Four and a half LIM protein 1C (FHL1C)

Four-and-a-half LIM domain protein 1 isoform A (FHL1A) is predominantly expressed in skeletal and cardiac muscle. Mutations in the FHL1 gene are causative for several types of hereditary myopathies including X-linked myopathy with postural muscle atrophy (XMPMA). We here studied myoblasts from XMPMA patients. We found that functional FHL1A protein is completely absent in patient myoblasts. In parallel, expression of FHL1C is either unaffected or increased. Furthermore, a decreased proliferation rate of XMPMA myoblasts compared to controls was observed but an increased number of XMPMA myoblasts was found in the G(0)/G(1) phase. Furthermore, low expression of K(v1.5), a voltage-gated potassium channel known to alter myoblast proliferation during the G(1) phase and to control repolarization of action potential, was detected. In order to substantiate a possible relation between K(v1.5) and FHL1C, a pull-down assay was performed. A physical and direct interaction of both proteins was observed in vitro. In addition, confocal microscopy revealed substantial colocalization of FHL1C and K(v1.5) within atrial cells, supporting a possible interaction between both proteins in vivo. Two-electrode voltage clamp experiments demonstrated that coexpression of K(v1.5) with FHL1C in Xenopus laevis oocytes markedly reduced K(+) currents when compared to oocytes expressing K(v1.5) only. We here present the first evidence on a biological relevance of FHL1C

Frequency Scaling as a Security Threat on Multicore Systems

Most modern processors use Dynamic Voltage and Frequency Scaling (DVFS) for power management. DVFS allows to optimize power consumption by scaling voltage and frequency depending on performance demand. Previous research has indicated that this frequency scaling might pose a security threat in the form of a covert channel, which could leak sensitive information. However, an analysis able to determine whether DVFS is a serious security issue is still missing. In this paper, we conduct a detailed analysis of the threat potential of a DVFS-based covert channel. We investigate two multicore platforms representative of modern laptops and hand-held devices. Furthermore, we develop a channel model to determine an upper bound to the channel capacity, which is in the order of 1 bit per channel use. Last, we perform an experimental analysis using a novel transceiver implementation. The neural network based receiver yields packet error rates between 1% and 8% at average throughputs of up to 1.83 and 1.20 bits per second for platforms representative of laptops and hand-held devices, respectively. Considering the well-known small message criterion, our results show that a relevant covert channel can be established by exploiting the behaviour of computing systems with DVFS.ISSN:0278-0070ISSN:1937-415

Four and a Half LIM Protein 1C (FHL1C): A Binding Partner for Voltage-Gated Potassium Channel Kv1.5

Four-and-a-half LIM domain protein 1 isoform A (FHL1A) is predominantly expressed in skeletal and cardiac muscle. Mutations in the FHL1 gene are causative for several types of hereditary myopathies including X-linked myopathy with postural muscle atrophy (XMPMA). We here studied myoblasts from XMPMA patients. We found that functional FHL1A protein is completely absent in patient myoblasts. In parallel, expression of FHL1C is either unaffected or increased. Furthermore, a decreased proliferation rate of XMPMA myoblasts compared to controls was observed but an increased number of XMPMA myoblasts was found in the G0/G1 phase. Furthermore, low expression of Kv1.5, a voltage-gated potassium channel known to alter myoblast proliferation during the G1 phase and to control repolarization of action potential, was detected. In order to substantiate a possible relation between Kv1.5 and FHL1C, a pull-down assay was performed. A physical and direct interaction of both proteins was observed in vitro. In addition, confocal microscopy revealed substantial colocalization of FHL1C and Kv1.5 within atrial cells, supporting a possible interaction between both proteins in vivo. Two-electrode voltage clamp experiments demonstrated that coexpression of Kv1.5 with FHL1C in Xenopus laevis oocytes markedly reduced K+ currents when compared to oocytes expressing Kv1.5 only. We here present the first evidence on a biological relevance of FHL1C

Optimal inference with suboptimal models:Addiction and active Bayesian inference

When casting behaviour as active (Bayesian) inference, optimal inference is defined with respect to an agent's beliefs - based on its generative model of the world. This contrasts with normative accounts of choice behaviour, in which optimal actions are considered in relation to the true structure of the environment - as opposed to the agent's beliefs about worldly states (or the task). This distinction shifts an understanding of suboptimal or pathological behaviour away from aberrant inference as such, to understanding the prior beliefs of a subject that cause them to behave less 'optimally' than our prior beliefs suggest they should behave. Put simply, suboptimal or pathological behaviour does not speak against understanding behaviour in terms of (Bayes optimal) inference, but rather calls for a more refined understanding of the subject's generative model upon which their (optimal) Bayesian inference is based. Here, we discuss this fundamental distinction and its implications for understanding optimality, bounded rationality and pathological (choice) behaviour. We illustrate our argument using addictive choice behaviour in a recently described 'limited offer' task. Our simulations of pathological choices and addictive behaviour also generate some clear hypotheses, which we hope to pursue in ongoing empirical work

Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM) - associated up-regolation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto placental endothelium

CONTEXT: Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion. OBJECTIVE: Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis. DESIGN: Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors. RESULTS: Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor. CONCLUSIONS: GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature

Experimental induction of peritraumatic dissociation: The role of negative affect and pain and their psychophysiological and neural correlates

While research has elucidated processes underlying dissociative symptoms in patients with posttraumatic stress disorder, little is known about the circumstances under which trauma-related dissociation initially arises. To experimentally investigate causes and concomitants of peritraumatic dissociation, we subjected sixty-nine healthy women to aversive-audiovisual and painful-electrical stimulation in a 2(aversive/neutral film) x 2(pain/no pain) within-subject design while recording psychophysiological and fMRI-BOLD responses. Afterwards, participants rated negative-affect, pain, and dissociation for each condition. Using Bayesian multilevel regression models, we examined (1) whether aversive-audiovisual and painful-electrical stimulation elicit higher dissociation-levels than control conditions and (2) whether stronger negative-affect and pain responses (operationalized via self-report, psychophysiological, and neural markers) correlate with higher dissociation-levels. Several key findings emerged: Both aversive-audiovisual and painful-electrical stimulation elicited dissociation. Dissociation was linked to higher self-reported negative-affect, but we did not find enough evidence linking it to psychophysiological and neural negative-affect markers. However, dissociation was associated with higher levels of self-reported pain, a skin-conductance-response-based pain marker, and the fMRI-BOLD-based Neurologic-Pain-Signature. Results indicate that both aversive-audiovisual and painful stimuli can independently cause dissociation. Critically, pain responses captured via self-report, psychophysiological, and neural markers were consistently linked to higher dissociation-levels suggesting a specific, evolutionary meaningful, contribution of pain to the rise of dissociation

Estradiol during (analogue-)trauma: Risk- or protective factor for intrusive re-experiencing?

Intrusions, a key symptom of posttraumatic stress disorder (PTSD), can occur in the form of images but also as pain sensations. Similar to audiovisual intrusions, the frequency and persistence of pain intrusions varies greatly between individuals. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels are a biologic factor associated with subsequent audiovisual (i.e., film) and pain intrusion development, and whether peritraumatic stress levels modulate this relationship. Forty-one free-cycling women participated in an ecologically informed trauma-pain-conditioning (TPC) paradigm, using trauma-films and pain as unconditioned stimuli. Independent variables were salivary peritraumatic E2 levels and stress indexed by salivary cortisol and self-reported state-anxiety during TPC. Outcomes were film- and pain-intrusions occurring during daily-life in the week following TPC and a Memory-Triggering-Task in response to conditioned stimuli 24 h after TPC. In the week after analogue-trauma, higher peritraumatic E2 levels were associated with a greater probability of experiencing film-intrusions in the beginning of the week, which switched to a lower probability toward the end of the week. This time-dependent relationship between E2 and film-intrusions only held for higher state-anxious women. In contrast, results indicated a consistent inverse relationship between peritraumatic E2 levels and pain-intrusions during daily-life and Memory-Triggering-Task. Together, these data suggest that higher peritraumatic E2 levels could be associated with lower long-term visual trauma intrusions, as well as lower pain-intrusions, and thereby possibly constitute a protective biologic factor for PTSD and potentially also for chronic pain

How a co-actor’s task affects monitoring of own errors: evidence from a social event-related potential study

Efficient flexible behavior requires continuous monitoring of performance for possible deviations from the intended goal of an action. This also holds for joint action. When jointly performing a task, one needs to not only know the other’s goals and intentions but also generate behavioral adjustments that are dependent on the other person’s task. Previous studies have shown that in joint action people not only represent their own task but also the task of their co-actor. The current study investigated whether these so-called shared representations affect error monitoring as reflected in the response-locked error-related negativity (Ne/ERN) following own errors. Sixteen pairs of participants performed a social go/no-go task, while EEG and behavioral data were obtained. Responses were compatible or incompatible relative to the go/no-go action of the co-actor. Erroneous responses on no-go stimuli were examined. The results demonstrated increased Ne/ERN amplitudes and longer reaction times following errors on compatible compared to incompatible no-go stimuli. Thus, Ne/ERNs were larger after errors on trials that did not require a response from the co-actor either compared to errors on trials that did require a response from the co-actor. As the task of the other person is the only difference between these two types of errors, these findings show that people also represent their co-actor’s task during error monitoring in joint action. An extension of existing models on performance monitoring in individual action is put forward to explain the current findings in joint action. Importantly, we propose that inclusion of a co-actor’s task in performance monitoring may facilitate adaptive behavior in social interactions enabling fast anticipatory and corrective actions

Damage to insula abolishes cognitive distortions during simulated gambling.

This is the accepted version of an article originally published in PNAS. The version of record is available at http://www.pnas.org/content/early/2014/04/02/1322295111.Gambling is a naturalistic example of risky decision-making. During gambling, players typically display an array of cognitive biases that create a distorted expectancy of winning. This study investigated brain regions underpinning gambling-related cognitive distortions, contrasting patients with focal brain lesions to the ventromedial prefrontal cortex (vmPFC), insula, or amygdala ("target patients") against healthy comparison participants and lesion comparison patients (i.e., with lesions that spare the target regions). A slot machine task was used to deliver near-miss outcomes (i.e., nonwins that fall spatially close to a jackpot), and a roulette game was used to examine the gambler's fallacy (color decisions following outcome runs). Comparison groups displayed a heightened motivation to play following near misses (compared with full misses), and manifested a classic gambler's fallacy effect. Both effects were also observed in patients with vmPFC and amygdala damage, but were absent in patients with insula damage. Our findings indicate that the distorted cognitive processing of near-miss outcomes and event sequences may be ordinarily supported by the recruitment of the insula. Interventions to reduce insula reactivity could show promise in the treatment of disordered gambling.LC was supported by a grant from the Medical Research Council (UK) (G1100554). BS was supported by a PhD studentship from the Medical Research Council. AB and DT, as well as the lesion patient research, were supported by grants from the National Institute of Health, namely the National Institute of Neurological Disorders and Stroke [P01 NS19632], and by the National Institute on Drug Abuse [R01 DA023051, R01 DA022549]

Rewards that are near increase impulsive action

International audienceIn modern society, the natural drive to behave impulsively in order to obtain rewards must often be curbed. A continued failure to do so is associated with a range of outcomes including drug abuse, pathological gambling, and obesity. Here, we used virtual reality technology to investigate whether spatial proximity to rewards has the power to exacerbate the drive to behave impulsively toward them. We embedded two behavioral tasks measuring distinct forms of impulsive behavior, impulsive action, and impulsive choice, within an environment rendered in virtual reality. Participants responded to three-dimensional cues representing food rewards located in either near or far space. Bayesian analyses revealed that participants were significantly less able to stop motor actions when rewarding cues were near compared with when they were far. Since factors normally associated with proximity were controlled for, these results suggest that proximity plays a distinctive role in driving impulsive actions for reward