SignaLink3: a multi-layered resource to uncover tissue-specific signaling networks.

Signaling networks represent the molecular mechanisms controlling a cell's response to various internal or external stimuli. Most currently available signaling databases contain only a part of the complex network of intertwining pathways, leaving out key interactions or processes. Hence, we have developed SignaLink3 (http://signalink.org/), a value-added knowledge-base that provides manually curated data on signaling pathways and integrated data from several types of databases (interaction, regulation, localisation, disease, etc.) for humans, and three major animal model organisms. SignaLink3 contains over 400 000 newly added human protein-protein interactions resulting in a total of 700 000 interactions for Homo sapiens, making it one of the largest integrated signaling network resources. Next to H. sapiens, SignaLink3 is the only current signaling network resource to provide regulatory information for the model species Caenorhabditis elegans and Danio rerio, and the largest resource for Drosophila melanogaster. Compared to previous versions, we have integrated gene expression data as well as subcellular localization of the interactors, therefore uniquely allowing tissue-, or compartment-specific pathway interaction analysis to create more accurate models. Data is freely available for download in widely used formats, including CSV, PSI-MI TAB or SQL.

Augmenting lung cancer diagnosis on chest radiographs: positioning artificial intelligence to improve radiologist performance.

AIM: To evaluate the role that artificial intelligence (AI) could play in assisting radiologists as the first reader of chest radiographs (CXRs), to increase the accuracy and efficiency of lung cancer diagnosis by flagging positive cases before passing the remaining examinations to standard reporting. MATERIALS AND METHODS: A dataset of 400 CXRs including 200 difficult lung cancer cases was curated. Examinations were reviewed by three FRCR radiologists and an AI algorithm to establish performance in tumour identification. AI and radiologist labels were combined retrospectively to simulate the proposed AI triage workflow. RESULTS: When used as a standalone algorithm, AI classification was equivalent to the average radiologist performance. The best overall performances were achieved when AI was combined with radiologists, with an average reduction of missed cancers of 60%. Combination with AI also standardised the performance of radiologists. The greatest improvements were observed when common sources of errors were present, such as distracting findings. DISCUSSION: The proposed AI implementation pathway stands to reduce radiologist errors and improve clinician reporting performance. Furthermore, taking a radiologist-centric approach in the development of clinical AI holds promise for catching systematically missed lung cancers. This represents a tremendous opportunity to improve patient outcomes for lung cancer diagnosis.

Authentic Self and Last Resort: International Perceptions of Psychiatric Neurosurgery.

Psychiatric neurosurgery has resurfaced over the past two decades for the treatment of severe mental health disorders, with improved precision and safety over older interventions alongside the development of novel ones. Little is known, however, about current public opinions, expectations, hopes, and concerns over this evolution in neurotechnology, particularly given the controversial history of psychosurgery. To fill this knowledge gap, we conducted a study with eight focus groups in Vancouver and Montreal (Canada; n = 14), Berlin (Germany; n = 22), and Madrid (Spain; n = 12). Focus group texts were transcribed and analyzed using qualitative content analysis in the language local to each city, guided by the theoretical framework of pragmatic neuroethics. Findings indicate that participants across all cities hold concerns about the last resort nature of psychiatric neurosurgery and the potential impact on the authentic self of patients who undergo these procedures. The views captured serve to advance discussion on the appropriate timing for psychiatric neurosurgery, promote sound health policy for the allocation of this resource, and foster scientific literacy about advances for mental health internationally.

Embodiment and Estrangement: Results from a First-in-Human "Intelligent BCI" Trial.

While new generations of implantable brain computer interface (BCI) devices are being developed, evidence in the literature about their impact on the patient experience is lagging. In this article, we address this knowledge gap by analysing data from the first-in-human clinical trial to study patients with implanted BCI advisory devices. We explored perceptions of self-change across six patients who volunteered to be implanted with artificially intelligent BCI devices. We used qualitative methodological tools grounded in phenomenology to conduct in-depth, semi-structured interviews. Results show that, on the one hand, BCIs can positively increase a sense of the self and control; on the other hand, they can induce radical distress, feelings of loss of control, and a rupture of patient identity. We conclude by offering suggestions for the proactive creation of preparedness protocols specific to intelligent-predictive and advisory-BCI technologies essential to prevent potential iatrogenic harms.

Perspectives on strategies and challenges in the conversation about stem cells for spinal cord injury.

STUDY DESIGN: Qualitative study. OBJECTIVE: To examine how trusted communication between individuals with spinal cord injury (ISCIs) and physicians who care for ISCIs is affected by the discussion of advances in stem cell research and interventions locally and abroad. SETTING: Canada and the United States (US). METHODS: Semi-structured interviews with ISCIs and physicians. A thematic analysis approach was applied to more than 12 h of data to derive prominent themes and describe relationships between them. RESULTS: A convergence of factors involving transparency impact trusted communication between ISCIs and physicians about stem cells and spinal cord injury (SCI). ISCIs expressed that trusted communication is strengthened when physicians exhibit caring, attentive and positive attitudes that are underpinned by domain-specific knowledge and scholarship. Perceived reluctance to communicate or lack of knowledge poses significant challenges. Physicians also emphasised the importance of transparency for trusted communication but expressed that the still limited clinical reality of treatment choices for SCI and the pressures imposed by external resources are significant stressors that complicate the communication landscape. Both groups cited the range and variable quality of information sources, and the difficulty associated with navigating them, as priorities for action that would remediate these tensions. CONCLUSIONS: (1) Epistemic transparency should be privileged over silence. (2) A new generation of innovations in research and clinical trial dissemination about stem cells for SCI is needed to remedy the perceived inadequacies of existing information content and accessibility.

Dissociations in the meaning of risk between health-care professionals and individuals with spinal cord injury.

OBJECTIVE: Risks have been a central concern in stem cell research overall, and in clinical trials of individuals with spinal cord injury (ISCIs) in particular. We sought to elucidate how two important stakeholder groups-health-care professionals (HCPs) and ISCIs-view and value both the physical and non-physical risks of stem cell interventions. SETTING: The study was conducted in Canada, and included participants from both Canada and the United States America. STUDY DESIGN: We used semi-structured interviews to gain perspectives on risk from HCPs and ISCIs. METHODS: We applied a constant comparative analytic strategy to derive themes from the discourse collected through the interviews. RESULTS: We identified three major themes about risk from 12 HCP and 24 ISCI participants: focus, rationale and approach. The salient components of the themes differed: HCPs focus on the physical causes of risks, and the ISCIs on their downstream consequences as well as on non-physical risks; HCPs are concerned about evidence, and ISCIs about experience; and HCPs approach risk narrowly, whereas the approach of ISCIs is more broad and contextualized. CONCLUSION: Although major themes were common to the two stakeholder groups, the components of the themes were dissociable and illustrate differences in what HCPs and ISCIs worry about, why they worry and how they approach their worries. We draw upon these findings to make recommendations for improving risk communication and informed consent for stem cell research for spinal cord injury.

Ethical implications of neuroimaging in sports concussion.

The Centers for Disease Control and Prevention estimates that 1.6 to 3.8 million traumatic brain injuries that occur each year are related to sports injuries. New research has broadened the understanding of the acute and chronic pathophysiology of concussion associated with brain injury, and recent advances in diagnostic capabilities with neuroimaging are leading to new ethical questions around sport and care of the head-injured athlete. In this review, we synthesize the current literature on neuroimaging for assessing concussed athletes and explore ethical issues in the context of return to play, short- and long-term neurologic health effects following concussion and resource allocation that are emerging with new implications as neurotechnology becomes an increasingly powerful tool on the playing field of health.

More education, less administration: reflections of neuroimagers' attitudes to ethics through the qualitative looking glass.

In follow-up to a large-scale ethics survey of neuroscientists whose research involves neuroimaging, brain stimulation and imaging genetics, we conducted focus groups and interviews to explore their sense of responsibility about integrating ethics into neuroimaging and readiness to adopt new ethics strategies as part of their research. Safety, trust and virtue were key motivators for incorporating ethics into neuroimaging research. Managing incidental findings emerged as a predominant daily challenge for faculty, while student reports focused on the malleability of neuroimaging data and scientific integrity. The most frequently cited barrier was time and administrative burden associated with the ethics review process. Lack of scholarly training in ethics also emerged as a major barrier. Participants constructively offered remedies to these challenges: development and dissemination of best practices and standardized ethics review for minimally invasive neuroimaging protocols. Students in particular, urged changes to curricula to include early, focused training in ethics.

Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue.

Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (ICaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 µM ACh caused an ≈15% decrease in ICaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 µM ACh resulted in an ≈23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O'Hara-Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in ICaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward ICaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization.

Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery.

MOTIVATION: Signaling pathways control a large variety of cellular processes. However, currently, even within the same database signaling pathways are often curated at different levels of detail. This makes comparative and cross-talk analyses difficult. RESULTS: We present SignaLink, a database containing eight major signaling pathways from Caenorhabditis elegans, Drosophila melanogaster and humans. Based on 170 review and approximately 800 research articles, we have compiled pathways with semi-automatic searches and uniform, well-documented curation rules. We found that in humans any two of the eight pathways can cross-talk. We quantified the possible tissue- and cancer-specific activity of cross-talks and found pathway-specific expression profiles. In addition, we identified 327 proteins relevant for drug target discovery. CONCLUSIONS: We provide a novel resource for comparative and cross-talk analyses of signaling pathways. The identified multi-pathway and tissue-specific cross-talks contribute to the understanding of the signaling complexity in health and disease, and underscore its importance in network-based drug target selection. AVAILABILITY: http://SignaLink.org.

Human microRNAs co-silence in well-separated groups and have different predicted essentialities.

BACKGROUND: Short regulating RNAs guide many cellular processes. Compared with transcription factor proteins they appear to provide more specialized control and their deletions are less frequently lethal. RESULTS: We find large differences between computationally predicted lists of human microRNA (miRNA)-target pairs. Instead of integrating these lists we use the two most accurate of them. Next, we construct the co-regulation network of human miRNAs as nodes by computing the correlation (link weight) between the gene silencing scores of individual miRNAs. In this network, we locate groups of tightly co-regulating nodes (modules). Despite explicitly allowing overlaps the co-regulation modules of miRNAs are well separated. We use the modules and miRNA co-expression data to define and compute miRNA essentiality. Instead of focusing on particular biological functions we identify a miRNA as essential, if it has a low co-expression with the miRNAs in its module. This may be thought of as having many workers performing the same tasks together in one place (non-essential miRNAs) as opposed to a single worker performing those tasks alone (essential miRNA). CONCLUSIONS: On the system level, we quantitatively confirm previous findings about the specialized control provided by miRNAs. For knock-out tests we list the groups of our predicted most and least essential miRNAs. In addition, we provide possible explanations for (i) the low number of individually essential miRNAs in Caenorhabdtits elegans and (ii) the high number of ubiquitous miRNAs influencing cell and tissue-specific miRNA expression patterns in mouse and human.

Human neuroelectric patterns predict performance accuracy.

In seven right-handed adults, the brain electrical patterns before accurate performance differed from the patterns before inaccurate performance. Activity overlying the left frontal cortex and the motor and parietal cortices contralateral to the performing hand preceded accurate left- or right-hand performance. Additional strong activity overlying midline motor and premotor cortices preceded left-hand performance. These measurements suggest that brief, spatially distributed neural activity patterns, or "preparatory sets," in distinct cognitive, somesthetic-motor, and integrative motor areas of the human brain may be essential precursors of accurate visuomotor performance.

In the mind's eye: provider and patient attitudes on functional brain imaging.

Success in functional neuroimaging has brought the promise of quantitative data in the form of brain images to the diagnosis of disorders of the central nervous system for which only qualitative clinical criteria have previously existed. Even though the translation of research to clinical neuroimaging for conditions such as major depression may not be available yet, rapid innovation along this trajectory of discovery to implementation compels exploration of how such information will eventually affect providers and patients. Clinical neuroethics is devoted to elucidating ethical challenges prior to and during the transfer of new research capabilities to the bedside. Through a model of proactive ethics, clinical neuroethics promotes the development of responsible social and public policies in response to new diagnostic and prognostic capabilities for the benefit of patients and their families, and for providers within the health care systems in which they practice. To examine views about the potential interaction of clinical neuroimaging and depression, we surveyed both mental health providers and outpatients and inpatients diagnosed with major depressive disorder. From responses of 52 providers and 72 patients, we found high receptivity to brain scans for treatment tailoring and choice, for improving understanding of and coping with disease, and for mitigating the effects of stigma and self-blame. Our results suggest that, once ready, roll out of the fully validated technology has significant potential to reduce social burden associated with highly stigmatized illnesses like depression.

Ethics in published brain-computer interface research.

OBJECTIVE: Sophisticated signal processing has opened the doors to more research with human subjects than ever before. The increase in the use of human subjects in research comes with a need for increased human subjects protections. APPROACH: We quantified the presence or absence of ethics language in published reports of brain-computer interface (BCI) studies that involved human subjects and qualitatively characterized ethics statements. MAIN RESULTS: Reports of BCI studies with human subjects that are published in neural engineering and engineering journals are anchored in the rationale of technological improvement. Ethics language is markedly absent, omitted from 31% of studies published in neural engineering journals and 59% of studies in biomedical engineering journals. SIGNIFICANCE: As the integration of technological tools with the capacities of the mind deepens, explicit attention to ethical issues will ensure that broad human benefit is embraced and not eclipsed by technological exclusiveness.

Spatial flocking: Control by speed, distance, noise and delay.

Fish, birds, insects and robots frequently swim or fly in groups. During their three dimensional collective motion, these agents do not stop, they avoid collisions by strong short-range repulsion, and achieve group cohesion by weak long-range attraction. In a minimal model that is isotropic, and continuous in both space and time, we demonstrate that (i) adjusting speed to a preferred value, combined with (ii) radial repulsion and an (iii) effective long-range attraction are sufficient for the stable ordering of autonomously moving agents in space. Our results imply that beyond these three rules ordering in space requires no further rules, for example, explicit velocity alignment, anisotropy of the interactions or the frequent reversal of the direction of motion, friction, elastic interactions, sticky surfaces, a viscous medium, or vertical separation that prefers interactions within horizontal layers. Noise and delays are inherent to the communication and decisions of all moving agents. Thus, next we investigate their effects on ordering in the model. First, we find that the amount of noise necessary for preventing the ordering of agents is not sufficient for destroying order. In other words, for realistic noise amplitudes the transition between order and disorder is rapid. Second, we demonstrate that ordering is more sensitive to displacements caused by delayed interactions than to uncorrelated noise (random errors). Third, we find that with changing interaction delays the ordered state disappears at roughly the same rate, whereas it emerges with different rates. In summary, we find that the model discussed here is simple enough to allow a fair understanding of the modeled phenomena, yet sufficiently detailed for the description and management of large flocks with noisy and delayed interactions. Our code is available at http://github.com/fij/floc.

Prospects for prediction: ethics analysis of neuroimaging in Alzheimer's disease.

This article focuses on the prospects and ethics of using neuroimaging to predict Alzheimer's disease (AD). It is motivated by consideration of the historical roles of science in medicine and society, and considerations specifically contemporary of capabilities in imaging and aging, and the benefits and hope they bring. A general consensus is that combinations of imaging methods will ultimately be most fruitful in predicting disease. Their roll-out into translational practice will not be free of complexity, however, as culture and values differ in terms of what defines benefit and risk, who will benefit and who is at risk, what methods must be in place to assure the maximum safety, comfort, and protection of subjects and patients, and educational and policy needs. Proactive planning for the ethical and societal implications of predicting diseases of the aging brain is critical and will benefit all stakeholders-researchers, patients and families, health care providers, and policy makers.

Topological basis of signal integration in the transcriptional-regulatory network of the yeast, Saccharomyces cerevisiae.

BACKGROUND: Signal recognition and information processing is a fundamental cellular function, which in part involves comprehensive transcriptional regulatory (TR) mechanisms carried out in response to complex environmental signals in the context of the cell's own internal state. However, the network topological basis of developing such integrated responses remains poorly understood. RESULTS: By studying the TR network of the yeast Saccharomyces cerevisiae we show that an intermediate layer of transcription factors naturally segregates into distinct subnetworks. In these topological units transcription factors are densely interlinked in a largely hierarchical manner and respond to external signals by utilizing a fraction of these subnets. CONCLUSION: As transcriptional regulation represents the 'slow' component of overall information processing, the identified topology suggests a model in which successive waves of transcriptional regulation originating from distinct fractions of the TR network control robust integrated responses to complex stimuli.

Focus on People and the Science Will Follow: Motivating Forces for Professional Movement in Stem Cell Research.

The migration of researchers across geographic borders, or "brain drain" as it is commonly called, remains an important issue for governments around the world as loss or gain of highly qualified personnel in research can have substantial social, economic and political consequences. In the present study we seek to examine the forces that drive international professional migration of stem cell (SC) researchers, for which variation of SC policy in different jurisdictions has previously been implicated as a driving force. Structured interviews were carried out with a purposive sample of SC researchers in the professoriate who had made international moves after postdoctoral work between the years 2001-2014, or were actively anticipating a future move. Participants were asked to rank motivators of international movement on a 5-point Likert scale and prompted to elaborate on their answers. The results suggest that career considerations, availability of research funding, and personal considerations are of high importance to the participants when considering an international move, while the permissiveness or restrictiveness SC research policy is of comparably lower importance. Participants also expressed that international movements are beneficial to scientific careers overall. The findings have important implications for policy and strategies to attract and retain members of the SC research community.

Keeping speed and distance for aligned motion.

The cohesive collective motion (flocking, swarming) of autonomous agents is ubiquitously observed and exploited in both natural and man-made settings, thus, minimal models for its description are essential. In a model with continuous space and time we find that if two particles arrive symmetrically in a plane at a large angle, then (i) radial repulsion and (ii) linear self-propelling toward a fixed preferred speed are sufficient for them to depart at a smaller angle. For this local gain of momentum explicit velocity alignment is not necessary, nor are adhesion or attraction, inelasticity or anisotropy of the particles, or nonlinear drag. With many particles obeying these microscopic rules of motion we find that their spatial confinement to a square with periodic boundaries (which is an indirect form of attraction) leads to stable macroscopic ordering. As a function of the strength of added noise we see--at finite system sizes--a critical slowing down close to the order-disorder boundary and a discontinuous transition. After varying the density of particles at constant system size and varying the size of the system with constant particle density we predict that in the infinite system size (or density) limit the hysteresis loop disappears and the transition becomes continuous. We note that animals, humans, drones, etc., tend to move asynchronously and are often more responsive to motion than positions. Thus, for them velocity-based continuous models can provide higher precision than coordinate-based models. An additional characteristic and realistic feature of the model is that convergence to the ordered state is fastest at a finite density, which is in contrast to models applying (discontinuous) explicit velocity alignments and discretized time. To summarize, we find that the investigated model can provide a minimal description of flocking.

Role of ipsilateral forebrain in lateral hypothalamic stimulation reward in rats.

The forebrain was ablated unilaterally to a level dorsal to the thalamus and anterior commissure. Ipsilateral lateral hypothalamic electrodes were then implanted and the animal was tested for self-stimulation behavior. Tests included an initial test for behavioral reactivity to changes in reward level and then two estimates of the quantitative relationships between stimulation parameters: the number-current and charge-duration relationships. Comparison between these findings and those known for intact rats suggest that the substrate for unilateral hypothalamic stimulation reward is not impaired by removal of the ipsilateral tissue.