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Low-frequency oscillations in the electroencephalogram (EEG) are thought to reflect periodic excitability changes of large neural networks. Consistent with this notion, detection probability of near-threshold somatosensory, visual, and auditory targets has been reported to co-vary with the phase of oscillations in the EEG. In audition, entrainment of δ-oscillations to the periodic occurrence of sounds has been suggested to function as a mechanism of attentional selection. Here, we examine in humans whether the detection of brief near-threshold sounds in quiet depends on the phase of EEG oscillations. When stimuli were presented at irregular intervals, we did not find a systematic relationship between detection probability and phase. When stimuli were presented at regular intervals (2-s), reaction times were significantly shorter and we observed phase entrainment of EEG oscillations corresponding to the frequency of stimulus presentation (0.5 Hz), revealing an adjustment of the system to the regular stimulation. The amplitude of the entrained oscillation was higher for hits than for misses, suggesting a link between entrainment and stimulus detection. However, detection was independent of phase at frequencies ≥ 1 Hz. Furthermore, we show that when the data are analyzed using acausal, though common, algorithms, an apparent ‘entrainment’ of the δ-phase to presented stimuli emerges and detection probability appears to depend on δ-phase, similar to reports in the literature. We show that these effects are artifacts from phase distortion at stimulus onset by contamination with the event-related potential, which differs markedly for hits and misses. This highlights the need to carefully deal with this common problem, since otherwise it might bias and mislead this exciting field of research.

Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell (ESC) self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas and pregnancy-associated breast cancer (30.7-48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2 and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeli

Conspiracy theories are ubiquitous when it comes to explaining political events and societal phenomena. Individuals differ not only in the degree to which they believe in specific conspiracy theories, but also in their general susceptibility to explanations based on such theories, that is, their conspiracy mentality. We present the Conspiracy Mentality Questionnaire (CMQ), an instrument designed to efficiently assess differences in the generic tendency to engage in conspiracist ideation within and across cultures. The CMQ is available in English, German, and Turkish. In four studies, we examined the CMQ’s factorial structure, reliability, measurement equivalence across cultures, and its convergent, discriminant, and predictive validity. Analyses based on a cross-cultural sample (Study 1a; N = 7,766) supported the conceptualization of conspiracy mentality as a one-dimensional construct across the three language versions of the CMQ that is stable across time (Study 1b; N = 141). Multigroup confirmatory factor analysis demonstrated cross-cultural measurement equivalence of the CMQ items. The instrument could therefore be used to examine differences in conspiracy mentality between European, North American, and Middle Eastern cultures. In Studies 2-4 (total N = 476), we report (re-)analyses of 3 datasets demonstrating the validity of the CMQ in student and working population samples in the UK and Germany. First, attesting to its convergent validity, the CMQ was highly correlated with another measure of generic conspiracy belief. Second, the CMQ showed patterns of meaningful associations with personality measures (e.g., Big Five dimensions, schizotypy), other generalized political attitudes (e.g., social dominance orientation and right-wing authoritarianism), and further individual differences (e.g., paranormal belief, lack of socio-political control). Finally, the CMQ predicted beliefs in specific conspiracy theories over and above other individual difference measures.

Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single-wavelength GECIs, RCaMPs, engineered from circular permutation of the thermostable red fluorescent protein mRuby. High-resolution crystal structures of mRuby, the red sensor RCaMP, and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca2+-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering mitochondrial and somatic [Ca2+]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMP, are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GECO1, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca2+ affinity and larger dynamic range than RCaMP, but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics.

The ability to extract word forms from continuous speech is a prerequisite for constructing a vocabulary and emerges in the first year of life. Electrophysiological (ERP) studies of speech segmentation by nine- to 12-month-old listeners in several languages have found a left-localized negativity linked to word onset as a marker of word detection. We report an ERP study showing significant evidence of speech segmentation in Dutch-learning seven-month-olds. In contrast to the left-localized negative effect reported with older infants, the observed overall mean effect had a positive polarity. Inspection of individual results revealed two participant sub-groups: a majority showing a positive-going response, and a minority showing the left negativity observed in older age groups. We retested participants at age three, on vocabulary comprehension and word and sentence production. On every test, children who at seven months had shown the negativity associated with segmentation of words from speech outperformed those who had produced positive-going brain responses to the same input. The earlier that infants show the left-localized brain responses typically indicating detection of words in speech, the better their early childhood language skills.

This article will be positioned on our previous work demonstrating the importance of adhering to a carefully selected set of criteria when choosing the suitable method from those available ensuring its adequate performance when applied to real temporal signals, such as fMRI BOLD, to evaluate one important facet of their behavior, fractality.Earlier, we have reviewed on a range of monofractal tools and evaluated their performance. Given the advance in the fractal field, in this article we will discuss the most widely used implementations of multifractal analyses, too.Our recommended flowchart for the fractal characterization of spontaneous, low frequency fluctuations in fMRI BOLD will be used as the framework for this article to make certain that it will provide a hands-on experience for the reader in handling the perplexed issues of fractal analysis. The reason why this particular signal modality and its fractal analysis has been chosen was due to its high impact on today's neuroscience given it had powerfully emerged as a new way of interpreting the complex functioning of the brain (see intrinsic activity).The reader will first be presented with the basic concepts of mono and multifractal time series analyses, followed by some of the most relevant implementations, characterization by numerical approaches. The notion of the dichotomy of fractional Gaussian noise (fGn) and fractional Brownian motion (fBm) signal classes and their impact on fractal time series analyses will be thoroughly discussed as the central theme of our application strategy. Sources of pitfalls and way how to avoid them will be identified followed by a demonstration on fractal studies of fMRI BOLD taken from the literature and that of our own in an attempt to consolidate the best practice in fractal analysis of empirical fMRI-BOLD signals mapped throughout the brain as an exemplary case of potentially wide interest.

The build-up of auditory stream segregation refers to the notion that sequences of alternating A and B sounds initially tend to be heard as a single stream, but with time appear to split into separate streams. The central assumption in the analysis of this phenomenon is that streaming sequences are perceived as one stream at the beginning by default. In the present study, we test the validity of this assumption and document its impact on the apparent build-up phenomenon. Human listeners were presented with ABAB sequences, where A and B were harmonic tone complexes of seven different fundamental frequency separations (∆f) ranging from 2 to 14 semitones. Subjects had to indicate, as promptly as possible, their initial percept of the sequences, as either one stream or two streams, and any changes thereof during the sequences. We found that subjects did not generally indicate a one-stream percept at the beginning of streaming sequences. Instead, the first perceptual decision depended on ∆f, with the probability of a one-stream percept decreasing, and that of a two-stream percept increasing, with increasing ∆f. Furthermore, subjects required some time to make and report a decision on their perceptual organization. Taking this time into account, the resulting time courses of two-stream probabilities differ markedly from those suggested by the conventional analysis. A build-up-like increase in two-stream probability was found only for the ∆f of 6 semitones. At the other ∆f conditions no or only minor increases in two-stream probability occurred. These results shed new light on the build-up of stream segregation and its possible neural correlates.

Objectives: Converging research suggests that mindfulness training exerts its therapeutic effectson depression by reducing rumination. Theoretically, rumination is a multifaceted construct thataggregates multiple neurocognitive aspects of depression, including poor executive control,negative and overgeneral memory bias, and persistence or stickiness of negative mind states.Current measures of rumination, most often self-reports, do not capture these different aspects ofruminative tendencies, and therefore are limited in providing detailed information about themechanisms of mindfulness.Methods: We developed new insights into the potential mechanisms of rumination, based onthree model-based metrics of free recall dynamics. These three measures reflect the patterns ofmemory retrieval of valenced information: The probability of first recall (Pstart) whichrepresents initial affective bias, the probability of staying with the same valence category ratherthan switching, which indicates strength of positive or negative association networks (Pstay);and probability of stopping (Pstop) or ending recall within a given valence, which indicatesdrift persistence or stickiness of a mind state. We then investigated the effects of MBCT(N=29) vs wait-list control (N=23) on these recall dynamics in a Randomized Controlled Trial(RCT) in individuals with recurrent depression. Participants completed a standard laboratorystressor, the Trier Social Stress Test (TSST), to induce negative mood and activate ruminativetendencies. Then, participants completed a free recall task consisting of three word lists. Thisassessment was conducted both before and after treatment or wait-list.Results: While MBCT participant’s Pstart remained relatively stable, controls showed multipleindications of depression-related deterioration towards more negative and less positive bias.Following the intervention, MBCT participants decreased in their tendency to sustain trains ofnegative words

It is well-known that, within ERP paradigms of sentence processing, semantically anomalous words elicit N400 effects. Less clear, however, is what happens after the N400. In some cases N400 effects are followed by Late Positive Complexes (LPC), whereas in other cases such effects are lacking. We investigated several factors which could affect the LPC, such as contextual constraint, inter-individual variation and working memory. Seventy-two participants read sentences containing a semantic manipulation (Whipped cream tastes sweet/anxious and creamy). Neither contextual constraint nor working memory correlated with the LPC. Inter-individual variation played a substantial role in the elicitation of the LPC with about half of the participants showing a negative response and the other half showing an LPC. This individual variation correlated with a syntactic ERP as well as an alternative semantic manipulation. In conclusion, our results show that inter-individual variation plays a large role in the elicitation of the LPC and this may account for the diversity in LPC findings in language research.

When people see a snake, they are likely to activate both affective information (e.g., dangerous) and non-affective information about its ontological category (e.g., animal). According to the Affective Primacy Hypothesis, the affective information has priority, and its activation can precede identification of the ontological category of a stimulus. Alternatively, according to the Cognitive Primacy Hypothesis, perceivers must know what they are looking at before they can make an affective judgment about it. We propose that neither hypothesis holds at all times. Here we show that the relative speed with which affective and non-affective information gets activated by pictures and words depends upon the contexts in which stimuli are processed. Results illustrate that the question of whether affective information has processing priority over ontological information (or vice versa) is ill posed. Rather than seeking to resolve the debate over Cognitive vs. Affective Primacy in favor of one hypothesis or the other, a more productive goal may be to determine the factors that cause affective information to have processing priority in some circumstances and ontological information in others. Our findings support a view of the mind according to which words and pictures activate different neurocognitive representations every time they are processed, the specifics of which are co-determined by the stimuli themselves and the contexts in which they occur.

In speaking, semantic encoding is the conversion of a nonverbal mental representation (the reference) into a semantic structure suitable for expression (the sense). In this fMRI study on sentence production we investigate how the speaking brain accomplishes this transition from nonverbal to verbal representations. In an overt picture description task, we manipulated repetition of sense (the semantic structure of the sentence) and reference (the described situation) separately. By investigating brain areas showing response adaptation to repetition of each of these sentence properties, we disentangle the neuronal infrastructure for these two components of semantic encoding. We also performed a control experiment with the same stimuli and design but without any linguistic task to identify areas involved in perception of the stimuli per se. The bilateral inferior parietal lobes were selectively sensitive to repetition of reference, while left inferior frontal gyrus showed selective suppression to repetition of sense. Strikingly, a widespread network of areas associated with language processing (left middle frontal gyrus, bilateral superior parietal lobes and bilateral posterior temporal gyri) all showed repetition suppression to both sense and reference processing. These areas are probably involved in mapping reference onto sense, the crucial step in semantic encoding. These results enable us to track the transition from nonverbal to verbal representations in our brains.

Understanding the causal chain from genotypic to phenotypic variation is a tremendous challenge with huge implications for personalized medicine. Here we argue that linking computational physiology to genetic concepts, methodology and data provides a new framework for this endeavor. We exemplify this causally cohesive genotype-phenotype (cGP) modeling approach using a detailed mathematical model of a heart cell. In silico genetic variation is mapped to parametric variation, which propagates through the physiological model to generate multivariate phenotypes for the action potential and calcium transient under regular pacing, and ion currents under voltage clamping. The resulting genotype-to-phenotype map is characterized using standard quantitative genetic methods and novel applications of high-dimensional data analysis. These analyses reveal many well-known genetic phenomena like intralocus dominance, interlocus epistasis and varying degrees of phenotypic correlation. In particular, we observe penetrance features such as the masking/release of genetic variation, so that without any change in the regulatory anatomy of the model, traits may appear monogenic, oligogenic or polygenic depending on which genotypic variation is actually present in the data. The results suggest that a cGP modeling approach may pave the way for a computational physiological genomics capable of generating biological insight about the genotype-phenotype relation in ways that statistical-genetic approaches cannot.

We report a 57-year old female patient with a rapid and dramatic dynamic of whole brain edema caused by tuberculous meningitis. After initiation of tuberculostatic medication, general condition of the patient worsened and finally she was intubated due to a progredient loss of consciousness and respiratory insufficiency. Repeated cerebral computer tomography (CCT) revealed a global brain edema with slit ventricles and a dramatic progress of generalized brain swelling. Highly interesting, a rapid expanded regime of brain pressure monitoring and treatment according to a neurosurgical intensive standard ICP/CPP management protocol, which was complemented by the tuberculostatic therapy and high dose steroidapplication, dramatically improved the general conditions, so that the patient is now in a general condition which corresponds that before the occurrence of tuberculous meningitis. Thus, it is mandatory in situations with a rapid progressive brain swelling caused by bacterial meningitis to consider an intensified cerebral monitoring and stratified treatment protocol in order to avoid the devasting effects of a long lasting increase in intracranical pressure.

Background: Microangiopathic brain lesions can be separated in diffuse lesions - leukoaraiosis - and focal lesions - lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. Methods: 64 consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood and urine parameters. Results: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, MMSE, ME) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy and a higher NIHSS increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. Conclusions: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts.

Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel), however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Purpose: The purpose of this study is to describe priority setting in cardiac surgery and evaluate it using an ethical framework, "accountability for reasonableness"., Introduction: Cardiac surgery is an expensive part of hospital budgets. Priority setting decisions are made daily regarding ever increasing volumes of patients. While much attention has been paid to the management of cardiac surgery waiting lists, little empirical research exists into the way actual decision makers deliberate upon and resolve priority setting decisions on a daily basis. A key goal of priority setting, in cardiac surgical areas as well as others, is fairness. "Accountability for reasonableness" is a leading ethical framework for fair priority setting, and can be used to identify opportunities for improvement (i.e. make it fairer) and highlight good practices., Methods: A case study was conducted to examine the process of priority setting processes at three University of Toronto affiliated cardiac surgery centres. Relevant documents were examined, weekly triage rounds were observed for 27 months, and interviews were carried out with 23 key participants including cardiac surgeons, cardiologists, and triage nurses. In data analysis, the conditions of "accountability for reasonableness" (relevance, publicity, appeals and enforcement) were used as an analytic lens., Relevance: While decisions may appear to be based strictly upon clinical criteria (e.g. coronary anatomy); non-clinical criteria also have an impact upon decision-making (e.g. patients' lifestyle choices, type of surgical practice and departmental constraints on resource use). Participants stated that these factors influence their decision-making and can result in unfair and inconsistent decisions. PUBLICITY: Non-clinical reasons are not publicly accessible, nor are they clearly acknowledged in discussions between cardiac clinicians. APPEALS: There are mechanisms for challenging decisions however without access to the non-clinical reasons, this can be problematic. Enforcement: Participants cite little departmental or institutional support to engage in fairer priority setting., Conclusions: To our knowledge, this is the first study to describe actual priority setting practices for cardiac surgery practices and evaluate them using an ethical framework, in this case, "accountability for reasonableness". Priority setting decision making in cardiac surgery has been described and evaluated with lessons learned include specific findings regarding the contextual and dynamic nature of decision making in cardiac surgery. The approach of combining a descriptive case study with the ethical framework of "accountability for reasonableness" is a useful tool for identifying good practices and highlighting areas for improvement. The good practices (including surgeons strongly facilitating patients seeking second opinions and approaching patients from a holistic perspective in consideration for surgery) and areas for improvement (including lack of transparency and lack of institutional support for "fair" decision making) that we have identified in this case study can be used to reflect upon the present tool used in priority setting and improve the fairness and legitimacy of priority setting decision making in cardiac surgery.