Multiple Response Systems Research Articles

Identification of a copper-responsive small molecule inhibitor of uropathogenic Escherichia coli.

Urinary tract infections (UTIs) are a major global health problem and are caused predominantly by uropathogenic Escherichia coli (UPEC). UTIs are a leading cause of prescription antimicrobial use. Incessant increase in antimicrobial resistance in UPEC and other uropathogens poses a serious threat to the current treatment practices. Copper is an effector of nutritional immunity that impedes the growth of pathogens during infection. We hypothesized that copper would augment the toxicity of select small molecules against bacterial pathogens. We conducted a small molecule screening campaign with a library of 51,098 molecules to detect hits that inhibit a UPEC ΔtolC mutant in a copper-dependent manner. A molecule, denoted as E. coli inhibitor or ECIN, was identified as a copper-responsive inhibitor of wild-type UPEC strains. Our gene expression and metal content analysis results demonstrate that ECIN works in concert with copper to exacerbate Cu toxicity in UPEC. ECIN has a broad spectrum of activity against pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. Subinhibitory levels of ECIN eliminate UPEC biofilm formation. Transcriptome analysis of UPEC treated with ECIN reveals induction of multiple stress response systems. Furthermore, we demonstrate that L-cysteine rescues the growth of UPEC exposed to ECIN. In summary, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC.IMPORTANCEUrinary tract infection (UTI) is a ubiquitous infectious condition affecting millions of people annually. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTI. However, UTIs are becoming increasingly difficult to resolve with antimicrobials due to increased antimicrobial resistance in UPEC and other uropathogens. Here, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC. In addition to E. coli, this small molecule also inhibits pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus.

Interpersonal stress and proinflammatory activity in emerging adults with a history of suicide risk: A pilot study

Interpersonal stress during adolescence and young adulthood can threaten healthy developmental trajectories. A “primed” proinflammatory response to acute stress may serve as an underlying process that results in negative outcomes for youth. The present pilot study examined the relation between interpersonal stress and two proinflammatory cytokines in a sample of 42 university-recruited emerging adults with recent suicidal thoughts and behaviors. Participants completed self-report measures of mood, suicidal thoughts and behaviors, recent peer-related stressors, and interpersonal sensitivity. They also participated in an acute laboratory social stress task and provided three saliva samples to measure their proinflammatory responses (IL-6 and TNF-α) to the stressor. Participants reported significant increases in sadness and exclusion, and significant decreases in inclusion, following task participation. Importantly, no participants reported an increase in or onset of suicidal thoughts. No significant associations between interpersonal stress and proinflammatory cytokines were found. Changes in affect during the task coupled with lack of increased suicidal thoughts indicate it is acceptable to use this exclusion and rejection paradigm with this population, with proper debriefing and positive mood induction procedures. Given all other nonsignificant associations, future research considerations are discussed, including impact of COVID-19 on task potency and incorporation of multiple stress response systems.

Evolving Concepts of the Schizophrenia Spectrum: A Research Domain Criteria Perspective.

Several trends intersecting over the past two decades have generated increasing debate as to how the concepts of schizophrenia, the schizophrenia spectrum, and the psychotic disorders spectrum should be regarded. These trends are reflected in various areas of research such as genomics, neuroimaging, and data-driven computational studies of multiple response systems. Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disease entity, that is part of a multi-faceted psychosis spectrum. Progress in explicating these various developments has been hampered by the dependence upon sets of symptoms and signs for determining a diagnosis, and by the reliance on traditional diagnostic categories in reviewing clinical research grants. To address these concerns, the U.S. National Institute of Mental Health initiated the Research Domain Criteria (RDoC) project, a translational research program that calls for studies designed in terms of empirically-based functions (such as cognitive control or reward learning) rather than diagnostic groups. RDoC is a research framework rather than an alternative diagnostic system, intended to provide data that can inform future nosological manuals. This commentary includes a brief summary of RDoC as it pertains to schizophrenia and psychotic spectra, examples of recent data that highlight the utility of the approach, and conclusions regarding the implications for evolving conceptualizations of serious mental illness.

Externalizing behavior and stress system functioning in infants exposed to early adversity: A multi-system exploration.

Children who experience early adversity often show alterations across multiple stress response systems, including the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Changes in the diurnal rhythm of salivary cortisol (a marker of HPA axis functioning) and alpha-amylase (a marker of ANS functioning) may increase their probability of developing behavior problems. The goal of this study is to examine how these analytes may interact to predict externalizing behavior in infants exposed to early stress. Participants included 179 parents and their 6- to 20-month old infants recruited from a low-income neighborhood. Parents reported on their infants' externalizing behaviors and collected saliva samples from their children at wake-up and bedtime over three days. Diurnal cortisol and alpha-amylase were modeled using latent difference scores. Four models were tested examining the effects of cortisol and alpha-amylase morning values and slopes, as well as their interactions, on externalizing behavior. Results showed a significant interaction effect of cortisol and alpha-amylase morning values, such that low morning cortisol was associated with decreased externalizing behavior when morning alpha-amylase was high but not low. These findings highlight the importance of examining multiple systems when characterizing the physiological correlates of externalizing behavior among infants experiencing adversity.

Exploring the role of Muscovite in poly(alkyl methacrylate)-based ternary nanocomposite cryogels with selective functional groups: formation via cryogelling with the aid of inorganic clay.

Easy fabrication of inorganic clay muscovite (MUS) embedded poly(2-acrylamido-2-methyl-1-propane sulfonic acid-co-diethylaminoethyl methacrylate-co-hydroxyethyl methacrylate) (PADH) nanocomposite cryogels with dual temperature/pH dependent catalytic potential was reported. Nanocomposite cryogels were fabricated by a method involving cryogelation and free radical crosslinking of aqueous systems containing MUS ranging from 0% to 1.50% (w/v). The changes in the properties of polybasic PADH networks were investigated to explain how the network parameters and gel properties were affected by the addition of clay, with the formation of a single terpolymer-MUS structure. The potential of the addition of different amounts of MUS to strengthen the prepared terpolymer matrix was investigated by uniaxial compression tests. By lowering the polymerization temperature or increasing the MUS content, the PADH/MUS nanocomposite cryogels became more elastic and compressible with stronger entanglement of terpolymer chains between the clay layers. With the addition of 1.50% (w/v) MUS, the swelling capacity was reduced by 50%, resulting in a two-fold increase in compression elasticity. The nanocomposite gels showed a strong pH-dependence, and when the pH of the swelling medium decreased from 9.8 to 2.1, there was a significant increase in the degree of swelling with increasing protonation of tertiary amine groups. Under an acidic environment, the swelling capacity of the nanocomposite gel containing 1.10% (w/v) MUS increased by 49.5%. In temperature dependent swelling between 15 and 75 °C, all ternary PADH/MUS-Ngels showed a tendency to swell at low and high swelling temperatures, by the predominance of DEAEM units at low temperatures and HEMA monomers at high temperatures, respectively. As the temperature was increased to 55 °C, the swelling decreased and reached a minimum, and then the nanocomposite gels tended to swell again. The obtained results provide an insight into the effect of MUS addition on the properties of poly(alkyl methacrylate)-based ternary nanocomposite gels and demonstrate a simple and efficient way to produce multiple response systems with enhanced elasticity.

Sympathetic responding to unconditioned stimuli predicts subsequent threat expectancy, orienting, and visuocortical bias in human aversive Pavlovian conditioning

Threat expectancy is the ability to predict an aversive outcome. What is not known is the influence of initial threat responding on the acquisition of verbal, attentional and perceptual biases towards conditioned threat cues. This study evaluated the extent to which initial unconditioned stimulus (UCS) responding was related to trial-by-trial self-reported expectancy, sensory processing (visuocortical EEG) and orienting (heart rate deceleration) to threat cues during extinction learning. Participants (n = 38) viewed oriented Gabor gratings, associated with the presence (CS+) or absence (CS-) of a 96 dB white noise (UCS), flickering at 12 Hz to elicit steady state visually evoked potentials (ssVEPs). Multivariate multiple regression revealed greater initial UCS skin conductance responding to predict extinction responding: enhanced visuocortical discrimination, greater heart rate deceleration to CS+, and greater threat expectancy endorsements. These results suggest that the motivational intensity of initial threat reactivity (sympathetic UCS responding) drives learning-induced defensive dispositions across multiple response systems.

Emotional coherence in early and later adulthood during sadness reactivity and regulation.

The current study reports the first investigation of age-related changes in emotional coherence across multiple response systems (experiential, physiological, and expressive) in sadness reactivity and regulation. Some accounts indirectly suggest that blunted physiological responses to emotional stimuli (e.g., Mendes, 2010) may lead to an age-related decline in emotional coherence, whereas a conflicting account suggests that age-relevant content can modulate responses across multiple systems (e.g., Kunzmann & Grühn, 2005), which has the potential to increase emotional coherence in older adults. We therefore examined emotional coherence in 60 younger (Mage = 20) and 60 older adults (Mage = 71) during emotional reactivity and regulation (suppression and acceptance) while participants watched sadness-eliciting videos. Emotional experience (sadness intensity self-report), physiological (heart period) responses, and behavioral facial expression (corrugator supercilii muscle activity) were assessed while participants viewed these videos. Importantly, older adults showed greater emotional coherence between experience and heart period and maintained coherence between experience and expression responses compared to younger adults. These findings are consistent with the idea that, because of motivational relevance and life experiences, sadness-eliciting content may lead to a greater coupling between sadness experience and physiology in older than in younger adults. Age is therefore an important individual difference factor to consider when examining within-individual associations between emotion systems. (PsycINFO Database Record

New Insights into the Genetic Basis of Monge's Disease and Adaptation to High-Altitude.

Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology, and molecular mechanisms that underlie long-term exposure to hypoxia. Here, we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and nonCMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in nonexonic regions, were significantly different between CMS and nonCMS subjects. Closer examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1, and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3, and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, nonHIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. Taken together, the PreCIOSS algorithm, applied on a large number of genomes, identifies the involvement of both new and previously reported genes in selection sweeps, highlighting the involvement of multiple hypoxia response systems. Since the overwhelming majority of SNPs are in nonexonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia.

Adaptive synchronization of multiple uncertain coupled chaotic systems via sliding mode control

This paper mainly investigates two kinds of sliding mode synchronization (SMS) for multiple chaotic systems with unknown parameters and disturbances. Both multiple coupled systems and uncoupled systems are considered. For multiple uncoupled chaotic systems (MUCSs), the sliding mode control scheme is designed to ensure that multiple response systems synchronize with one drive system under the effects of external disturbances, and the appropriate adaptive laws are proposed to estimate unknown parameters. For multiple coupled chaotic systems (MCCSs), the definition of transmission synchronization is given first. Furthermore, a special integral sliding surfaces is selected, and the corresponding controllers with the compensation terms are developed to realize SMS between every drive chaotic system and every respond system in transmission mode. Finally, some numerical examples are presented to illustrate the validity of theoretical results.

Sliding mode synchronization of multiple chaotic systems with uncertainties and disturbances

This paper investigates two classes of synchronization problems of multiple chaotic systems with unknown uncertainties and disturbances by employing sliding mode control. Modified projective synchronization and transmission synchronization are discussed here. For the modified projective synchronization problem, sliding mode controllers are designed to ensure that multiple response systems synchronize with one drive system under the effects of external disturbances. For the transmission synchronization problem, based on adaptive sliding mode control, an integral sliding surface is selected and the adaptive laws are derived to tackle unknown uncertainties and disturbances for such systems. A class of nonlinear adaptive sliding mode controllers is developed to guarantee asymptotical stability of the error systems so that all chaotic systems can synchronize with each other. Simulation results are given to illustrate the effectiveness of the proposed schemes by comparing with the existing methods.

Topology identification of complex delayed dynamical networks with multiple response systems

This paper proposes an approach to identify the topological structure and unknown parameters for one drive and multiple response complex delayed networks. We achieve synchronization by designing effective controllers not only among one drive and multiple response complex delayed networks, but also between multiple response complex delayed networks. The unknown network topological structure and system parameters of multiple uncertain response complex delayed networks are identified simultaneously in the process of synchronization. Several synchronization criteria are obtained. Finally, an illustrative example is presented to demonstrate the application of the theoretical results.

Temporal stability of multiple response systems to 7.5% carbon dioxide challenge

Self-reported anxiety, and potentially physiological response, to maintained inhalation of carbon dioxide (CO2) enriched air shows promise as a putative marker of panic reactivity and vulnerability. Temporal stability of response systems during low-dose, steady-state CO2 breathing challenge is lacking. Outcomes on multiple levels were measured two times, one week apart, in 93 individuals. Stability was highest during the CO2 breathing phase compared to pre-CO2 and recovery phases, with anxiety ratings, respiratory rate, skin conductance level, and heart rate demonstrating good to excellent temporal stability (ICCs≥0.71). Cognitive symptoms tied to panic were somewhat less stable (ICC=0.58) than physical symptoms (ICC=0.74) during CO2 breathing. Escape/avoidance behaviors and DSM-5 panic attacks were not stable. Large effect sizes between task phases also were observed. Overall, results suggest good-excellent levels of temporal stability for multiple outcomes during respiratory stimulation via 7.5% CO2.

To each its own? Gender differences in affective, autonomic, and behavioral responses to same-sex and opposite-sex visual sexual stimuli

A large body of research on gender differences in response to erotic stimuli has focused on genital and/or subjective sexual arousal. On the other hand, studies assessing gender differences in emotional psychophysiological responding to sexual stimuli have only employed erotic pictures of male-female couples or female/male nudes. The present study aimed at investigating differences between gynephilic men and androphilic women in emotional responding to visual sexual stimuli depicting female-male, female-female and male-male couples. Affective responses were explored in multiple response systems, including autonomic indices of emotional activation, i.e., heart rate and skin conductance, along with standardized measures of valence and arousal. Blood pressure was measured as an index of autonomic activation associated with sexual arousal, and free viewing times as an index of interest/avoidance. Overall, men showed gender-specific activation characterized by clearly appetitive reactions to the target of their sexual attraction (i.e., women), with physiological arousal discriminating female-female stimuli as the most effective sexual cues. In contrast, women's emotional activation to sexual stimuli was clearly non-specific in most of the considered variables, with the notable exception of the self-report measures. Overall, affective responses replicate patterns of gender-specific and gender-nonspecific sexual responses in gynephilic men and androphilic women.

Almost sure adaptive asymptotically synchronization for neutral-type multi-slave neural networks with Markovian jumping parameters and stochastic perturbation

In this paper, the problem of adaptive synchronization for time-delay neutral-type multi-slave neural networks with Markovian jumping parameters and stochastic noise is researched. The adaptive synchronization model which contains a drive system and multiple response systems is presented. By using of the generalized Ito^’s formula and the M-matrix method, the sufficient condition is obtained to guarantee that the error control system is stable, and the update law of the feedback controller is designed to ensure that every slave system synchronizes with master system. Finally, a numerical example is given to illustrate the effectiveness of the method and result obtained in this paper.

Predictive validity of explicit and implicit threat overestimation in contamination fear

We examined the predictive validity of explicit and implicit measures of threat overestimation in relation to contamination-fear outcomes using structural equation modeling. Undergraduate students high in contamination fear (N=56) completed explicit measures of contamination threat likelihood and severity, as well as looming vulnerability cognitions, in addition to an implicit measure of danger associations with potential contaminants. Participants also completed measures of contamination-fear symptoms, as well as subjective distress and avoidance during a behavioral avoidance task, and state looming vulnerability cognitions during an exposure task. The latent explicit (but not implicit) threat overestimation variable was a significant and unique predictor of contamination fear symptoms and self-reported affective and cognitive facets of contamination fear. On the contrary, the implicit (but not explicit) latent measure predicted behavioral avoidance (at the level of a trend). Results are discussed in terms of differential predictive validity of implicit versus explicit markers of threat processing and multiple fear response systems.

Issues in the extinction of specific stimulus-outcome associations in Pavlovian conditioning

This paper reviews a variety of studies designed to examine the effects of extinction upon control by specific stimulus-outcome (S-O) associations in Pavlovian conditioning. Studies conducted with rats in a magazine approach conditioning paradigm have shown that control by specific S-O associations is normally unaffected by extinction treatments, although other aspects of conditioned responding seem affected in a more enduring way. However, recent work suggests that extinction can undermine control by such associations if it is administered after the conditioned stimulus is weakly encoded. The results from these studies suggest that it may be important to consider multiple response systems in assessing the impact of extinction. Studies conducted with the flavor preference learning paradigm in rats also show that specific S-O associations can be undermined by procedures that involve presenting a flavor cue in the absence of its associated nutrient. These findings provide no support for the view that flavor preference learning necessarily entails some unique learning process that differs from more conventional processes. As in other situations, some of these effects likely involve a masking process, but the extent to which masking or true associative weakening occurs in extinction more generally is a topic that is not well understood. Finally, we present some data to suggest that extinction also involves conditional "occasion-setting" control by contextual cues. Special procedures are recommended in assessing such learning when the goal is to distinguish this form of learning from other more conventional mechanisms of extinction.

Design-for-six-sigma for multiple response systems

An important upstream activity in the overall design of a system is the allocation of the means and tolerances. This is a daunting task because of the need to satisfy multiple competing demands that arise from performance, cost and quality policies. Herein, the so-called design-for-six-sigma is adopted for the allocation process whereby the philosophy of zero defects in Six Sigma is now applied to the system performances. Probability-constrained optimisation is invoked. Robustness and cost measures are required. The production cost provides the objective function to be minimised and a maximum allowable system probability of non-conformance (e.g. a system defect rate) provides the primary design constraint. The design of an electro-mechanical servo system with three responses, three control variables and two noise variables is given. Means and tolerances for the three control variables plus system costs for progressively lower product defect rates show the practicality and potential of the approach.

The SsrA-SmpB Ribosome Rescue System Is Important for Growth ofBacillus subtilisat Low and High Temperatures

Bacillus subtilis has multiple stress response systems whose integrated action promotes growth and survival under unfavorable conditions. Here we address the function and transcriptional organization of a five-gene cluster containing ssrA, previously known to be important for growth at high temperature because of the role of its tmRNA product in rescuing stalled ribosomes. Reverse transcription-PCR experiments detected a single message for the secG-yvaK-rnr-smpB-ssrA cluster, suggesting that it constitutes an operon. However, rapid amplification of cDNA ends-PCR and lacZ fusion experiments indicated that operon transcription is complex, with at least five promoters controlling different segments of the cluster. One sigma(A)-like promoter preceded secG (P(1)), and internal sigma(A)-like promoters were found in both the rnr-smpB (P(2)) and smpB-ssrA intervals (P(3) and P(HS)). Another internal promoter lay in the secG-yvaK intercistronic region, and this activity (P(B)) was dependent on the general stress factor sigma(B). Null mutations in the four genes downstream from P(B) were tested for their effects on growth. Loss of yvaK (carboxylesterase E) or rnr (RNase R) caused no obvious phenotype. By contrast, smpB was required for growth at high temperature (52 degrees C), as anticipated if its product (a small ribosomal binding protein) is essential for tmRNA (ssrA) function. Notably, smpB and ssrA were also required for growth at low temperature (16 degrees C), a phenotype not previously associated with tmRNA activity. These results extend the known high-temperature role of ssrA and indicate that the ribosome rescue system is important at both extremes of the B. subtilis temperature range.

Cardiovascular and affective responses to social stress in adolescents with internalizing and externalizing problems

Behavioral responses to stress and challenge are based in emotional and physiological arousal reactions. Adolescents with maladaptive or problematic behavior patterns, such as internalizing or externalizing problems, are likely to show atypical emotional and physiological reactions to stress. Relations between problems and reactions to stress were examined in a sample of 55 young adolescents with normal to clinical levels of internalizing and externalizing problems. Youth had their self-reported emotional states, heart rate, and blood pressure levels measured before and after engaging in two socially challenging, evaluative manipulations. Internalizing problems were associated with less positive affect but greater anxiety and cardiovascular arousal, whereas externalizing problems predicted greater hostility and positive affect but less cardiovascular arousal. The necessity of recognizing and incorporating comorbid characteristics and multiple response systems into studies of the links between problems and reactivity is emphasized in the discussion.

Functional analysis of chick ONT1 reveals distinguishable activities among olfactomedin-related signaling factors

The Olfactomedin family is a relatively new class of extracellular proteins. Two family members have been shown to play roles in the early development of ectodermal tissues: Noelin enhances neural crest generation in chick and Tiarin promotes dorsal neural specification in Xenopus. In this study, we introduce a novel member of the Olfactomedin family, ONT1. In the early chick embryo, ONT1 expression first appears at Hensen's node and subsequently in the axial and paraxial mesoderm. When the neural tube closes, strong expression of ONT1 is transiently found in the roof plate region from the rostral midbrain to the hindbrain. Overexpression of ONT1 in these regions prolongs the generation of neural crest cells in a manner similar to that of Noelin. Interestingly, ONT1 and Noelin have opposing effects on the expression of the migrating neural crest marker HNK-1 in the chick: they, respectively, cause suppression and ectopic induction of this marker. Differential activities among Olfactomedin-related factors are further examined in Xenopus. Microinjection of ONT1 mRNA into the Xenopus embryo expands the expression domain of the neural crest marker FoxD3 at the neurula stage whereas overexpression of Tiarin or Noelin suppresses FoxD3. ONT1 exhibits no dorsalizing effects on the Xenopus neural tube, which contrasts with the strong dorsalizing activity seen for Tiarin. Thus, distinct Olfactomedin-related factors evoke qualitatively different phenotypes even in the same experimental systems, suggesting that Olfactomedin family uses multiple response systems to mediate its signals in embryogenesis.