolog of two-component regulators that are known almost exclusively in prokaryotes. The two-component regulators in prokaryotes are involved in the perception and transduction of a wide range of environmental signals leading to adaptive responses. The CTR1 gene encodes a homolog of the Raf family of serine/threonine protein kinases. Raf is part of a mitogen-activated protein kinase cascade known to regulate cell growth and development in mammals, worms, and flies. The ethylene response pathway may, therefore, exemplify a conserved protein kinase cascade regulated by a two-component system. The dominance of all known mutant alleles of ETR1 may be due to either constitutive activation of the ETR1 protein or dominant interference of wild-type activity. The discovery of Arabidopsis genes encoding proteins related to ETR1 suggests that the failure to recover recessive etr1 mutant alleles may be due to the presence of redundant genes.

Adaptive Institutional Transference in the Treatment of Individuals with Borderline Personality Disorder.

This paper introduces "adaptive institutional transference" (AIT) and describes how it develops in some clients in response to psychotherapist transfer in psychology training clinics. Individuals with borderline personality disorder are especially likely to develop AIT because of difficulties related to abandonment depression. Directors, supervisors, and student psychotherapists in psychology training clinics should be aware of these dynamics because they have important treatment implications, which are described. Limitations and ideas for future exploratory and qualitative research are also discussed .

Investigating the Role of cAMP-Signaling in the Regulation of Vascular Endothelial Cell Adaptive Responses to Fluid Shear Stress

The circulating blood exerts a force on the vascular endothelium, termed fluid shear stress (FSS), which directly impacts numerous vascular endothelial cell (VEC) functions. For example, high rates of linear and undisturbed (i.e. laminar) blood flow maintains a protective and quiescent VEC phenotype. Meanwhile, deviations in blood flow, which can occur at vascular branchpoints and large curvatures, create areas of low, and/or oscillatory FSS, and promote a pro-inflammatory, pro-thrombotic and hyperpermeable phenotype. Indeed, it is known that these areas are prone to the development of atherosclerotic lesions. Herein, we show that cyclic nucleotide phosphodiesterase (PDE) 4D (PDE4D) activity is increased by FSS in human arterial endothelial cells (HAECs) and that this activation regulates the activity of cAMP-effector protein, Exchange Protein-activated by cAMP-1 (EPAC1), in these cells. Importantly, we also show that these events directly and critically impact HAEC responses to FSS, especially when FSS levels are low. Both morphological events induced by FSS, as measured by changes in cell alignment and elongation in the direction of FSS, and the expression of critical FSS-regulated genes, including Krüppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS) and thrombomodlin (TM), are mediated by EPAC1/PDE4D signaling. At a mechanistic level, we show that EPAC1/PDE4D acts through the vascular endothelial-cadherin (VECAD)/ platelet-cell adhesion molecule-1 (PECAM1)/vascular endothelial growth factor receptor 2 (VEGFR2) mechanosensor to activate downstream signaling though Akt. Given the critical role of PDE4D in mediating these effects, we also investigated the impact of various patterns of FSS on the expression of individual PDE genes in HAECs. Notably, PDE2A was significantly upregulated in response to high, laminar FSS, while PDE3A was upregulated under low, oscillatory FSS conditions only. These data may provide novel therapeutic targets to limit FSS-dependent endothelial cell dysfunction (ECD) and atherosclerotic development.

Countermanding in rats as a practical model for investigation of adaptive control of behaviour, lifespan changes in behavioural control and neurotransmitter function

The countermanding paradigm was designed to investigate the ability to cancel a prepotent response when a stop signal is presented and allows estimation of the stop signal response time (SSRT), an otherwise unobservable behaviour. Humans exhibit adaptive control of behaviour in the countermanding task, proactively lengthening response time (RT) in expectation of stopping and reactively lengthening RT following stop trials or errors. Human performance changes throughout the lifespan, with longer RT, SSRT and greater emphasis on post-error slowing reported for older compared to younger adults. Inhibition in the task has generally been improved by drugs that increase extracellular norepinephrine. The current thesis examined a novel choice response countermanding task in rats to explore whether rodent countermanding performance is a suitable model for the study of adaptive control of behaviour, lifespan changes in behavioural control and the role of neurotransmitters in these behaviours. Rats reactively adjusted RT in the countermanding task, shortening RT after consecutive correct go trials and lengthening RT following non-cancelled, but not cancelled stop trials, in sessions with a 10 s, but not a 1 s post-error timeout interval. Rats proactively lengthened RT in countermanding task sessions compared to go trial-only sessions. Together, these findings suggest that rats strategically lengthened RT in the countermanding task to improve accuracy and avoid longer, unrewarded timeout intervals. Next, rats exhibited longer RT and relatively conserved post-error slowing, but no significant change in SSRT when tested at 12, compared to 7 months of age, suggesting that rats exhibit changes in countermanding task performance with aging similar to those observed in humans. Finally, acute administration of yohimbine (1.25, 2.5 mg/kg) and d-amphetamine (0.25, 0.5 mg/kg), which putatively increase extracellular norepinephrine and dopamine respectively, resulted in RT shortening, baseline-dependent effects on SSRT, and attenuated adaptive RT adjustments in rats in the case of d-amphetamine. These findings suggest that dopamine and norepinephrine encouraged motivated, reward-seeking behaviour and supported inhibitory control in an inverted-U-like fashion. Taken together, these observations validate the rat countermanding task for further study of the neural correlates and neurotransmitters mediating adaptive control of behaviour and lifespan changes in behavioural control.

N-terminal fusion of a toll-like receptor 2-ligand to a Neospora caninum chimeric antigen efficiently modifies the properties of the specific immune response

Immunoprophylactic products against neosporosis during pregnancy should induce an appropriately balanced immune response. In this respect, OprI, a bacterial lipoprotein targeting toll like receptor (TLR)2, provides promising adjuvant properties. We report on the manipulation of the innate and the T-cell immune response through the fusion of OprI with the Neospora caninum chimeric protein Mic3-1-R. In contrast to Mic3-1-R, OprI-MIC3-1-R significantly activated bone-marrow dendritic cells from naïve mice. Mice immunized with OprI-Mic3-1-R induced an immune response with mixed T helper (Th)1 and Th2 properties (high levels of both immunoglobulin (Ig)G1 and IgG2a and of interleukin (IL)-10, IL-12(p70) and interferon-γ responses) whereas Mic3-1-R+saponin induced a clear Th2-biased response (low IgG2a and high IL-4 and IL-10). After mating and challenge with N. caninum, increased expression of interferon-γ was only found in placentas from OprI-Mic3-1-R immunized dams. However, no protection against vertical transmission and neonatal mortality was observed in either of the two groups. These results indicated that more exhaustive studies must be done to elucidate the immune mechanisms associated with transplacental transmission. Antigen linkage to TLR2-ligands, such as OprI, is a useful tool to investigate this enigma by reorienting the innate and adaptive immune responses against other candidate antigens in future studies.

Real leadership and the U.S. Army : overcoming a failure of imagination to conduct adaptive work /

This monograph begins with a case study that provides a means for analyzing the complexity of organizational leadership in the contemporary security environment. As such, it presents a high stakes problem-set that required an operational adaptation by a cavalry squadron conducting combat operations in Baghdad. This problematic reality triggered the struggle to find a creative response to a very deadly problem, while cultural norms served as barriers that prevented the rejection of previously accepted solutions that had proven successful in the past, even though those successful solutions no longer fit in the context of the reality of the present. The case study highlights leaders who were constrained by deeply-held assumptions that inhibited their ability to adapt quickly to a changed environment. The case study then moves on to provide an example of a successful application of adaptive leadership and adaptive work that was performed by the organization after a period of reflection and the willingness to experiment and assume risk. The case study serves as a microcosm of the challenges facing the U.S. Army, and the corresponding leadership framework presented in this monograph can be used as a model for the Army as it attempts to move forward in its effort to make adaptation an institutional imperative. The paper presents a more holistic approach to leadership where the leader transcends that of simply being an authority figure and becomes a real leader who provides a safe and creative learning environment where the organization can tackle and solve adaptive challenges. The paper concludes by recommending that U.S. Army leaders apply Harvard Professor Dean Williams's theory to the challenges confronting the Army's leader development process thereby fostering a culture of adaptive leaders.

Adaptive responses of wild mungbean (Vigna radiata ssp sublobata) to photo-thermal environment. I. Phenology

The phenology of 11 diverse accessions of wild mungbean was observed under natural and artificial photoperiod - temperature conditions, in order to examine whether genotypic differences might be attributed to adaptive responses to photo-thermal conditions. There was large variation in phenological response among accessions and across environments, much of which was due to differences in the duration of the pre-flowering phase. Accessions that flowered earlier tended to flower for longer, apart from 2 earlier flowering, inland Australian lines that were also earlier maturing. The patterns of response in time from sowing to flowering over environment were consistent with quantitative short-day photoperiodic adaptation, a conclusion supported by the effects of artificial day-length extension and by 'goodness of fit' of the observed responses to standard models relating rate of development to photoperiod and temperature. The fitted models indicated that rate of development towards flowering was hastened by warmer temperatures, and delayed by longer day lengths, with differential sensitivity between accessions to both factors. The models also suggested that photoperiod was more important for accessions collected closer to the equator, which were generally later flowering as a consequence. Conversely, temperature was relatively more important in lines from higher latitudes. Modelling also suggested that the period from first flowering to maturity was sensitive to photoperiod and temperature. Again, longer days appeared to prolong growth and delay maturity. However, cooler temperatures accelerated rather than slowed maturity, by suppressing further vegetative growth. The variation observed indicated that there is considerable scope for using the wild population to broaden the adaptation of cultivated mungbean. In particular, the unusual response of a late-flowering, photoperiod-insensitive accession warrants further study to establish whether the wild population contains a unique 'long juvenile' trait analogous to that being used for improving phenological adaptation in soybean.

The development of calibration and adaptive filtering procedures for neuromagnetic studies of human visual function

This thesis first considers the calibration and signal processing requirements of a neuromagnetometer for the measurement of human visual function. Gradiometer calibration using straight wire grids is examined and optimal grid configurations determined, given realistic constructional tolerances. Simulations show that for gradiometer balance of 1:104 and wire spacing error of 0.25mm the achievable calibration accuracy of gain is 0.3%, of position is 0.3mm and of orientation is 0.6°. Practical results with a 19-channel 2nd-order gradiometer based system exceed this performance. The real-time application of adaptive reference noise cancellation filtering to running-average evoked response data is examined. In the steady state, the filter can be assumed to be driven by a non-stationary step input arising at epoch boundaries. Based on empirical measures of this driving step an optimal progression for the filter time constant is proposed which improves upon fixed time constant filter performance. The incorporation of the time-derivatives of the reference channels was found to improve the performance of the adaptive filtering algorithm by 15-20% for unaveraged data, falling to 5% with averaging. The thesis concludes with a neuromagnetic investigation of evoked cortical responses to chromatic and luminance grating stimuli. The global magnetic field power of evoked responses to the onset of sinusoidal gratings was shown to have distinct chromatic and luminance sensitive components. Analysis of the results, using a single equivalent current dipole model, shows that these components arise from activity within two distinct cortical locations. Co-registration of the resulting current source localisations with MRI shows a chromatically responsive area lying along the midline within the calcarine fissure, possibly extending onto the lingual and cuneal gyri. It is postulated that this area is the human homologue of the primate cortical area V4.

Factors affecting the accommodative response to sustained visual tasks

In the absence of adequate visual stimulation accommodation adopts an intermediate resting position, appropriately termed tonic accommodation (TA). A period of sustained fixation can modify the tonic resting position, and indicate the adaptation properties of TA. This thesis investigates various factors contributing to the accommodative response during sustained visual tasks, in particular the adaptation of TA. Objective infra-red optometry was chosen as the most effective method of measurement of accommodation. This technique was compared with other methods of measuring TA and the results found to be well correlated. The inhibitory sympathetic input to the ciliary muscle provides the facility to attenuate the magnitude and duration of adaptive changes in TA. This facility is, however, restricted to those individuals having relatively high levels of pre-task TA. Furthermore, the facility is augmented by substantial levels of concurrent parasympathetic activity. The imposition of mental effort can induce concurrent changes in TA which are predominantly positive and largely the result of an increase in parasympathetic innervation of the ciliary muscle although there is some evidence for sympathetic attentuation at higher levels of TA. In emmetropes sympathetic inhibition can modify the effect of mental effort on the steady-state accommodative response at near. Late-onset myopes (onset after the age of 15 years) have significantlylower values of TA then emmetropes. Similarly, late-onset myopes show lower values of steady-state accommodative response for nearstimuli. The imposition of mental effort induces concurrent increases in TA and steady-state accommodative response in the myopic group which are significantly greater than those for emmetropes. Estimates of TA made under bright empty-field conditions are well correlated with those made under darkroom conditions. The method by which the accommodative loop is opened has no significant effect on the magnitude and duration of post-task shifts in TA induced by a near vision task. Significant differences in the post-task shifts in TA induced by a near vision task exist between emmetropes and late-onset myopes, the post-task shifts being more sustained for the myopic group.

RELAX:a language to address uncertainty in self-adaptive systems requirement

Self-adaptive systems have the capability to autonomously modify their behavior at run-time in response to changes in their environment. Self-adaptation is particularly necessary for applications that must run continuously, even under adverse conditions and changing requirements; sample domains include automotive systems, telecommunications, and environmental monitoring systems. While a few techniques have been developed to support the monitoring and analysis of requirements for adaptive systems, limited attention has been paid to the actual creation and specification of requirements of self-adaptive systems. As a result, self-adaptivity is often constructed in an ad-hoc manner. In order to support the rigorous specification of adaptive systems requirements, this paper introduces RELAX, a new requirements language for self-adaptive systems that explicitly addresses uncertainty inherent in adaptive systems. We present the formal semantics for RELAX in terms of fuzzy logic, thus enabling a rigorous treatment of requirements that include uncertainty. RELAX enables developers to identify uncertainty in the requirements, thereby facilitating the design of systems that are, by definition, more flexible and amenable to adaptation in a systematic fashion. We illustrate the use of RELAX on smart home applications, including an adaptive assisted living system.

Goal-based modeling of dynamically adaptive system requirements

Self-adaptation is emerging as an increasingly important capability for many applications, particularly those deployed in dynamically changing environments, such as ecosystem monitoring and disaster management. One key challenge posed by Dynamically Adaptive Systems (DASs) is the need to handle changes to the requirements and corresponding behavior of a DAS in response to varying environmental conditions. Berry et al. previously identified four levels of RE that should be performed for a DAS. In this paper, we propose the Levels of RE for Modeling that reify the original levels to describe RE modeling work done by DAS developers. Specifically, we identify four types of developers: the system developer, the adaptation scenario developer, the adaptation infrastructure developer, and the DAS research community. Each level corresponds to the work of a different type of developer to construct goal model(s) specifying their requirements. We then leverage the Levels of RE for Modeling to propose two complementary processes for performing RE for a DAS. We describe our experiences with applying this approach to GridStix, an adaptive flood warning system, deployed to monitor the River Ribble in Yorkshire, England.

A language for self-adaptive system requirements

Self-adaptive systems have the capability to autonomously modify their behaviour at run-time in response to changes in their environment. Such systems are now commonly built in domains as diverse as enterprise computing, automotive control systems, and environmental monitoring systems. To date, however, there has been limited attention paid to how to engineer requirements for such systems. As a result, selfadaptivity is often constructed in an ad-hoc manner. In this paper, we argue that a more rigorous treatment of requirements relating to self-adaptivity is needed and that, in particular, requirements languages for self-adaptive systems should include explicit constructs for specifying and dealing with the uncertainty inherent in self-adaptive systems. We present some initial thoughts on a new requirements language for selfadaptive systems and illustrate it using examples from the services domain. © 2008 IEEE.

A goal-based modeling approach to develop requirements of an adaptive system with environmental uncertainty

Dynamically adaptive systems (DASs) are intended to monitor the execution environment and then dynamically adapt their behavior in response to changing environmental conditions. The uncertainty of the execution environment is a major motivation for dynamic adaptation; it is impossible to know at development time all of the possible combinations of environmental conditions that will be encountered. To date, the work performed in requirements engineering for a DAS includes requirements monitoring and reasoning about the correctness of adaptations, where the DAS requirements are assumed to exist. This paper introduces a goal-based modeling approach to develop the requirements for a DAS, while explicitly factoring uncertainty into the process and resulting requirements. We introduce a variation of threat modeling to identify sources of uncertainty and demonstrate how the RELAX specification language can be used to specify more flexible requirements within a goal model to handle the uncertainty. © 2009 Springer Berlin Heidelberg.

RELAX:incorporating uncertainty into the specification of self-adaptive systems

Self-adaptive systems have the capability to autonomously modify their behaviour at run-time in response to changes in their environment. Self-adaptation is particularly necessary for applications that must run continuously, even under adverse conditions and changing requirements; sample domains include automotive systems, telecommunications, and environmental monitoring systems. While a few techniques have been developed to support the monitoring and analysis of requirements for adaptive systems, limited attention has been paid to the actual creation and specification of requirements of self-adaptive systems. As a result, self-adaptivity is often constructed in an ad-hoc manner. In this paper, we argue that a more rigorous treatment of requirements explicitly relating to self-adaptivity is needed and that, in particular, requirements languages for self-adaptive systems should include explicit constructs for specifying and dealing with the uncertainty inherent in self-adaptive systems. We present RELAX, a new requirements language for selfadaptive systems and illustrate it using examples from the smart home domain. © 2009 IEEE.