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In neuroscience, numerous experimental procedures in animal models require surgical interventions, such as the implantation of recording electrodes or cannulas before main experiments. These surgeries can take several hours and should rely on principles that are common in the field of research and medicine. Considering the characteristics of the avian respiratory physiology, the development of a safe and replicable protocol for birds is necessary to minimize side effects of anesthetic agents, circumvent technical limitations due to the insufficient availability of patient monitoring, and to maintain stable intraoperative anesthesia. Through the consistent and responsible implementation of the three R principle of animal welfare in science (“Replace, Reduce, Refine”), we aimed to optimize experimental methods to minimize the burden on pigeons (Columba livia) during surgical procedures. Here, surgeries were conducted under balanced anesthesia and perioperative monitoring of heart rate, oxygen saturation, body temperature, and the reflex state. The protocol we developed is based on the combination of injectable and inhalative anesthetic drugs [ketamine, xylazine, and isoflurane, supported by the application of an opiate for analgesia (e.g., butorphanol, buprenorphine)]. The combination of ketamine and xylazine with a pain killer is established in veterinary medicine across a vast variety of species. Practicability was verified by survival of the animals, fast and smooth recovery quantified by clinical examination, sufficiency, and stability of anesthesia. Independent of painful stimuli like incision or drilling, or duration of surgery, vital parameters were within known physiological ranges for pigeons. Our approach provides a safe and conservative protocol for surgeries of extended duration for scientific applications as well as for veterinary medicine in pigeons which can be adapted to other bird species.

In order to continuously monitor the intensity and position of an electron beam of a few hundred pA, a system of resonant cavities has been set up. The current measurement relies on signals of a few fW power extracted out of a cylindrical resonator, excited at its TM_{010} mode. The demodulated cavity pickup signal allows the reconstruction of the beam current with a precision of a few pA. For beam position measurements, we designed two resonators, one each for the horizontal and vertical plane. They are excited at their TM_{110} dipole modes, the signal strength vanishing with the beam passing on their symmetry axis. Commercial digital lock-in amplifiers perform a phase-sensitive detection of the position signals, separating them from background noise. A frequency mixing scheme was applied to transform the signals into the passband of the amplifiers. Great care was taken to prevent cross talk by using special shielding. With these techniques, a relative beam position resolution of 50 μm was achieved. The position readings are sampled with a maximum rate of 9 Hz. A standard PC is used to read out the lock-in amplifiers. It transfers the measured raw data as well as processed values to the accelerator control system for graphical display.

In neuroscience, numerous experimental procedures in animal models require surgical interventions, such as the implantation of recording electrodes or cannulas before main experiments. These surgeries can take several hours and should rely on principles that are common in the field of research and medicine. Considering the characteristics of the avian respiratory physiology, the development of a safe and replicable protocol for birds is necessary to minimize side effects of anesthetic agents, circumvent technical limitations due to the insufficient availability of patient monitoring, and to maintain stable intraoperative anesthesia. Through the consistent and responsible implementation of the three R principle of animal welfare in science ("Replace, Reduce, Refine"), we aimed to optimize experimental methods to minimize the burden on pigeons ( Columba livia ) during surgical procedures. Here, surgeries were conducted under balanced anesthesia and perioperative monitoring of heart rate, oxygen saturation, body temperature, and the reflex state. The protocol we developed is based on the combination of injectable and inhalative anesthetic drugs [ketamine, xylazine, and isoflurane, supported by the application of an opiate for analgesia (e.g., butorphanol, buprenorphine)]. The combination of ketamine and xylazine with a pain killer is established in veterinary medicine across a vast variety of species. Practicability was verified by survival of the animals, fast and smooth recovery quantified by clinical examination, sufficiency, and stability of anesthesia. Independent of painful stimuli like incision or drilling, or duration of surgery, vital parameters were within known physiological ranges for pigeons. Our approach provides a safe and conservative protocol for surgeries of extended duration for scientific applications as well as for veterinary medicine in pigeons which can be adapted to other bird species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Serir, Tuff, Rook, Fongaro, Schreiber, Peus, Güntürkün, Manahan-Vaughan, Rose and Pusch.)

Many cognitive neuroscientists believe that both a large brain and an isocortex are crucial for complex cognition. Yet corvids and parrots possess non-cortical brains of just 1-25 g, and these birds exhibit cognitive abilities comparable with those of great apes such as chimpanzees, which have brains of about 400 g. This opinion explores how this cognitive equivalence is possible. We propose four features that may be required for complex cognition: a large number of associative pallial neurons, a prefrontal cortex (PFC)-like area, a dense dopaminergic innervation of association areas, and dynamic neurophysiological fundaments for working memory. These four neural features have convergently evolved and may therefore represent 'hard to replace' mechanisms enabling complex cognition., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Working memory is the cognitive capability to maintain and process information over short periods. Behavioral and computational studies have shown that visual information is associated with working memory performance. However, the underlying neural correlates remain unknown. To identify how visual information affects working memory performance, we conducted behavioral experiments in pigeons (Columba livia) and single unit recordings in the avian prefrontal analog, the nidopallium caudolaterale (NCL). Complex pictures featuring luminance, spatial and color information, were associated with higher working memory performance compared to uniform gray pictures in conjunction with distinct neural coding patterns. For complex pictures, we found a multiplexed neuronal code displaying visual and value-related features that switched to a representation of the upcoming choice during a delay period. When processing gray stimuli, NCL neurons did not multiplex and exclusively represented the choice already during stimulus presentation and throughout the delay period. The prolonged representation possibly resulted in a decay of the memory trace ultimately leading to a decrease in performance. In conclusion, we found that high stimulus complexity is associated with neuronal multiplexing of the working memory representation possibly allowing a facilitated read-out of the neural code resulting in enhancement of working memory performance., (© 2023. The Author(s).)

Purpose: Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC)., Methods: A total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy., Results: 8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0-57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1-3., Conclusion: The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile., (© 2023. The Author(s).)

Birds are excellent model organisms to study perceptual categorization and concept formation. The renewed focus on avian neuroscience has sparked an explosion of new data in the field. At the same time, our understanding of sensory and particularly visual structures in the avian brain has shifted fundamentally. These recent discoveries have revealed how categorization is mediated in the avian brain and has generated a theoretical framework that goes beyond the realm of birds. We review the contribution of avian categorization research-at the methodical, behavioral, and neurobiological levels. To this end, we first introduce avian categorization from a behavioral perspective and the common elements model of categorization. Second, we describe the functional and structural organization of the avian visual system, followed by an overview of recent anatomical discoveries and the new perspective on the avian 'visual cortex'. Third, we focus on the neurocomputational basis of perceptual categorization in the bird's visual system. Fourth, an overview of the avian prefrontal cortex and the prefrontal contribution to perceptual categorization is provided. The fifth section outlines how asymmetries of the visual system contribute to categorization. Finally, we present a mechanistic view of the neural principles of avian visual categorization and its putative extension to concept learning., (© 2022. The Author(s).)

In the past 12 months a plethora of relevant novel data for the treatment of metastatic HER2 positive breast cancer were published. To bring this new evidence into a clinical perspective, a group of Austrian breast cancer specialists updated their previously published treatment algorithm for those patients. For this consensus paper a total of eight scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus., (© 2022. The Author(s).)

Pigeons are classic model animals to study perceptual category learning. To achieve a deeper understanding of the cognitive mechanisms of categorization, a careful consideration of the employed stimulus material and a thorough analysis of the choice behavior is mandatory. In the present study, we combined the use of "virtual phylogenesis", an evolutionary algorithm to generate artificial yet naturalistic stimuli termed digital embryos and a machine learning approach on the pigeons' pecking responses to gain insight into the underlying categorization strategies of the animals. In a forced-choice procedure, pigeons learned to categorize these stimuli and transferred their knowledge successfully to novel exemplars. We used peck tracking to identify where on the stimulus the animals pecked and further investigated whether this behavior was indicative of the pigeon's choice. Going beyond the classical analysis of the binary choice, we were able to predict the presented stimulus class based on pecking location using a k-nearest neighbor classifier, indicating that pecks are related to features of interest. By analyzing error trials with this approach, we further identified potential strategies of the pigeons to discriminate between stimulus classes. These strategies remained stable during category transfer, but differed between individuals indicating that categorization learning is not limited to a single learning strategy., (© 2022. The Author(s).)

Discriminating between object categories (e.g., conspecifics, food, potential predators) is a critical function of the primate and bird visual systems. We examined whether a similar hierarchical organization in the ventral stream that operates for processing faces in monkeys also exists in the avian visual system. We performed electrophysiological recordings from the pigeon Wulst of the thalamofugal pathway, in addition to the entopallium (ENTO) and mesopallium ventrolaterale (MVL) of the tectofugal pathway, while pigeons viewed images of faces, scrambled controls, and sine gratings. A greater proportion of MVL neurons fired to the stimuli, and linear discriminant analysis revealed that the population response of MVL neurons distinguished between the stimuli with greater capacity than ENTO and Wulst neurons. While MVL neurons displayed the greatest response selectivity, in contrast to the primate system no neurons were strongly face-selective and some responded best to the scrambled images. These findings suggest that MVL is primarily involved in processing the local features of images, much like the early visual cortex., (© 2022. The Author(s).)

Cognitive functions are similar in birds and mammals. So, are therefore pallial cellular circuits and neuronal computations also alike? In search of answers, we move in from bird's pallial connectomes, to cortex-like sensory canonical circuits and connections, to forebrain micro-circuitries and finally to the avian "prefrontal" area. This voyage from macro- to micro-scale networks and areas reveals that both birds and mammals evolved similar neural and computational properties in either convergent or parallel manner, based upon circuitries inherited from common ancestry. Thus, these two vertebrate classes evolved separately within 315 million years with highly similar pallial architectures that produce comparable cognitive functions., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Extinction learning, the process of ceasing an acquired behavior in response to altered reinforcement contingencies, is not only essential for survival in a changing environment, but also plays a fundamental role in the treatment of pathological behaviors. During therapy and other forms of training involving extinction, subjects are typically exposed to several sessions with a similar structure. The effects of this repeated exposure are not well understood. Here, we studied the behavior of pigeons across several sessions of a discrimination-learning task in context A, extinction in context B, and a return to context A to test the context-dependent return of the learned responses (ABA renewal). By focusing on individual learning curves across animals, we uncovered a session-dependent variability of behavior: (1) during extinction, pigeons preferred the unrewarded alternative choice in one-third of the sessions, predominantly during the first one. (2) In later sessions, abrupt transitions of behavior at the onset of context B emerged, and (3) the renewal effect decayed as sessions progressed. We show that the observed results can be parsimoniously accounted for by a computational model based only on associative learning between stimuli and actions. Our work thus demonstrates the critical importance of studying the trial-by-trial dynamics of learning in individual sessions, and the power of "simple" associative learning processes., (© 2021. The Author(s).)

Reward prediction errors (RPEs) have been suggested to drive associative learning processes, but their precise temporal dynamics at the single-neuron level remain elusive. Here, we studied the neural correlates of RPEs, focusing on their trial-by-trial dynamics during an operant extinction learning paradigm. Within a single behavioral session, pigeons went through acquisition, extinction and renewal - the context-dependent response recovery after extinction. We recorded single units from the avian prefrontal cortex analogue, the nidopallium caudolaterale (NCL) and found that the omission of reward during extinction led to a peak of population activity that moved backwards in time as trials progressed. The chronological order of these signal changes during the progress of learning was indicative of temporal shifts of RPE signals that started during reward omission and then moved backwards to the presentation of the conditioned stimulus. Switches from operant choices to avoidance behavior (and vice versa) coincided with changes in population activity during the animals' decision-making. On the single unit level, we found more diverse patterns where some neurons' activity correlated with RPE signals whereas others correlated with the absolute value during the outcome period. Finally, we demonstrated that mere sensory contextual changes during the renewal test were sufficient to elicit signals likely associated with RPEs. Thus, RPEs are truly expectancy-driven since they can be elicited by changes in reward expectation, without an actual change in the quality or quantity of reward., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although optogenetics has revolutionized rodent neuroscience, it is still rarely used in other model organisms as the efficiencies of viral gene transfer differ between species and comprehensive viral transduction studies are rare. However, for comparative research, birds offer valuable model organisms as they have excellent visual and cognitive capabilities. Therefore, the following study establishes optogenetics in pigeons on histological, physiological, and behavioral levels. We show that AAV1 is the most efficient viral vector in various brain regions and leads to extensive anterograde and retrograde ChR2 expression when combined with the CAG promoter. Furthermore, transient optical stimulation of ChR2 expressing cells in the entopallium decreases pigeons' contrast sensitivity during a grayscale discrimination task. This finding demonstrates causal evidence for the involvement of the entopallium in contrast perception as well as a proof of principle for optogenetics in pigeons and provides the groundwork for various other methods that rely on viral gene transfer in birds.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds-a vertebrate class of which some clades are cognitively on par with primates.

In this article, we present PixelClipper, a tool built for facilitating data engagement events. PixelClipper supports conversations around visualizations in public settings through annotation and commenting capabilities. It is recognized that understanding data is important for an informed society. However, even when visualizations are available on the web, open data is not yet reaching all audiences. Public facilitated events centered around data visualizations may help bridge this gap. PixelClipper is designed to promote discussion and engagement with visualizations in public settings. It allows viewers to quickly and expressively extract visual clippings from visualizations and add comments to them. Ambient and facilitator displays attract attention by showing clippings. They function as entry points to the full visualizations while supporting deeper conversations about the visualizations and data. We describe the design goals of PixelClipper, share our experiences from deploying it, and discuss its future potential in supporting data visualization engagement events.

Cue competition refers to phenomena indicating that learning about the relationship between a cue and an outcome is influenced by learning about the predictive significance of other cues that are concurrently present. In two autoshaping experiments with pigeons, we investigated the strength of competition among cues for predictive value. In each experiment, animals received an overexpectation training (A+, D+ followed by AD+). In addition, the training schedule of each experiment comprised two control conditions-one condition to evaluate the presence of overexpectation (B+ followed by BY+) and a second one to assess the strength of competition among cues (C+ followed by CZ-). Training trials were followed by a test with individual stimuli (A, B, C). Experiment 1 revealed no evidence for cue competition as responding during the test mirrored the individual cue-outcome contingencies. The test results from Experiment 2, which included an outcome additivity training, showed cue competition in form of an overexpectation effect as responding was weaker for Stimulus A than Stimulus B. However, the test results from Experiment 2 also revealed that responding to Stimulus A was stronger than to Stimulus C, which indicates that competition among cues was not as strong as predicted by some influential theories of associative learning.

Landfill site's selection represents a complicated process due to the large number of variables to be adopted. In this study, an arid area (Babylon Governorate as a case study) was selected. It is located in the middle region of Iraq. In this area, the landfills do not satisfy the required international criteria. Fifteen of the most significant criteria were selected for this purpose. For suitable weight for each criterion, the multi-criteria decision-making (MCDM) methods were applied. These methods are AHP and RSW. In the GIS software 10.5, the raster maps of the chosen criterion were arranged and analyzed. The method of change detection was implemented to determine the matching pixels and non-matching pixels. The final results showed that there are two candidate locations for landfills for each district in the governorate (ten sites). The areas of the selected sites were sufficient to contain the cumulative quantity of solid waste from 2020 until 2030.

Extinction learning is a fundamental capacity for adaptive and flexible behavior. As extinguished conditioned responding is prone to relapse under certain conditions, the necessity of memory consolidation for recovery phenomena to occur has been highlighted recently. Several studies have demonstrated that both acquisition and extinction training need to be properly consolidated for a relapse of the original acquired memory trace to occur. Does this imply that extinguished responses cannot relapse before memory consolidation? To answer this question, we investigated the renewal effect subsequent to an immediate or a delayed (24 h) extinction in a discriminative operant conditioning paradigm. In three different experiments, we could show (1) that acquisition learning does not need to be long-term consolidated for the occurrence of renewal, (2) that the offset of extinction training is a reliable marker for extinction recall in a free-operant extinction learning paradigm where organisms undergo consecutive acquisition training, extinction training as well as testing of conditioned responding and (3), that immediate and long-term consolidated renewal do not demonstrate any qualitative difference in terms of the behavioral output. Our results indicate on the behavioral level that the inhibitory nature of extinction is already present in free-operant learning paradigms and that it does not seem to be affected by the absence of long-term memory consolidation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The medial striatum of birds resembles the mammalian dorsal striatum, which plays a key role in the extinction of learned behavior. To uncover the variant and invariant neural properties of extinction learning across species, we use pigeons as an animal model in an appetitive extinction paradigm. Here, we targeted a medial sub-region of the pigeon's striatum that receives executive, visual and motor pallial projections. By locally antagonizing the N -methyl-D-aspartate (NMDA) receptors through 2-Amino-5-phosphonovalerianacid (APV) during extinction, we observed an unspecific disinhibition effect, namely an increase in conditioned pecking to a rewarded control stimulus. In addition, blocking the NMDA receptors substantially deteriorated the extinction acquisition, implying that the pigeons still responded vigorously to the CS- even without food reward during extinction. After correcting for the unspecific effect of APV, the impaired extinction acquisition remained significant, which leads to the assumption that the delayed extinction effect is possibly caused by deficits in the updating of value coding of altered reward contingencies. Also, the APV-induced disinhibition seems to result from local hyperactivity that primarily drives actions towards cues of high appetitive value. The overall correspondence of our results with those from mammals suggests common neural substrates of extinction and highlights the shared functionality of the avian and mammalian dorsal striatum despite 300 million years of independent evolution.

Purpose: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer., Methods: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires., Results: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in "discordant" groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients' State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients., Conclusions: MammaPrint and BluePrint test results strongly impacted physicians' therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

Recognizing and categorizing visual stimuli are cognitive functions vital for survival, and an important feature of visual systems in primates as well as in birds. Visual stimuli are processed along the ventral visual pathway. At every stage in the hierarchy, neurons respond selectively to more complex features, transforming the population representation of the stimuli. It is therefore easier to read-out category information in higher visual areas. While explicit category representations have been observed in the primate brain, less is known on equivalent processes in the avian brain. Even though their brain anatomies are radically different, it has been hypothesized that visual object representations are comparable across mammals and birds. In the present study, we investigated category representations in the pigeon visual forebrain using recordings from single cells responding to photographs of real-world objects. Using a linear classifier, we found that the population activity in the visual associative area mesopallium ventrolaterale (MVL) distinguishes between animate and inanimate objects, although this distinction is not required by the task. By contrast, a population of cells in the entopallium, a region that is lower in the hierarchy of visual areas and that is related to the primate extrastriate cortex, lacked this information. A model that pools responses of simple cells, which function as edge detectors, can account for the animate vs. inanimate categorization in the MVL, but performance in the model is based on different features than in MVL. Therefore, processing in MVL cells is very likely more abstract than simple computations on the output of edge detectors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We are surrounded by an endless variation of objects. The ability to categorize these objects represents a core cognitive competence of humans and possibly all vertebrates. Research on category learning in nonhuman animals started with the seminal studies of Richard Herrnstein on the category "human" in pigeons. Since then, we have learned that pigeons are able to categorize a large number of stimulus sets, ranging from Cubist paintings to English orthography. Strangely, this prolific field has largely neglected to also study the avian neurobiology of categorization. Here, we present a hypothesis that combines experimental results and theories from categorization research in pigeons with neurobiological insights on visual processing and dopamine-mediated learning in primates. We conclude that in both fields, similar conclusions on the mechanisms of perceptual categorization have been drawn, despite very little cross-reference or communication between these two areas to date. We hypothesize that perceptual categorization is a two-component process in which stimulus features are first rapidly extracted in a feed-forward process, thereby enabling a fast subdivision along multiple category borders. In primates this seems to happen in the inferotemporal cortex, while pigeons may primarily use a cluster of associative visual forebrain areas. The second process rests on dopaminergic error-prediction learning that enables prefrontal areas to connect top down the relevant visual category dimension to the appropriate action dimension.

We empirically evaluate the extent to which people perceive non-constant time and speed encoded on 2D paths. In our graphical perception study, we evaluate nine encodings from the literature for both straight and curved paths. Visualizing time and speed information is a challenge when the x and y axes already encode other data dimensions, for example when plotting a trip on a map. This is particularly true in disciplines such as time-geography and movement analytics that often require visualizing spatio-temporal trajectories. A common approach is to use 2D+time trajectories, which are 2D paths for which time is an additional dimension. However, there are currently no guidelines regarding how to represent time and speed on such paths. Our study results provide InfoVis designers with clear guidance regarding which encodings to use and which ones to avoid; in particular, we suggest using color value to encode speed and segment length to encode time whenever possible.

We investigate whether the notion of active reading for text might be usefully applied to visualizations. Through a qualitative study we explored whether people apply observable active reading techniques when reading paper-based node-link visualizations. Participants used a range of physical actions while reading, and from these we synthesized an initial set of active reading techniques for visualizations. To learn more about the potential impact such techniques may have on visualization reading, we implemented support for one type of physical action from our observations (making freeform marks) in an interactive node-link visualization. Results from our quantitative study of this implementation show that interactive support for active reading techniques can improve the accuracy of performing low-level visualization tasks. Together, our studies suggest that the active reading space is ripe for research exploration within visualization and can lead to new interactions that make for a more flexible and effective visualization reading experience.

Al-Hillah Qadhaa is located in the central part of Iraq. It covers an area of 908 km(2) with a total population of 856,804 inhabitants. This Qadhaa is the capital of Babylon Governorate. Presently, no landfill site exists in that area based on scientific site selection criteria. For this reason, an attempt has been carried out to find the best locations for landfills. A total of 15 variables were considered in this process (groundwater depth, rivers, soil types, agricultural land use, land use, elevation, slope, gas pipelines, oil pipelines, power lines, roads, railways, urban centres, villages and archaeological sites) using a geographic information system. In addition, an analytical hierarchy process was used to identify the weight for each variable. Two suitable candidate landfill sites were determined that fulfil the requirements with an area of 9.153 km(2) and 8.204 km(2) These sites can accommodate solid waste till 2030., (© The Author(s) 2016.)

Pigeons are well known for their visual capabilities as well as their ability to categorize visual stimuli at both the basic and superordinate level. We adopt a reverse engineering approach to study categorization learning: Instead of training pigeons on predefined categories, we simply present stimuli and analyze neural output in search of categorical clustering on a solely neural level. We presented artificial stimuli, pictorial and grating stimuli, to pigeons without the need of any differential behavioral responding while recording from the nidopallium frontolaterale (NFL), a higher visual area in the avian brain. The pictorial stimuli differed in color and shape; the gratings differed in spatial frequency and amplitude. We computed representational dissimilarity matrices to reveal categorical clustering based on both neural data and pecking behavior. Based on neural output of the NFL, pictorial and grating stimuli were differentially represented in the brain. Pecking behavior showed a similar pattern, but to a lesser extent. A further subclustering within pictorial stimuli according to color and shape, and within gratings according to frequency and amplitude, was not present. Our study gives proof-of-concept that this reverse engineering approach-namely reading out categorical information from neural data--can be quite helpful in understanding the neural underpinnings of categorization learning., (© 2015 Society for the Experimental Analysis of Behavior.)

Sensory systems provide organisms with information on the current status of the environment, thus enabling adaptive behavior. The neural mechanisms by which sensory information is exploited for action selection are typically studied with mammalian subjects performing perceptual decision-making tasks, and most of what is known about these mechanisms at the single-neuron level is derived from cortical recordings in behaving monkeys. To explore the generality of neural mechanisms underlying perceptual decision making across species, we recorded single-neuron activity in the pigeon nidopallium caudolaterale (NCL), a non-laminated associative forebrain structure thought to be functionally equivalent to mammalian prefrontal cortex, while subjects performed a visual categorisation task. We found that, whereas the majority of NCL neurons unspecifically upregulated or downregulated activity during stimulus presentation, ~20% of neurons exhibited differential activity for the sample stimuli and predicted upcoming choices. Moreover, neural activity in these neurons was ramping up during stimulus presentation and remained elevated until a choice was initiated, a response pattern similar to that found in monkey prefrontal and parietal cortices in saccadic choice tasks. In addition, many NCL neurons coded for movement direction during choice execution and differentiated between choice outcomes (reward and punishment). Taken together, our results implicate the NCL in the selection and execution of operant responses, an interpretation resonating well with the results of previous lesion studies. The resemblance of the response patterns of NCL neurons to those observed in mammalian cortex suggests that, despite differing neural architectures, mechanisms for perceptual decision making are similar across classes of vertebrates., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This article presents a summary and critical review of what is known about the 'grouped retina', a peculiar type of retinal organization in fish in which groups of photoreceptor cell inner and outer segments are arranged in spatially separated bundles. In most but not all cases, these bundles are embedded in light-reflective cups that are formed by the retinal pigment epithelial cells. These cups constitute a specialized type of retinal tapetum (i.e., they are biological 'mirrors' that cause eye shine) and appear to be optimized for different purposes in different fishes. Generally, the large retinal pigment epithelial cells are filled with light-reflecting photonic crystals that consist of guanine, uric acid, or pteridine depending on species, and which ensure that the incoming light becomes directed onto the photoreceptor outer segments. This structural specialization has so far been found in representatives of 17 fish families; of note, not all members of a given family must possess a grouped retina, and the 17 families are not all closely related to each other. In many cases (e.g., in Osteoglossomorpha and Aulopiformes) the inner surface of the cup is formed by three to four layers of strikingly regularly shaped and spaced guanine platelets acting as an optical multilayer. It has been estimated that this provides an up to 10fold increase of the incident light intensity. In certain deep-sea fish (many Aulopiformes and the Polymixidae), small groups of rods are embedded in such 'parabolic mirrors'; most likely, this is an adaptation to the extremely low light intensities available in their habitat. Some of these fishes additionally possess similar tapetal cups that surround individual cones and, very likely, also serve as amplifiers of the weak incident light. In the Osteoglossomorpha, however, that inhabit the turbid water of rivers or streams, the structure of the cups is more complex and undergoes adaptation-dependent changes. At dim daylight, probably representing the usual environmental conditions of the fish, the outer segments of up to 30 cone cells are placed at the bottom of the cup where light intensity is maximized. Strikingly, however, a large number of rod receptor cells are positioned behind each mirroring cup. This peculiar arrangement (i) allows vision at deep red wavelenghts, (ii) matches the sensitivity of rod and cone photoreceptors, and (iii) facilitates the detection of low-contrast and color-mixed stimuli, within the dim, turbid habitat. Thus, for these fish the grouped retina appears to aid in reliable and quick detection of large, fast moving, biologically relevant stimuli such as predators. Overall, the grouped retina appears as a peculiar type of general retinal specialization in a variety of fish species that is adaptive in particular habitats such as turbid freshwater but also the deep-sea. The authors were prompted to write this review by working on the retina of Gnathonemus petersii; the data resulting from this work (Landsberger et al., 2008; Kreying et al., 2012) are included in the present review., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The retina of the weakly electric fish Gnathonemus petersii is a so-called grouped retina where photoreceptors are bundled. These bundles are regarded as functional units and this type of retinal specialization is uniquely found in teleosts. To understand how this anatomical organization influences visual information processing we investigated the morphology and distribution of retinal ganglion cells (GCs) and the response properties of retinal afferents terminating in the major retinorecipient area, the optic tectum. GCs were classified based on their dendritic morphology (dendritic field diameters <90-100 μm: narrow-field GCs; 110-280 μm: widefield GCs; >280 μm: giant GCs). Within these classes subtypes were distinguished based on the ramification patterns of the dendrites in the sublaminae of the inner plexiform layer. Properties of presumed optic nerve terminals were investigated in the optic tectum using extracellular recordings. Physiological classes could be observed based on their response to visual stimuli (on; off; on-off, and fast units). Receptive field sizes and spatiotemporal properties were classified and the topographical representation of the visual space was mapped in the tectum. Gratings of low spatial frequencies were best responded to and followed up to high temporal frequencies (>30 Hz). Most of the recorded units were directionally selective. No evidence of distorted topographies in the tectum was found, i.e., no overrepresentation of the retina was seen in the tectum opticum. The grouped retina of G. petersii seems to be optimized for the detection of large, fast objects in an environment of low optical quality., (Copyright © 2013 Wiley Periodicals, Inc.)

Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.

Weakly electric fish orient, hunt and communicate by emitting electrical pulses, enabling them to discriminate objects, conspecifics and prey. In addition to the electrosensory modality - although dominating in importance in these fishes - other modalities, like vision, play important roles for survival. The visual system of Gnathonemus petersii, a member of the family mormyridae living in West African blackwater streams shows remarkable specializations: Cone photoreceptors are grouped in bundles within a light reflecting tapetum lucidum, while the rods are also bundled but located at the back within a light-scattering guanine layer. Such an organization does not improve light sensitivity nor does it provide high spatial resolution. Thus, the function of the grouped retinal arrangement for the visual performance of the fish remains unclear. Here we investigated the contrast sensitivity of the temporal transfer properties of the visual system of Gnathonemus. To do so, we analyzed visual evoked potentials in the optic tectum and tested the critical flicker fusion frequency in a behavioral paradigm. Results obtained in Gnathonemus are compared to results obtained with goldfish (Carassius auratus), revealing differences in the filter characteristics of their visual systems: While goldfish responds best to low frequencies, Gnathonemus responds best at higher frequencies. The visual system of goldfish shows characteristics of a low-pass filter while the visual system of Gnathonemus has characteristics of a band-pass filter. Furthermore we show that the visual system of Gnathonemus is more robust towards contrast reduction as compared to the goldfish. The grouped retina might enable Gnathonemus to see large, fast moving objects even under low contrast conditions. Due to the fact that the electric sense is a modality of limited range, it is tempting to speculate that the retinal specialization of Gnathonemus petersii might be advantageous for predator avoidance even when brightness differences are small., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Despite their diversity, vertebrate retinae are specialized to maximize either photon catch or visual acuity. Here, we describe a functional type that is optimized for neither purpose. In the retina of the elephantnose fish (Gnathonemus petersii), cone photoreceptors are grouped together within reflecting, photonic crystal-lined cups acting as macroreceptors, but rod photoreceptors are positioned behind these reflectors. This unusual arrangement matches rod and cone sensitivity for detecting color-mixed stimuli, whereas the photoreceptor grouping renders the fish insensitive to spatial noise; together, this enables more reliable flight reactions in the fish's dim and turbid habitat as compared with fish lacking this retinal specialization.

Palliative care is aimed to improve the quality of life of both patients and their family members during the course of life-threatening diseases through the prevention, early identification and treatment of the symptoms of physical, psychological, spiritual and social suffering. Palliative care should be provided to every critically ill patient; this requirement renders the training of intensive care practitioners and education initiatives fundamental. Continuing the Technical Council on End of Life and Palliative Care of the Brazilian Association of Intensive Medicine activities and considering previously established concepts, the II Forum of the End of Life Study Group of the Southern Cone of America was conducted in October 2010. The forum aimed to develop palliative care recommendations for critically ill patients.

Withholding of treatment in patients with terminal disease is increasingly common in intensive care units, throughout the world. Notwithstanding, Brazilian intensivists still have a great difficulty to offer the best treatment to patients that have not benefited from curative care. The objective of this comment is to suggest an algorithm for the care of terminally ill patients. It was formulated based upon literature and the experience of experts, by members of the ethics committee and end-of-life of AMIB - Brazilian Association of Intensive Care.

Weakly electric fish can serve as model systems for active sensing because they actively emit electric signals into the environment, which they also perceive with more than 2000 electroreceptor organs (mormyromasts) distributed over almost their entire skin surface. In a process called active electrolocation, animals are able to detect and analyse objects in their environment, which allows them to perceive a detailed electrical picture of their surroundings even in complete darkness. The African mormyrid fish Gnathonemus petersii can not only detect nearby objects, but in addition can perceive other properties such as their distance, their complex electrical impedance, and their three-dimensional shape. Because most of the sensory signals the fish perceive during their nightly activity period are self-produced, evolution has shaped and adapted the mechanisms for signal production, signal perception and signal analysis by the brain. Like in many other sensory systems, so-called prereceptor mechanisms exist, which passively improve the sensory signals in such a way that the signal carrier is optimized for the extraction of relevant sensory information. In G. petersii prereceptor mechanisms include properties of the animal's skin and internal tissue and the shape of the fish's body. These lead to a specific design of the signal carrier at different skin regions of the fish, preparing them to perform certain detection tasks. Prereceptor mechanisms also ensure that the moveable skin appendix of G. petersii, the 'Schnauzenorgan', receives an optimal sensory signal during all stages of its movement. Another important aspect of active sensing in G. petersii concerns the locomotor strategies during electrolocation. When foraging, the animals adopt a particular position with the body slanted forward bringing the so-called 'nasal region' in a position to examine the environment in front of and at the side of the fish. Simultaneously, the Schnauzenorgan performs rhythmic left-right searching movements. When an object of interest is encountered, the Schnauzenorgan is brought in a twitching movement towards the object and is moved over it for further exploration. The densities of electroreceptor organs is extraordinary high at the Schnauzenorgan and, to a lesser extend, at the nasal region. In these so-called foveal regions, the mormyromasts have a different morphology compared to other parts of the electroreceptive skin. Our results on mormyromast density and morphology, prereceptor mechanisms and electric images, central processing of electroreceptive information, and on behavioural strategies of G. petersii lead us to formulate the hypothesis that these fish possess two separate electric foveae, each of which is specialized for certain perceptional tasks.

The electric sense of mormyrids is often regarded as an adaptation to conditions unfavourable for vision and in these fish it has become the dominant sense for active orientation and communication tasks. With this sense, fish can detect and distinguish the electrical properties of the close environment, measure distance, perceive the 3-D shape of objects and discriminate objects according to distance or size and shape, irrespective of conductivity, thus showing a degree of abstraction regarding the interpretation of sensory stimuli. The physical properties of images projected on the sensory surface by the fish's own discharge reveal a "Mexican hat" opposing centre-surround profile. It is likely that computation of the image amplitude to slope ratio is used to measure distance, while peak width and slope give measures of shape and contrast. Modelling has been used to explore how the images of multiple objects superimpose in a complex manner. While electric images are by nature distributed, or 'blurred', behavioural strategies orienting sensory surfaces and the neural architecture of sensory processing networks both contribute to resolving potential ambiguities. Rostral amplification is produced by current funnelling in the head and chin appendage regions, where high density electroreceptor distributions constitute foveal regions. Central magnification of electroreceptive pathways from these regions particularly favours the detection of capacitive properties intrinsic to potential living prey. Swimming movements alter the amplitude and contrast of pre-receptor object-images but image modulation is normalised by central gain-control mechanisms that maintain excitatory and inhibitory balance, removing the contrast-ambiguity introduced by self-motion in much the same way that contrast gain-control is achieved in vision.

Weakly electric fish generate electric fields with an electric organ and perceive them with cutaneous electroreceptors. During active electrolocation, nearby objects are detected by the distortions they cause in the electric field. The electrical properties of objects, their form and their distance, can be analysed and distinguished. Here we focus on Gnathonemus petersii (Günther 1862), an African fish of the family Mormyridae with a characteristic chin appendix, the Schnauzenorgan. Behavioural and anatomical results suggest that the mobile Schnauzenorgan and the nasal region serve special functions in electroreception, and can therefore be considered as electric foveae. We investigated passive pre-receptor mechanisms that shape and enhance the signal carrier. These mechanisms allow the fish to focus the electric field at the tip of its Schnauzenorgan where the density of electroreceptors is highest (tip-effect). Currents are funnelled by the open mouth (funnelling-effect), which leads to a homogenous voltage distribution in the nasal region. Field vectors at the trunk, the nasal region and the Schnauzenorgan are collimated but differ in the angle at which they are directed onto the sensory surface. To investigate the role of those pre-receptor effects on electrolocation, we recorded electric images of objects at the foveal regions. Furthermore, we used a behavioural response (novelty response) to assess the sensitivity of different skin areas to electrolocation stimuli and determined the receptor densities of these regions. Our results imply that both regions - the Schnauzenorgan and the nasal region - can be termed electric fovea but they serve separate functions during active electrolocation.

Weakly electric fish perceive their actively generated electrical field with cutaneous electroreceptors. This active sensory system is used both for orientation and for communication. In a recent paper1 we focussed on how anatomical adaptations (pre-receptor mechanisms), biophysical constraints and behavior all contribute to active electrolocation, i.e., the fishes' unique ability to determine and distinguish the electrical properties of objects based on the modulation of a self-generated carrier signal, the so-called electric organ discharge.

Adhesion of T cells after stimulation of the T-cell receptor (TCR) is mediated via signaling processes that have collectively been termed inside-out signaling. The molecular basis for inside-out signaling is not yet completely understood. Here, we show that a signaling module comprising the cytosolic adapter proteins ADAP and SKAP55 is involved in TCR-mediated inside-out signaling and, moreover, that the interaction between ADAP and SKAP55 is mandatory for integrin activation. Disruption of the ADAP/SKAP55 module leads to displacement of the small GTPase Rap1 from the plasma membrane without influencing its GTPase activity. These findings suggest that the ADAP/SKAP55 complex serves to recruit activated Rap1 to the plasma membrane. In line with this hypothesis is the finding that membrane targeting of the ADAP/SKAP55 module induces T-cell adhesion in the absence of TCR-mediated stimuli. However, it appears as if the ADAP/SKAP55 module can exert its signaling function outside of the classical raft fraction of the cell membrane.

SH3 domains represent versatile scaffolds within eukaryotic cells by targeting proline-rich sequences within intracellular proteins. More recently, binding of SH3 domains to unusual peptide motifs, folded proteins or lipids has been reported. Here we show that the newly defined hSH3 domains of immune cell adapter proteins bind lipid membranes with distinct affinities. The interaction of the hSH3 domains of adhesion and degranulation promoting adapter protein (ADAP) and PRAM-1 (Promyelocytic-Retinoic acid receptor alpha target gene encoding an Adaptor Molecule-1), with phosphatidylcholine-containing liposomes is observed upon incorporation of phosphatidylserine (PS) or phosphoinositides (PIs) into the membrane bilayer. Mechanistically we show that stable association of the N-terminal, amphipathic helix with the beta-sheet scaffold favours lipid binding and that the interaction with PI(4,5)P(2)-containing liposomes is consistent with a single-site, non-cooperative binding mechanism. Functional investigations indicate that deletion of both amphipathic helices of the hSH3 domains reduces the ability of ADAP to enhance adhesion and migration in stimulated T cells.

Regulation of the cytoskeleton in cells of the haematopoietic system is essential for fulfilling diverse tasks such as migration towards a chemoattractant, phagocytosis or cell-cell communication. This is particularly true for the many types of T cells, which are at the foundation of the adaptive immune system in vertebrates. Deregulation of actin filament turnover is known to be involved in the development of severe immunodeficiencies or immunoproliferative diseases. Therefore, molecular dissection of signalling complexes and effector molecules, which leads to controlled cytoskeletal assembly, has been the focus of immunological research in the last decade. In the past, cytoskeletal remodelling was frequently understood as the finish line of signalling, while today it becomes increasingly evident that actin and microtubule dynamics are required for proper signal transmission in many processes such as T cell activation. Significant effort is made in many laboratories to further elucidate the contribution of cytoskeletal remodelling to immune function. The objective of this article is to summarise the current knowledge on how actin and microtubules are reorganised to support the formation of structures as diverse as the immunological synapse and peripheral protrusions during cell migration.

Ras-GTP imaging studies using the Ras-binding domain (RBD) of the Ras effector c-Raf as a reporter for overexpressed Ras have produced discrepant results about the possible activation of Ras at the Golgi apparatus. We report that RBD oligomerization provides probes for visualization of endogenous Ras-GTP, obviating Ras overexpression and the side effects derived thereof. RBD oligomerization results in tenacious binding to Ras-GTP and interruption of Ras signalling. Trimeric RBD probes fused to green fluorescent protein report agonist-induced endogenous Ras activation at the plasma membrane (PM) of COS-7, PC12 and Jurkat cells, but do not accumulate at the Golgi. PM illumination is exacerbated by Ras overexpression and its sensitivity to dominant-negative RasS17N and pharmacological manipulations matches Ras-GTP formation assessed biochemically. Our data illustrate that endogenous Golgi-located Ras is not under the control of growth factors and argue for the PM as the predominant site of agonist-induced Ras activation.

Signaling of receptor tyrosine kinases (RTKs) is regulated by protein-tyrosine phosphatases (PTPs). We previously discovered the efficient downregulation of Ros RTK signaling by the SH2 domain PTP SHP-1, which involves a direct interaction of both molecules. Here, we studied the mechanism of this interaction in detail. Phosphopeptides representing the SHP-1 candidate binding sites in the Ros cytoplasmic domain, pY2267 and pY2327, display high affinity binding to the SHP-1 N-terminal SH2 domain (Kd=217 nM and 171 nM, respectively). Y2327 is, however, a poor substrate of Ros kinase and, therefore, contributes little to SHP-1 binding in vitro. To explore the mechanism of association in intact cells, functional fluorescent fusion proteins of Ros and SHP-1 were generated. Complexes of both molecules could be detected by Förster resonance energy transfer (FRET) in intact HEK293 and COS7 cells. As expected, the association required the functional SHP-1 N-terminal SH2 domain. Unexpectedly, pY2267 and pY2327 both contributed to the association. Mutation of Y2327 reduced constitutive association in COS7 cells. Ligand-dependent association was abrogated upon mutation of Y2267 but remained intact when Y2327 was mutated. A phosphopeptide representing the binding site pY2267 was a poor substrate for SHP-1, whereas Ros activation loop phosphotyrosines were effectively dephosphorylated. We propose a model for SHP-1-Ros interaction in which ligand-stimulated phosphorylation of Ros Y2267 by Ros, phosphorylation of Y2327 by a heterologous kinase, and inactivation of Ros by SHP-1-mediated dephosphorylation play a role in the regulation of complex stability.

Top covers of waste landfills conventionally contain a drain layer over a 1(low-permeable clay liner usually containing smectite minerals. The rate of percolation of the clay liner, which may require tens of years to become water-saturated, determines the downward transport of ions released from the underlying waste to and through the bottom clay liner. The percolation rate is controlled by the composition and density of the tipper liner, which should be as tight as possible. This implies a high density and therefore a high swelling potential which must be moderated by proper design. The bottom clay liner is a less effective and reliable barrier since cation exchange will increase the hydraulic conductivity and cause a significant rise in percolation rate and risk of chemical attack by the percolate. The top liner will undergo very moderate strain if the ash fill is effectively compacted and undergoes little self-compaction. Processes that may cause degradation are freezing and drying and require proper design. In this paper the authors examine the performance of ash-fills isolated by clay liners and conclude that the most important issue is to design and construct the top liner to be as impermeable as possible paying less attention to the tightness of the bottom layer.