The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Mental rotation task of hands: differential influence number of rotational axes

Various studies on the hand laterality judgment task, using complex sets of stimuli, have shown that the judgments during this task are dependent on bodily constraints. More specific, these studies showed that reaction times are dependent on the participant’s posture or differ for hand pictures rotated away or toward the mid-sagittal plane (i.e., lateral or medial rotation, respectively). These findings point to the use of a cognitive embodied process referred to as motor imagery. We hypothesize that the number of axes of rotation of the displayed stimuli during the task is a critical factor for showing engagement in a mental rotation task, with an increased number of rotational axes leading to a facilitation of motor imagery. To test this hypothesis, we used a hand laterality judgment paradigm in which we manipulated the difficulty of the task via the manipulation of the number of rotational axes of the shown stimuli. Our results showed increased influence of bodily constraints for increasing number of axes of rotation. More specifically, for the stimulus set containing stimuli rotated over a single axis, no influence of biomechanical constraints was present. The stimulus sets containing stimuli rotated over more than one axes of rotation did induce the use of motor imagery, as a clear influence of bodily constraints on the reaction times was found. These findings extend and refine previous findings on motor imagery as our results show that engagement in motor imagery critically depends on the used number of axes of rotation of the stimulus set

Temporal Accumulation and Decision Processes in the Duration Bisection Task Revealed by Contingent Negative Variation

The duration bisection paradigm is a classic task used to examine how humans and other animals perceive time. Typically, participants first learn short and long anchor durations and are subsequently asked to classify probe durations as closer to the short or long anchor duration. However, the specific representations of time and the decision rules applied in this task remain the subject of debate. For example, researchers have questioned whether participants actually use representations of the short and long anchor durations in the decision process rather than merely a response threshold that is derived from those anchor durations. Electroencephalographic (EEG) measures, like the contingent negative variation (CNV), can provide information about the perceptual and cognitive processes that occur between the onset of the timing stimulus and the motor response. The CNV has been implicated as an electrophysiological marker of interval timing processes such as temporal accumulation, representation of the target duration, and the decision that the target duration has been attained. We used the CNV to investigate which durations are involved in the bisection categorization decision. The CNV increased in amplitude up to the value of the short anchor, remained at a constant level until about the geometric mean (GM) of the short and long anchors, and then began to resolve. These results suggest that the short anchor and the GM of the short and long anchors are critical target durations used in the bisection categorization decision process. In addition, larger mean N1P2 amplitude differences were associated with larger amplitude CNVs, which may reflect the participant’s precision in initiating timing on each trial across a test session. Overall, the results demonstrate the value of using scalp-recorded EEG to address basic questions about interval timing

My Hand or Yours? Markedly Different Sensitivity to Egocentric and Allocentric Views in the Hand Laterality Task

In the hand laterality task participants judge the handedness of visually presented stimuli – images of hands shown in a variety of postures and views - and indicate whether they perceive a right or left hand. The task engages kinaesthetic and sensorimotor processes and is considered a standard example of motor imagery. However, in this study we find that while motor imagery holds across egocentric views of the stimuli (where the hands are likely to be one's own), it does not appear to hold across allocentric views (where the hands are likely to be another person's). First, we find that psychophysical sensitivity, d', is clearly demarcated between egocentric and allocentric views, being high for the former and low for the latter. Secondly, using mixed effects methods to analyse the chronometric data, we find high positive correlation between response times across egocentric views, suggesting a common use of motor imagery across these views. Correlations are, however, considerably lower between egocentric and allocentric views, suggesting a switch from motor imagery across these perspectives. We relate these findings to research showing that the extrastriate body area discriminates egocentric (‘self’) and allocentric (‘other’) views of the human body and of body parts, including hands

Unexpected Course of Nonlinear Cardiac Interbeat Interval Dynamics during Childhood and Adolescence

The fluctuations of the cardiac interbeat series contain rich information because they reflect variations of other functions on different time scales (e.g., respiration or blood pressure control). Nonlinear measures such as complexity and fractal scaling properties derived from 24 h heart rate dynamics of healthy subjects vary from childhood to old age. In this study, the age-related variations during childhood and adolescence were addressed. In particular, the cardiac interbeat interval series was quantified with respect to complexity and fractal scaling properties. The R-R interval series of 409 healthy children and adolescents (age range: 1 to 22 years, 220 females) was analyzed with respect to complexity (Approximate Entropy, ApEn) and fractal scaling properties on three time scales: long-term (slope β of the power spectrum, log power vs. log frequency, in the frequency range 10−4 to 10−2 Hz) intermediate-term (DFA, detrended fluctuation analysis, α2) and short-term (DFA α1). Unexpectedly, during age 7 to 13 years β and ApEn were higher compared to the age <7 years and age >13 years (β: −1.06 vs. −1.21; ApEn: 0.88 vs. 0.74). Hence, the heart rate dynamics were closer to a 1/f power law and most complex between 7 and 13 years. However, DFA α1 and α2 increased with progressing age similar to measures reflecting linear properties. In conclusion, the course of long-term fractal scaling properties and complexity of heart rate dynamics during childhood and adolescence indicates that these measures reflect complex changes possibly linked to hormonal changes during pre-puberty and puberty

Effects of Aesthetic Chills on a Cardiac Signature of Emotionality

Previous studies have shown that a cardiac signature of emotionality (referred to as EK, which can be computed from the standard 12 lead electrocardiogram, ECG), predicts inter-individual differences in the tendency to experience and express positive emotion. Here, we investigated whether EK values can be transiently modulated during stimulation with participant-selected music pieces and film scenes that elicit strongly positive emotion. The phenomenon of aesthetic chills, as indicated by measurable piloerection on the forearm, was used to accurately locate moments of peak emotional responses during stimulation. From 58 healthy participants, continuous EK values, heart rate, and respiratory frequency were recorded during stimulation with film scenes and music pieces, and were related to the aesthetic chills. EK values, as well as heart rate, increased significantly during moments of peak positive emotion accompanied by piloerection. These results are the first to provide evidence for an influence of momentary psychological state on a cardiac signature of emotional personality (as reflected in EK values). The possibility to modulate ECG amplitude signatures via stimulation with emotionally significant music pieces and film scenes opens up new perspectives for the use of emotional peak experiences in the therapy of disorders characterized by flattened emotionality, such as depression or schizoid personality disorder

Effects of hand orientation on motor imagery - event related potentials suggest kinesthetic motor imagery to solve the hand laterality judgment task

Motor imagery (MI) refers to the process of imagining the execution of a specific motor action without actually producing an overt movement. Two forms of MI have been distinguished: visual MI and kinesthetic MI. To distinguish between these forms of MI we employed an event related potential (ERP) study to measure interference effects induced by hand orientation manipulations in a hand laterality judgement task. We hypothesized that this manipulation should only affect kinesthetic MI but not visual MI. The ERPs elicited by rotated hand stimuli contained the classic rotation related negativity (RRN) with respect to palm view stimuli. We observed that laterally rotated stimuli led to a more marked RRN than medially rotated stimuli. This RRN effect was observed when participants had their hands positioned in either a straight (control) or an inward rotated posture, but not when their hands were positioned in an outward rotated posture. Posture effects on the ERP-RRN have not previously been studied. Apparently, a congruent hand posture (hands positioned in an outward rotated fashion) facilitates the judgement of the otherwise more demanding laterally rotated hand stimuli. These ERP findings support a kinesthetic interpretation of MI involved in solving the hand laterality judgement task. The RRN may be used as a non-invasive marker for kinesthetic MI and seems useful in revealing the covert behavior of MI in e.g. rehabilitation programs

Extracellular Sulfatases, Elements of the Wnt Signaling Pathway, Positively Regulate Growth and Tumorigenicity of Human Pancreatic Cancer Cells

BACKGROUND: Heparan sulfate proteoglycans (HSPGs) are control elements in Wnt signaling, which bind extracellularly to Wnt ligands and regulate their ability to interact with signal transduction receptors on the cell surface. Sulf-1 and Sulf-2 are novel extracellular sulfatases that act on internal glucosamine-6-sulfate (6S) modifications within HSPGs and thereby modulate HSPG interactions with various signaling molecules, including Wnt ligands. Emerging evidence indicates the importance of reactivated Wnt signaling in a number of cancers, including pancreatic adenocarcinoma. PRINCIPLE FINDINGS: Both Sulf proteins were upregulated in human pancreatic adenocarcinoma tumors and were broadly expressed in human pancreatic adenocarcinoma cell lines. Expression of human extracellular sulfatases Sulf-1 and Sulf-2 enhanced Wnt signaling in a reconstituted system. Three of four pancreatic adenocarcinoma cell lines tested exhibited autocrine Wnt signaling, in that extracellular Wnt ligands were required to initiate downstream Wnt signaling. Exposure of these pancreatic adenocarcinoma cells to a catalytically inactive form of Sulf-2 or siRNA-mediated silencing of endogenous Sulf-2 inhibited both Wnt signaling and cell growth. Sulf-2 silencing in two of these lines resulted in markedly reduced tumorigenesis in immunocompromised mice. CONCLUSIONS/SIGNIFICANCE: We have identified the Sulfs as potentiators of autocrine Wnt signaling in pancreatic cancer cells and have demonstrated their contribution to the growth and tumorigenicity of these cells. Since the Sulfs are extracellular enzymes, they would be attractive targets for therapy of pancreatic cancer. Our results run counter to the prevailing view in the literature that the Sulfs are negative regulators of tumorigenesis

The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017.

On March 24 and 25, 2017 researchers and clinicians from around the world met at Temple University in Philadelphia to discuss the current knowledge of Mycobacterium avium ssp. paratuberculosis (MAP) and its relationship to human disease. The conference was held because of shared concern that MAP is a zoonotic bacterium that poses a threat not only to animal health but also human health. In order to further study this problem, the conferees discussed ways to improve MAP diagnostic tests and discussed potential future anti-MAP clinical trials. The conference proceedings may be viewed on the www.Humanpara.org website. A summary of the salient work in this field is followed by recommendations from a majority of the conferees

Methodological limitations of psychosocial interventions in patients with an implantable cardioverter-defibrillator (ICD) A systematic review

<p>Abstract</p> <p>Background</p> <p>Despite the potentially life-saving benefits of the implantable cardioverter-defibrillator (ICD), a significant group of patients experiences emotional distress after ICD implantation. Different psychosocial interventions have been employed to improve this condition, but previous reviews have suggested that methodological issues may limit the validity of such interventions. Aim: To review the methodology of previously published studies of psychosocial interventions in ICD patients, according to CONSORT statement guidelines for non-pharmacological interventions, and provide recommendations for future research.</p> <p>Methods</p> <p>We electronically searched the PubMed, PsycInfo and Cochrane databases. To be included, studies needed to be published in a peer-reviewed journal between 1980 and 2008, to involve a human population aged 18+ years and to have an experimental design.</p> <p>Results</p> <p>Twelve studies met the eligibility criteria. Samples were generally small. Interventions were very heterogeneous; most studies used cognitive behavioural therapy (CBT) and exercise programs either as unique interventions or as part of a multi-component program. Overall, studies showed a favourable effect on anxiety (6/9) and depression (4/8). CBT appeared to be the most effective intervention. There was no effect on the number of shocks and arrhythmic events, probably because studies were not powered to detect such an effect. Physical functioning improved in the three studies evaluating this outcome. Lack of information about the indication for ICD implantation (primary vs. secondary prevention), limited or no information regarding use of anti-arrhythmic (9/12) and psychotropic (10/12) treatment, lack of assessments of providers' treatment fidelity (12/12) and patients' adherence to the intervention (11/12) were the most common methodological limitations.</p> <p>Conclusions</p> <p>Overall, this review supports preliminary evidence of a positive effect of psychosocial interventions on anxiety and physical functioning in ICD patients. However, these initial findings must be interpreted cautiously because of important methodological limitations. Future studies should be designed as large RCTs, whose design takes into account the specific challenges associated with the evaluation of behavioural interventions.</p