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Sustained exposure to an asynchronous multisensory signal causes perceived simultaneity to shift in the direction of the leading component of the adapting stimulus. This is known as temporal recalibration, and recent evidence suggests that it can occur very rapidly, even after a single asynchronous audiovisual (AV) stimulus. However, this form of rapid recalibration appears to be unique to AV stimuli, in contrast to recalibration following sustained asynchronies which occurs with audiotactile (AT) and visuotactile (VT) stimuli. This study examines temporal recalibration to AV, VT and AT asynchrony with spatially collocated stimuli using a design that produces both sustained and inter-trial recalibration by combining the traditional sustained adaptation approach with an inter-trial analysis of sequential dependencies in an extended test period. Thus, we compare temporal recalibration to both sustained and transient asynchrony in three crossmodal combinations using the same design, stimuli and observers. The results reveal that prolonged exposure to asynchrony produced equivalent temporal recalibration for all combinations: AV, AT and VT. The pattern for rapid, inter-trial recalibration was very different. Rapid recalibration occurred strongly for AV stimuli, weakly for AT and did not occur at all for VT. For all sensory pairings, recalibration from sustained asynchrony decayed to baseline during the test phase while inter-trial recalibration was present and stable throughout testing, suggesting different mechanisms may underlie adaptation at long and short timescales.

Recent work from several groups has shown that perception of various visual attributes in human observers at a given moment is biased toward what was recently seen. This positive serial dependency is a kind of temporal averaging that exploits short-term correlations in visual scenes to reduce noise and stabilize perception. To date, this stabilizing "continuity field" has been demonstrated on stable visual attributes such as orientation and face identity, yet it would be counterproductive to apply it to dynamic attributes in which change sensitivity is needed. Here, we tested this using motion direction discrimination and predict a negative perceptual dependency: a contrastive relationship that enhances sensitivity to change. Surprisingly, our data showed a cubic-like pattern of dependencies with positive and negative components. By interleaving various stimulus combinations, we separated the components and isolated a positive perceptual dependency for motion and a negative dependency for orientation. A weighted linear sum of the separate dependencies described the original cubic pattern well. The positive dependency for motion shows an integrative perceptual effect and was unexpected, although it is consistent with work on motion priming. These findings suggest that a perception-stabilizing continuity field occurs pervasively, occurring even when it obscures sensitivity to dynamic stimuli. SIGNIFICANCE STATEMENT Recent studies show that visual perception at a given moment is not entirely veridical, but rather biased toward recently seen stimuli: a positive serial dependency. This temporal smoothing process helps perceptual continuity by preserving stable aspects of the visual scene over time, yet, for dynamic stimuli, temporal smoothing would blur dynamics and reduce sensitivity to change. We tested whether this process is selective for stable attributes by examining dependencies in motion perception. We found a clear positive dependency for motion, suggesting that positive perceptual dependencies are pervasive. We also found a concurrent negative (contrastive) dependency for orientation. Both dependencies combined linearly to determine perception, showing that the brain can calculate contrastive and integrative dependencies simultaneously from recent stimulus history when making perceptual decisions., (Copyright © 2017 the authors 0270-6474/17/374381-10$15.00/0.)

Recently, Cass and Van der Burg demonstrated that temporal order judgment (TOJ) precision could be profoundly impaired by the mere presence of dynamic visual clutter elsewhere in the visual field. This study examines whether presenting target and distractor objects in different depth planes might ameliorate this remote temporal camouflage (RTC) effect. TOJ thresholds were measured under static and dynamic (flickering) distractor conditions. In Experiment 1, targets were presented at zero, crossed, or uncrossed disparity, with distractors fixed at zero disparity. Thresholds were significantly elevated under dynamic compared with static contextual conditions, replicating the RTC effect. Crossed but not uncrossed disparity targets improved performance in dynamic distractor contexts, which otherwise produce substantial RTC. In Experiment 2, the assignment of disparity was reversed: targets fixed at zero disparity; distractors crossed, uncrossed, or zero. Under these conditions, thresholds improved significantly in the nonzero distractor disparity conditions. These results indicate that presenting target and distractor objects in different planes can significantly improve TOJ performance in dynamic conditions. In Experiment 3, targets were each presented with a different sign of disparity (e.g., one crossed and the other uncrossed), with no resulting performance benefits. Results suggest that disparity can be used to alleviate the performance-diminishing effects of RTC, but only if both targets constitute a single and unique disparity-defined surface.

Peripheral vision can be severely impaired by nearby clutter. Decades of research using sparse displays have established that this phenomenon, known as visual crowding, follows Bouma's rule: Interference occurs for target-distractor separations up to half the target's eccentricity. Although considered a fundamental constraint on human vision, it is unclear whether Bouma's rule holds in dense heterogeneous visual environments. Using a genetic algorithm we investigated crowding in densely cluttered displays. Participants were instructed to identify the orientation of a target line (6° eccentricity) among 284 distractor lines. Displays supporting highest accuracy were selected ("survival of the fittest") and combined to create new displays. Performance improved over generations, predominantly driven by the emergence of horizontal flankers within 1° of the near-vertical target, but with no evidence of interference beyond this radius. We conclude that Bouma's rule does not necessarily hold in densely cluttered displays. Instead, a nearest-neighbor segmentation rule provides a better account. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Studies suggest that familiar faces are processed in a manner distinct from unfamiliar faces and that familiarity with a face confers an advantage in identity recognition. Our visual system seems to capitalize on experience to build stable face representations that are impervious to variation in retinal input that may occur due to changes in lighting, viewpoint, viewing distance, eye movements, etc. Emerging evidence also suggests that our visual system maintains a continuous perception of a face's identity from one moment to the next despite the retinal input variations through serial dependence. This study investigates whether interactions occur between face familiarity and serial dependence. In two experiments, participants used a continuous scale to rate attractiveness of unfamiliar and familiar faces (either experimentally learned or famous) presented in rapid sequences. Both experiments revealed robust inter-trial effects in which attractiveness ratings for a given face depended on the preceding face's attractiveness. This inter-trial attractiveness effect was most pronounced for unfamiliar faces. Indeed, when participants were familiar with a given face, attractiveness ratings showed significantly less serial dependence. These results represent the first evidence that familiar faces can resist the temporal integration seen in sequential dependencies and highlight the importance of familiarity to visual cognition.

Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours. However, it is unclear whether drugs that target BRCAness can also be used to prevent tumour formation in BRCA1-mutation carriers, especially as loss of wild-type BRCA1 may not be the first event in BRCA1-associated tumourigenesis. We performed prophylactic treatments in a genetically engineered mouse model in which de novo development of BRCA1-deficient mammary tumours is induced by stochastic loss of BRCA1 and p53. We found that prophylactic window therapy with nimustine, cisplatin or olaparib reduced the amount and size of mammary gland lesions, and significantly increased the median tumour latency. Similar results were obtained with intermittent prophylactic treatment with olaparib. Importantly, prophylactic window therapy with nimustine and cisplatin resulted in an increased fraction of BRCA1-proficient mammary tumours, suggesting selective survival and malignant transformation of BRCA1-proficient lesions upon prophylactic treatment with DNA-damaging agents. Prophylactic therapy with olaparib significantly prolonged mammary tumour-free survival without any significant increase in the fraction of BRCA1-proficient tumours, warranting the evaluation of this PARP inhibitor in prophylactic trials in BRCA1-mutation carriers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Visual attention serves to select salient and relevant events from the visual input. Selective attention to a visual event can be driven by a synchronous sound. Interestingly, recent evidence suggests that a sound can only drive selection of 1 concurrent visual event, suggesting that attentional capacity is much lower for audiovisual events than for purely visual events. Here we corroborate and extend this finding using a mixture modeling technique that distinguishes between the probability and precision of perception. Observers were presented with displays of multiple continuously flickering objects, of which either 1 or 2 were coupled to a single sound. In 2 experiments, we found that the probability of correctly reporting an object was almost halved when the number of synchronized visual objects increased from 1 to 2. Precision, however, was not affected. This indicates that rather than attention being distributed across multiple simultaneous audiovisual events, just 1 of them is singled out for attentional selection. This was not due to a capacity limit for selecting the visual objects per se; pure visual cues elicited a much higher probability of report and in that case there were clear declines in precision at larger set sizes, indicating the concurrent selection of multiple items. The results point toward a dissociation in capacity for visually and aurally cued prioritization of visual objects. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Visual search for color is thought to be performed either using color-opponent processes, or through the comparison of unique color categories. In the present study, we investigate these theories by using displays with a red or green hue, but varying levels of saturation. The linearly inseparable nature of this display makes search for the midsaturated target inefficient. A genetic algorithm was employed, which evolved the distractors in a search display to reveal the processes that people use to search color. Results show that participants were able to search within only midsaturated red items, but not within only midsaturated green items, providing evidence for color categories, as in English there is a basic color label for midsaturated red (i.e., pink), but not for midsaturated green. A follow-up experiment revealed that it was possible to search within midsaturated green items if the exact target color was primed before each trial. We therefore suggest that both priming and a unique color category increase the recognizability of the target color, which has been speculated to increase visual search performance. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Multisensory interactions are well established to convey an array of perceptual and behavioral benefits. One of the key features of multisensory interactions is the temporal structure of the stimuli combined. In an effort to better characterize how temporal factors influence multisensory interactions across the lifespan, we examined audiovisual simultaneity judgment and the degree of rapid recalibration to paired audiovisual stimuli (Flash-Beep and Speech) in a sample of 220 participants ranging from 7 to 86 years of age. Results demonstrate a surprisingly protracted developmental time-course for both audiovisual simultaneity judgment and rapid recalibration, with neither reaching maturity until well into adolescence. Interestingly, correlational analyses revealed that audiovisual simultaneity judgments (i.e., the size of the audiovisual temporal window of simultaneity) and rapid recalibration significantly co-varied as a function of age. Together, our results represent the most complete description of age-related changes in audiovisual simultaneity judgments to date, as well as being the first to describe changes in the degree of rapid recalibration as a function of age. We propose that the developmental time-course of rapid recalibration scaffolds the maturation of more durable audiovisual temporal representations., Competing Interests: The authors have declared that no competing interests exist.

Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K) signaling as a potential therapeutic strategy for targeting CLC., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the present study, we examine how observers search among complex displays. Participants were asked to search for a big red horizontal line among 119 distractor lines of various sizes, orientations and colours, leading to 36 different feature combinations. To understand how people search in such a heterogeneous display, we evolved the search display by using a genetic algorithm (Experiment 1). The best displays (i.e., displays corresponding to the fastest reaction times) were selected and combined to create new, evolved displays. Search times declined over generations. Results show that items sharing the same colour and orientation as the target disappeared over generations, implying they interfered with search, but items sharing the same colour and were 12.5° different in orientation only interfered if they were also the same size. Furthermore, and inconsistent with most dominant visual search theories, we found that non-red horizontal distractors increased over generations, indicating that these distractors facilitated visual search while participants were searching for a big red horizontally oriented target. In Experiments 2 and 3, we replicated these results using conventional, factorial experiments. Interestingly, in Experiment 4, we found that this facilitation effect was only present when the displays were very heterogeneous. While current models of visual search are able to successfully describe search in homogeneous displays, our results challenge the ability of these models to describe visual search in heterogeneous environments.

Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.

We have shown that obesity-associated attenuation of murine acute lung injury is driven, in part, by blunted neutrophil chemotaxis, yet differences were noted between the two models of obesity studied. We hypothesized that obesity-associated impairment of multiple neutrophil functions contributes to increased risk for respiratory infection but that such impairments may vary between murine models of obesity. We examined the most commonly used murine obesity models (diet-induced obesity, db/db, CPE(fat/fat), and ob/ob) using a Klebsiella pneumoniae pneumonia model and LPS-induced pneumonitis. Marrow-derived neutrophils from uninjured lean and obese mice were examined for in vitro functional responses. All obesity models showed impaired clearance of K. pneumoniae, but in differing temporal patterns. Failure to contain infection in obese mice was seen in the db/db model at both 24 and 48 hours, yet this defect was only evident at 24 hours in CPE(fat/fat) and ob/ob models, and at 48 hours in diet-induced obesity. LPS-induced airspace neutrophilia was decreased in all models, and associated with blood neutropenia in the ob/ob model but with leukocytosis in the others. Obese mouse neutrophils from all models demonstrated impaired chemotaxis, whereas neutrophil granulocyte colony-stimulating factor-mediated survival, LPS-induced cytokine transcription, and mitogen-activated protein kinase and signal transducer and activator of transcription 3 activation in response to LPS and granulocyte colony-stimulating factor, respectively, were variably impaired across the four models. Obesity-associated impairment of host response to lung infection is characterized by defects in neutrophil recruitment and survival. However, critical differences exist between commonly used mouse models of obesity and may reflect variable penetrance of elements of the metabolic syndrome, as well as other factors.

We tested whether fast flicker can capture attention using eight flicker frequencies from 20-96 Hz, including several too high to be perceived (>50 Hz). Using a 480 Hz visual display rate, we presented smoothly sampled sinusoidal temporal modulations at: 20, 30, 40, 48, 60, 69, 80, and 96 Hz. We first established flicker detection rates for each frequency. Performance was at or near ceiling until 48 Hz and dropped sharply to chance level at 60 Hz and above. We then presented the same flickering stimuli as pre-cues in a visual search task containing five elements. Flicker location varied randomly and was therefore congruent with target location on 20% of trials. Comparing congruent and incongruent trials revealed a very strong congruency effect (faster search for cued targets) for all detectable frequencies (20-48 Hz) but no effect for faster flicker rates that were detected at chance. This pattern of results (obtained with brief flicker cues: 58 ms) was replicated for long flicker cues (1000 ms) intended to allow for entrainment to the flicker frequency. These results indicate that only visible flicker serves as an exogenous attentional cue and that flicker rates too high to be perceived are completely ineffective.

Background: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer., Methods: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors., Results: BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance., Conclusions: In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The brain integrates signals from multiple modalities to provide a reliable estimate of environmental events. A temporally cluttered environment presents a challenge for sensory integration because of the risk of misbinding, yet it also provides scope for cross-modal binding to greatly enhance performance by highlighting multimodal events. We present a tactile search task in which fingertips received pulsed vibrations and participants identified which finger was stimulated in synchrony with an auditory signal. Results showed that performance for identifying the target finger was impaired when other fingers were stimulated, even though all fingers were stimulated sequentially. When the number of fingers vibrated was fixed, we found that both spatial and temporal factors constrained performance, because events occurring close to the target vibration in either space or time reduced accuracy. When tactile search was compared with visual search, we found overall performance was lower in touch than in vision, although the cost of reducing temporal separation between stimuli or increasing the presentation rate was similar for both target modalities. Audiotactile performance benefitted from increasing spatial separation between target and distractors, with a particularly strong benefit for locating the target on a different hand to the distractors, whereas the spatial manipulations did not affect audiovisual performance. The similar trends in performance for temporal manipulations across vision and touch suggest a common supramodal binding mechanism that, when combining audition and touch, is limited by the poor resolution of the underlying unisensory representation of touch in cluttered settings. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.

Temporal ventriloquism is the shift in perceived timing of a visual stimulus that occurs when an auditory stimulus is presented close in time. This study investigated whether crossmodal correspondence between auditory pitch and visual elevation modulates temporal ventriloquism. Participants were presented two visual stimuli (above and below fixation) across a range of stimulus onset asynchronies and were asked to judge the order of the events. A task-irrelevant auditory click was presented shortly before the first and another shortly after the second visual stimulus. There were two pitches used (low and high) and the congruency between the auditory and visual stimuli was manipulated. The results show that incongruent pairings between pitch and elevation abolish temporal ventriloquism. In contrast, the crossmodal correspondence effect was absent when the direction of the pitch change was fixed within sessions, reducing the saliency of the pitch change. The results support previous studies suggesting that in addition to spatial and temporal factors, crossmodal correspondences can influence binding of information across the senses, although these effects are likely to be dependent on the saliency of the crossmodal mapping.

Millions of people use online dating sites each day, scanning through streams of face images in search of an attractive mate. Face images, like most visual stimuli, undergo processes whereby the current percept is altered by exposure to previous visual input. Recent studies using rapid sequences of faces have found that perception of face identity is biased towards recently seen faces, promoting identity-invariance over time, and this has been extended to perceived face attractiveness. In this paper we adapt the rapid sequence task to ask a question about mate selection pertinent in the digital age. We designed a binary task mimicking the selection interface currently popular in online dating websites in which observers typically make binary decisions (attractive or unattractive) about each face in a sequence of unfamiliar faces. Our findings show that binary attractiveness decisions are not independent: we are more likely to rate a face as attractive when the preceding face was attractive than when it was unattractive.

Members of the Toll-like receptor and interleukin-1 (IL-1) receptor families all signal via Toll/IL-1R (TIR) domain-driven assemblies with adaptors such as MyD88. We here combine the mammalian two-hybrid system MAPPIT and saturation mutagenesis to complement and extend crystallographic and nuclear magnetic resonance data, and reveal how TIR domains interact. We fully delineate the interaction sites on the MyD88 TIR domain for homo-oligomerization and for interaction with Mal and TLR4. Interactions between three sites drive MyD88 homo-oligomerization. The BB-loop interacts with the αE-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The αC'-helix interacts symmetrically. The MyD88 TIR domains thus assemble into a left-handed helix, compatible with the Myddosome death domain crystal structure. This assembly explains activation of MyD88 by Mal and by an oncogenic mutation, and regulation by phosphorylation. These findings provide a paradigm for the interaction of mammalian TIR domains., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Perception and behavior are fundamentally shaped by the integration of different sensory modalities into unique multisensory representations, a process governed by spatio-temporal correspondence. Prior work has characterized temporal perception using the point in time at which subjects are most likely to judge multisensory stimuli to be simultaneous (PSS) and the temporal binding window (TBW) over which participants are likely to do so. Here we examine the relationship between the PSS and the TBW within and between individuals, and within and between three sensory combinations: audiovisual, audiotactile and visuotactile. We demonstrate that TBWs correlate within individuals and across multisensory pairings, but PSSs do not. Further, we reveal that while the audiotactile and audiovisual pairings show tightly related TBWs, they also exhibit a differential relationship with respect to true and perceived multisensory synchrony. Thus, audiotactile and audiovisual temporal processing share mechanistic features yet are respectively functionally linked to objective and subjective synchrony.

Combining signals across the senses improves precision and speed of perception, although this multisensory benefit declines for asynchronous signals. Multisensory events may produce synchronized stimuli at source but asynchronies inevitably arise due to distance, intensity, attention and neural latencies. Temporal recalibration is an adaptive phenomenon that serves to perceptually realign physically asynchronous signals. Recently, it was discovered that temporal recalibration occurs far more rapidly than previously thought and does not require minutes of adaptation. Using a classical audiovisual simultaneity task and a series of brief flashes and tones varying in onset asynchrony, perceived simultaneity on a given trial was found to shift in the direction of the preceding trial's asynchrony. Here we examine whether this inter-trial recalibration reflects the same process as prolonged adaptation by combining both paradigms: participants adapted to a fixed temporal lag for several minutes followed by a rapid series of test trials requiring a synchrony judgment. Interestingly, we find evidence of recalibration from prolonged adaptation and inter-trial recalibration within a single experiment. We show a dissociation in which sustained adaptation produces a large but decaying recalibration effect whilst inter-trial recalibration produces large transient effects whose sign matches that of the previous trial.

In the present review, we discuss how the evolution of oxytocin and vasopressin from a single ancestor peptide after gene duplication has stimulated the development of the vertebrate social brain. Separate production sites became possible with a hypothalamic development, which, interestingly, is triggered by the same transcription factors that underlie the development of various subcortical regions where vasopressin and oxytocin receptors are adjacently expressed and which are connected by inhibitory circuits. The opposite modulation of their output by vasopressin and oxytocin could thus create a dynamic equilibrium for rapid responsiveness to external stimuli. At the level of the individual, nurturing early in life can long-lastingly program oxytocin signaling, maintaining a capability of learning and sensitivity to external stimuli that contributes to development of social behavior in adulthood. Oxytocin and vasopressin are thus important for the development of a vertebrate brain that supports bonding between individuals and building of an interactive community.

The brain is adaptive. The speed of propagation through air, and of low-level sensory processing, differs markedly between auditory and visual stimuli; yet the brain can adapt to compensate for the resulting cross-modal delays. Studies investigating temporal recalibration to audiovisual speech have used prolonged adaptation procedures, suggesting that adaptation is sluggish. Here, we show that adaptation to asynchronous audiovisual speech occurs rapidly. Participants viewed a brief clip of an actor pronouncing a single syllable. The voice was either advanced or delayed relative to the corresponding lip movements, and participants were asked to make a synchrony judgement. Although we did not use an explicit adaptation procedure, we demonstrate rapid recalibration based on a single audiovisual event. We find that the point of subjective simultaneity on each trial is highly contingent upon the modality order of the preceding trial. We find compelling evidence that rapid recalibration generalizes across different stimuli, and different actors. Finally, we demonstrate that rapid recalibration occurs even when auditory and visual events clearly belong to different actors. These results suggest that rapid temporal recalibration to audiovisual speech is primarily mediated by basic temporal factors, rather than higher-order factors such as perceived simultaneity and source identity., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Frequency modulation is critical to human speech. Evidence from psychophysics, neurophysiology, and neuroimaging suggests that there are neuronal populations tuned to this property of speech. Consistent with this, extended exposure to frequency change produces direction specific aftereffects in frequency change detection. We show that this aftereffect occurs extremely rapidly, requiring only a single trial of just 100-ms duration. We demonstrate this using a long, randomized series of frequency sweeps (both upward and downward, by varying amounts) and analyzing intertrial adaptation effects. We show the point of constant frequency is shifted systematically towards the previous trial's sweep direction (i.e., a frequency sweep aftereffect). Furthermore, the perception of glide direction is also independently influenced by the glide presented two trials previously. The aftereffect is frequency tuned, as exposure to a frequency sweep from a set centered on 1,000 Hz does not influence a subsequent trial drawn from a set centered on 400 Hz. More generally, the rapidity of adaptation suggests the auditory system is constantly adapting and "tuning" itself to the most recent environmental conditions.

The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials., (© 2014 UICC.)

Following prolonged exposure to asynchronous multisensory signals, the brain adapts to reduce the perceived asynchrony. Here, in three separate experiments, participants performed a synchrony judgment task on audiovisual, audiotactile or visuotactile stimuli and we used inter-trial analyses to examine whether temporal recalibration occurs rapidly on the basis of a single asynchronous trial. Even though all combinations used the same subjects, task and design, temporal recalibration occurred for audiovisual stimuli (i.e., the point of subjective simultaneity depended on the preceding trial's modality order), but none occurred when the same auditory or visual event was combined with a tactile event. Contrary to findings from prolonged adaptation studies showing recalibration for all three combinations, we show that rapid, inter-trial recalibration is unique to audiovisual stimuli. We conclude that recalibration occurs at two different timescales for audiovisual stimuli (fast and slow), but only on a slow timescale for audiotactile and visuotactile stimuli.

Crossmodal integration of sensory signals can improve perception and behavior but requires the signals to occur close in time. Differences in propagation and processing speeds make this difficult. Temporal recalibration is a useful 're-alignment' process by which the point of subjective synchrony is temporally realigned towards an adapted asynchrony. A recent study by Van der Burg et al. (2013). J. Neurosci. 33, 14633-14637 showed temporal recalibration can occur rapidly following a single exposure to a brief audiovisual asynchrony. Using a similar procedure, this study confirms their rapid recalibration effect and shows that it occurs even when the single exposure differs in its auditory and visual features from the test stimulus. Using the same procedure in a unimodal context showed that rapid recalibration does not occur in audition following exposure to asynchronous tones of different frequencies, nor in vision following asynchronous lines differing in colour and orientation. This pattern of results suggests that rapid recalibration is in essence an inter-sensory temporal process. It serves to realign asynchronies between modalities with no selectivity for feature identity and does not operate within modalities., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We studied trends in genetic patent applications in order to identify the trends in the commercialization of research findings in genetics. To define genetic patent applications, the European version (ECLA) of the International Patent Classification (IPC) codes was used. Genetic patent applications data from the PATSTAT database from 1990 until 2009 were analyzed for time trends and regional distribution. Overall, the number of patent applications has been growing. In 2009, 152 000 patent applications were submitted under the Patent Cooperation Treaty (PCT) and within the EP (European Patent) system of the European Patent Office (EPO). The number of genetic patent applications increased until a peak was reached in the year 2000, with >8000 applications, after which it declined by almost 50%. Continents show different patterns over time, with the global peak in 2000 mainly explained by the USA and Europe, while Asia shows a stable number of >1000 per year. Nine countries together account for 98.9% of the total number of genetic patent applications. In The Netherlands, 26.7% of the genetic patent applications originate from public research institutions. After the year 2000, the number of genetic patent applications dropped significantly. Academic leadership and policy as well as patent regulations seem to have an important role in the trend differences. The ongoing investment in genetic research in the past decade is not reflected by an increase of patent applications.

Correctly perceiving the temporal order of events is essential to many tasks. Despite this, the factors constraining our ability to make timing judgments remain largely unspecified. Here we present a new phenomenon demonstrating that perceived timing of visual events may be profoundly impaired by the mere presence of irrelevant events elsewhere in the visual field. Human observers saw two abrupt luminance events presented across a range of onset asynchronies. Temporal order judgment (TOJ) just noticeable differences (JNDs) provided a behavioural index of temporal precision. When target events were presented in isolation or in static distractor environments temporal resolution was very precise (JNDs ∼20ms). However, when surrounded by dynamic distractor events, performance deteriorated more than a factor of four. This contextual effect we refer to as Remote Temporal Camouflage (RTC) operates across large spatial and temporal distances and possesses a unique spatial distribution conforming to neither the predictions of attentional capture by transient events, nor by stimulus dependencies associated with other contextual phenomena such as surround suppression, crowding, object-substitution masking or motion-induced blindness. We propose that RTC is a consequence of motion-related masking whereby irrelevant motion signals evoked by dynamic distractors interfere with TOJ-relevant target-related apparent motion. Consistent with this we also show that dynamic visual distractors do not interfere with audio-visual TOJs. Not only is RTC the most spatially extensive contextual effect ever reported, it offers vision science a new technique with which to investigate temporal order performance, free of motion-related sensory contributions., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 1992, at the request of the French labor ministry, an External Quality Control for lead in whole blood (F-EQCPbB) came into being. After 15 years (1996-2011), the ministry wished to exploit the database collected with a sufficient number of laboratories. Indeed, the number of participating laboratories had decreased from 73 to 41. However, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread of the results over the entire range of tested PbB (9 and 700 µg/l). So, it was that in laboratories having participated for >10 years, the good scores rose between 1996 and 2011 from 49% to 93%. To sum up, analysis has shown progressive and highly pronounced diminution of CVs (%) for all the ranges having undergone testing. We have observed increasing use of inductively coupled plasma with mass spectrometry (from 9% in 2005 to 29% in 2011) and decreasing use of electrothermal atomic absorption spectrometry. That said, and provided that they are based on the same degree of expertise in metrology, on all tested concentrations the two analytical techniques yield results that are not statistically different. Thanks to the F-EQCPbB, laboratories have enhanced their proficiency and registered demonstrably improved performance.

In the present study we investigate the rules governing the perception of audiovisual synchrony within spatio-temporally cluttered visual environments. Participants viewed a ring of 19 discs modulating in luminance while hearing an amplitude modulating tone. Each disc modulated with a unique temporal phase (40 ms intervals), with only one synchronized to the tone. Participants searched for the synchronised disc whose spatial location varied randomly across trials. Square-wave modulation facilitated search: the synchronized disc was frequently chosen, with tight response distributions centred near zero-phase lag. In the sinusoidal condition responses were equally distributed over the 19 discs regardless of phase. To investigate whether subjective synchrony in the square-wave condition was limited by spatial or temporal factors we repeated the experiment with either reduced spatial density (9 discs) or temporal density (80 ms phase intervals). Reduced temporal density greatly facilitated synchrony perception but left the synchrony bandwidth unchanged, while no influence of spatial density was found. We conclude that audio-visual synchrony is not strongly constrained by the spatial or temporal density of the visual display, but by a temporal window within which audio-visual events are perceived as synchronous, with a full bandwidth of ~185 ms.

Objectives: One of the hallmarks of severe pneumonia and associated acute lung injury is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and acute lung injury., Design: Controlled human and murine in vivo and ex vivo experimental studies., Setting: Research laboratory of a university hospital., Subjects: Healthy human volunteers and subjects hospitalized with bacterial and H1N1 pneumonia. C57Bl/6 and db/db mice were also used., Interventions: Lung samples from patients and mice with either bacterial or H1N1 pneumonia and associated acute lung injury were immunostained for leptin. Human bronchoalveolar lavage samples obtained after lipopolysaccharide-induced lung injury were assayed for leptin. C57Bl/6 mice were examined after oropharyngeal aspiration of recombinant leptin alone or in combination with Escherichia coli- or Klebsiella pneumoniae-induced pneumonia. Leptin-resistant (db/db) mice were also examined using the E. coli model. Bronchoalveolar lavage neutrophilia and cytokine levels were measured. Leptin-induced chemotaxis was examined in human blood- and murine marrow-derived neutrophils in vitro., Measurements and Main Results: Injured human and murine lung tissue showed leptin induction compared to normal lung, as did human bronchoalveolar lavage following lipopolysaccharide instillation. Bronchoalveolar lavage neutrophilia in uninjured and infected mice was increased and lung bacterial load decreased by airway leptin administration, whereas bronchoalveolar lavage neutrophilia in infected leptin-resistant mice was decreased. In sterile lung injury by lipopolysaccharide, leptin also appeared to decrease airspace neutrophil apoptosis. Both human and murine neutrophils migrated toward leptin in vitro, and this required intact signaling through the Janus Kinase 2/phosphatidylinositol-4,5-bisphosphate 3-kinase pathway., Conclusions: We demonstrate that pulmonary leptin is induced in injured human and murine lungs and that this cytokine is effective in driving alveolar airspace neutrophilia. This action appears to be caused by direct effects of leptin on neutrophils.

In 1992, at the request of the French labor ministry following questions on the ability of medical biology laboratories to satisfactorily measure blood lead level (PbB), a national PbB quality control came into being. Only in 1996 did this external quality control include a number of laboratories sufficient to allow for a significant retrospective evaluation. After fifteen years (1996-2011), The French National Agency for Medicines and Health Products Safety wished to exploit the database collected. The number of participating laboratories went down from 73 to 41. On the other hand, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread decrease of the results over the entire range of tested PbBs (9 to 700 μg/L). Since 2006, we have observed increasing use of the inductively coupled plasma with mass spectrometry and decreasing use of electrothermal atomic absorption spectrometry. Provided that they rely on identical metrology expertise, the two analytical techniques lead to results on all the tested concentrations that are not statistically different.

In manual choice reaction time (RT) tasks, people respond faster to a visual target stimulus when it is accompanied by a task-irrelevant tone than when it is presented alone. This intersensory facilitation effect is often attributed to multisensory integration, but here we show it to be a reflection of temporal preparation. According to this view, the more rapidly processed tone serves as a warning signal (S1), which initiates preparation for the more sluggish visual target (S2). To test this view, we varied the delay between S1 and S2 in conjunction with the modality of S1 (auditory or visual). For brief delays, responses to S2 were faster when S1 was auditory than when it was visual. Crucially, however, this intersensory facilitation effect disappeared after correction for the difference in S1-detection time, equating the effective preparation period. This shows that sound speeds response to a visual target only through preparation.

Stimuli from different sensory modalities are thought to be processed initially in distinct unisensory brain areas prior to convergence in multisensory areas. However, signals in one modality can influence the processing of signals from other modalities and recent studies suggest this cross-modal influence may occur early on, even in 'unisensory' areas. Some recent psychophysical studies have shown specific cross-modal effects between touch and vision during binocular rivalry, but these cannot completely rule out a response bias. To test for genuine cross-modal integration of haptic and visual signals, we investigated whether congruent haptic input could influence visual contrast sensitivity compared to incongruent haptic input in three psychophysical experiments using a two-interval, two-alternative forced-choice method to eliminate response bias. The initial experiment demonstrated that contrast thresholds for a visual grating were lower when exploring a haptic grating that shared the same orientation compared to an orthogonal orientation. Two subsequent experiments mapped the orientation and spatial frequency tunings for the congruent haptic facilitation of vision, finding a clear orientation tuning effect but not a spatial frequency tuning. In addition to an increased contrast sensitivity for iso-oriented visual-haptic gratings, we found a significant loss of sensitivity for orthogonally oriented visual-haptic gratings. We conclude that the tactile influence on vision is a result of a tactile input to orientation-tuned visual areas.

We examined the time course of temporal preparation in the practice of computer gaming. Participants held an infrared rifle to shoot animated figures ("terrorists") that appeared from an elevator that opened briefly after the sound of a bell. The sound was either loud or soft and the interval between the sound and the opening of the elevator varied between 100 and 600ms. We found that shooting latency decreased exponentially as a function of interval, reflecting growing temporal preparation towards an optimum. When the sound was soft, this function was shifted to the right as compared to when the sound was loud. These findings are consistent with a model assuming that preparation starts upon the detection of a warning (i.e., later for the soft than for the loud sound) and continues until the detection of a target (i.e., longer as the interval increases). These results signify a successful application of a theoretical model in an applied setting., (© 2013.)

Recently, Guzman-Martinez, Ortega, Grabowecky, Mossbridge, and Suzuki (Current Biology : CB, 22(5), 383-388, 2012) reported that observers could systematically match auditory amplitude modulations and tactile amplitude modulations to visual spatial frequencies, proposing that these cross-modal matches produced automatic attentional effects. Using a series of visual search tasks, we investigated whether informative auditory, tactile, or bimodal cues can guide attention toward a visual Gabor of matched spatial frequency (among others with different spatial frequencies). These cues improved visual search for some but not all frequencies. Auditory cues improved search only for the lowest and highest spatial frequencies, whereas tactile cues were more effective and frequency specific, although less effective than visual cues. Importantly, although tactile cues could produce efficient search when informative, they had no effect when uninformative. This suggests that cross-modal frequency matching occurs at a cognitive rather than sensory level and, therefore, influences visual search through voluntary, goal-directed behavior, rather than automatic attentional capture.

Mounting evidence suggests that obesity and the metabolic syndrome have significant but often divergent effects on the innate immune system. These effects have been best established in monocytes and macrophages, particularly as a consequence of the hypercholesterolemic state. We have recently described defects in neutrophil function in the setting of both obesity and hypercholesterolemia, and hypothesized that exposure to elevated levels of lipoproteins, particularly LDL its oxidized forms, contributed to these defects. As a model of chronic cholesterol exposure, we examined functional responses of bone marrow neutrophils isolated from non-obese mice with diet-induced hypercholesterolemia compared to normal cholesterol controls. Chemotaxis, calcium flux, CD11b display, and F-actin polymerization were assayed in response to several chemoattractants, while neutrophil cytokine transcriptional response was determined to LPS. Following this, the acute effects of isolated LDL and its oxidized forms on normal neutrophils were assayed using the same functional assays. We found that neutrophils from non-obese hypercholesterolemic mice had blunted chemotaxis, altered calcium flux, and normal to augmented CD11b display with prolonged actin polymerization in response to stimuli. In response to acute exposure to lipoproteins, neutrophils showed chemotaxis to LDL which increased with the degree of LDL oxidation. Paradoxically, LDL oxidation yielded the opposite effect on LDL-induced CD11b display and actin polymerization, and both native and oxidized LDL were found to induce neutrophil transcription of the monocyte chemoattractant MCP-1. Together these findings suggest that chronic hypercholesterolemia impairs neutrophil functional responses, and these defects may be in part due to protracted signaling responses to LDL and its oxidized forms., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Mitochondria are the main engine that generates ATP through oxidative phosphorylation within the respiratory chain. Mitochondrial respiration is regulated according to the metabolic needs of cells and can be modulated in response to metabolic changes. Little is known about the mechanisms that regulate this process. Here, we identify MCJ/DnaJC15 as a distinct cochaperone that localizes at the mitochondrial inner membrane, where it interacts preferentially with complex I of the electron transfer chain. We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain. The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production. Although MCJ is dispensable for mitochondrial function under normal physiological conditions, MCJ deficiency affects the pathophysiology resulting from metabolic alterations. Thus, enhanced mitochondrial respiration in the absence of MCJ prevents the pathological accumulation of lipids in the liver in response to both fasting and a high-cholesterol diet. Impaired expression or loss of MCJ expression may therefore result in a "rapid" metabolism that mitigates the consequences of metabolic disorders.

The human visual attention system is geared toward detecting the most salient and relevant events in an overwhelming stream of information. There has been great interest in measuring how many visual events can be processed at a time, and most of the work has suggested that the limit is three to four. However, attention to a visual stimulus can also be driven by a synchronous auditory event. The present work indicates that a fundamentally different limit applies to audiovisual processing, such that at most only a single audiovisual event can be processed at a time. This limited capacity is not due to a limitation in visual selection; participants were able to process about four visual objects simultaneously. Instead, we propose that audiovisual orienting is subject to a fundamentally different capacity limit than pure visual selection is.

In the present study we investigated whether a task-irrelevant distractor can induce a visual attentional blink pattern. Participants were asked to detect only a visual target letter (A, B, or C) and to ignore the preceding auditory, visual, or audiovisual distractor. An attentional blink was observed regardless of the distractor modality. The magnitude of the attentional blink was greater when the target was preceded by a visual or an audiovisual distractor than when the target letter was preceded by an auditory distractor. The presence of a distractor-induced attentional blink regardless of the distractor modality suggests that the attentional blink phenomenon is at least partly due to an amodal processing limitation.

Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response.

The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy., (©2012 AACR)

Visual search is markedly improved when a target color change is synchronized with a spatially non-informative auditory signal. This "pip and pop" effect is an automatic process as even a distractor captures attention when accompanied by a tone. Previous studies investigating visual attention have indicated that automatic capture is susceptible to the size of the attentional window. The present study investigated whether the pip and pop effect is modulated by the extent to which participants divide their attention across the visual field We show that participants were better in detecting a synchronized audiovisual event when they divided their attention across the visual field relative to a condition in which they focused their attention. We argue that audiovisual capture is reduced under focused conditions relative to distributed settings.

Rapid visual flicker is known to capture attention. Here we show slow flicker can also capture attention under reciprocal temporal conditions. Observers searched for a target line (vertical or horizontal) among tilted distractors. Distractor lines were surrounded by luminance modulating annuli, all flickering sinusoidally at 1.3 or 12.1 Hz, while the target's annulus flickered at frequencies within this range. Search times improved with increasing target/distractor frequency differences. For target-distractor frequency separations >5 Hz reaction times were minimal with high-frequency targets correctly identified more rapidly than low frequency targets (~400 ms). Critically, however, at these optimal frequency separations search times for low and high-frequency targets were unaffected by set size (slow flicker popped out from high flicker, and vice versa), indicating parallel and symmetric search performance when searching for high or low frequency targets. In a "cost" experiment using 1.3 and 12.1 Hz flicker, the unique flickering annulus sometimes surrounded a distractor and, on other trials, surrounded the target. When centered on a distractor, the unique frequency produced a clear and symmetrical search cost. Together, these symmetric pop-out and search costs demonstrate that temporal frequency is a pre-attentive visual feature capable of capturing attention, and that it is relative rather than absolute frequencies that are critical. The shape of the search functions strongly suggest that early visual temporal frequency filters underlie these effects.

Central amygdala (CeA) projections to hypothalamic and brain stem nuclei regulate the behavioral and physiological expression of fear, but it is unknown whether these different aspects of the fear response can be separately regulated by the CeA. We combined fluorescent retrograde tracing of CeA projections to nuclei that modulate fear-related freezing or cardiovascular responses with in vitro electrophysiological recordings and with in vivo monitoring of related behavioral and physiological parameters. CeA projections emerged from separate neuronal populations with different electrophysiological characteristics and different response properties to oxytocin. In vivo, oxytocin decreased freezing responses in fear-conditioned rats without affecting the cardiovascular response. Thus, neuropeptidergic signaling can modulate the CeA outputs through separate neuronal circuits and thereby individually steer the various aspects of the fear response.

Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30-40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10-15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.