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Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access) We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Supplementary methods

Summary of all validated variants identified by exome sequencing. Patterned shading indicates duplicate adenomas.

Pre- and Post-validation protein altering somatic variants identified by whole exome sequencing.

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721–32. ©2017 AACR.

Summary of the 62 recurrently mutated genes in the exome dataset (supplementary table 2) and the number of mutations identified in each gene. Total numbers of variants in each gene take into account any mutations identified in duplicate adenomas.

Database of somatic APC mutations reported in FAP and MAP duodenal and colorectal adenomas. NA, Not available. NI, Not identified

Histogram showing number of validated protein changing somatic variants identified per adenoma.

Although previous work provides evidence that observers experience biases in visual processing when they view stimuli in perihand space, a few recent investigations have questioned the reliability ...

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequenced normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 5-fold in all individuals, except for one showing a 33-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C>A changes. Different mutation rates and signatures between individuals were likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.Summary

Inhibition of return (IOR) is thought to reflect a cognitive mechanism that biases attention from returning to previously engaged items. While models of cognitive aging have proposed deficits within select inhibitory domains, older adults have demonstrated preserved IOR functioning in previous studies. The present study investigated whether inhibition associated with objects shows the same age patterns as inhibition associated with locations. Young adults (18–22 years) and older adults (60–86 years) were tested in two experiments measuring location- and object-based IOR. Using a dynamic paradigm (Experiment 1), both age groups produced significant location-based IOR, but only young adults produced significant object-based IOR, consistent with previous findings. However, with a static paradigm (Experiment 2), young adults and older adults produced both location- and object-based IOR, indicating that object-based IOR is preserved in older adults under some conditions. The findings provide partial support for unique age-related inhibitory patterns associated with attention to objects and locations.

Discovering how certain health factors contribute to functional declines may help to promote successful aging. To determine the independent and joint associations of handgrip strength (HGS) and cognitive function with instrumental activities of daily living (IADL) and activities of daily living (ADL) disability decline in aging Americans. Data from 18,391 adults aged 50 years and over who participated in at least one wave of the 2006–2014 waves of the Health and Retirement Study were analyzed. A hand-held dynamometer assessed HGS and cognitive functioning was examined with a modified version of the Telephone Interview of Cognitive Status. IADL and ADL abilities were self-reported. Participants were stratified into four distinct groups based on their HGS and cognitive function status. Separate covariate-adjusted multilevel models were conducted for the analyses. Participants who were weak, had a cognitive impairment, and had both weakness and a cognitive impairment had 1.70 (95% confidence interval (CI) 1.57–1.84), 1.97 (CI 1.74–2.23), and 3.13 (CI 2.73–3.59) greater odds for IADL disability decline, respectively, and 2.26 (CI 2.03–2.51), 1.26 (CI 1.05–1.51), and 4.48 (CI 3.72–5.39) greater odds for ADL disability decline, respectively. HGS and cognitive functioning were independently and jointly associated with IADL and ADL disability declines. Individuals with both weakness and cognitive impairment demonstrated substantially higher odds for functional decline than those with either risk factor alone. Including measures of both HGS and cognitive functioning in routine geriatric assessments may help to identify those at greatest risk for declining functional capacity.

Recent evidence has demonstrated that observers experience visual-processing biases in perihand space that may be tied to the hands' relevance for grasping actions. Our previous work suggested that when the hands are positioned to afford a power-grasp action, observers show increased temporal sensitivity that could aid with fast and forceful action, whereas when the hands are instead at the ready to perform a precision-grasp action, observers show enhanced spatial sensitivity that benefits delicate and detail-oriented actions. In the present investigation we seek to extend these previous findings by examining how object affordances may interact with hand positioning to shape visual biases in perihand space. Across three experiments, we examined how long participants took to perform a change detection task on photos of real objects, while we manipulated hand position (near/far from display), grasp posture (power/precision), and change type (orientation/identity). Participants viewed objects that afforded either a power grasp or a precision grasp, or were ungraspable. Although we were unable to uncover evidence of altered vision in perihand space in our first experiment, mirroring previous findings, in Experiments 2 and 3 our participants showed grasp-dependent biases near the hands when detecting changes to target objects that afforded a power grasp. Interestingly, ungraspable target objects were not subject to the same perihand space biases. Taken together, our results suggest that the influence of hand position on change detection performance is mediated not only by the hands' grasp posture, but also by a target object's affordances for grasping.

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero. ispartof: Psychonomic Bulletin & Review vol:29 issue:2 pages:613-626 ispartof: location:United States status: published

Although duodenal adenomas and cancer appear to occur significantly less frequently in autosomal recessive MUTYH-associated polyposis (MAP) than in autosomal dominant familial adenomatous polyposis (FAP),1 current guidelines recommend similar endoscopic surveillance for both disorders.2-4 This involves gastro-duodenoscopy starting at 25 to 35 years of age and repeated at intervals determined by Spigelman staging based on the number, size, histological type and degree of dysplasia of adenomas, and by ampullary staging. Case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced Spigelman stage benign disease and even without coexisting adenomas.1 Recent molecular analyses suggest thatMAPduodenal adenomashave a higher mutational burden than FAP adenomas and are more likely to harbor oncogenic drivermutations, such as those in KRAS.5 These apparent differences in the biology and natural history of duodenal polyposis in FAP and MAP challenge the assumption that the same surveillance should be applied in both conditions.

Psychological phenomena are embodied to the extent that bodily processes (whether perceptual, expressive, or action-oriented) contribute to them. A great deal of research, most of which has occurred in the past several decades, has revealed that embodied influences are seemingly ubiquitous and findings of this type have led to the suggestion that embodiment is foundational to the manner in which individuals think, feel, and act. In the present introductory chapter, phenomena of this type are initially reviewed in outlining the scope of enquiry. Subsequently, five major theoretical perspectives on embodiment are summarized as well as briefly compared and contrasted with each other. After a discussion of key questions and directions for research, the chapter introduces the content of the book, which consists of four sections related to Theoretical Foundations, Cognitive and Neuroscience Perspectives, Social and Personality Perspectives, and Current Issues and Future Directions. Although the book concentrates on the areas of cognitive and social psychology, it does so in broad terms, such that some of the chapters approach their content from ecological, philosophical, developmental, clinical, or evolutionary viewpoints. Thus, the volume is comprehensive and should appeal to multiple audiences.

Summary Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling., Graphical Abstract, Highlights • G3BPs act non-redundantly in the TSC-mTORC1 signaling axis • G3BPs reside at the lysosomal surface and inhibit mTORC1 • The TSC complex requires G3BPs as its lysosomal tether • G3BP1 deficiency phenocopies TSC complex loss in cancer cells and neurons, Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.

Previous studies have shown that after actively using a handheld tool for a period of time, participants show visual biases toward stimuli presented near the end of the tool. Research suggests this is driven by an incorporation of the tool into the observer’s body schema, extending peripersonal space to surround the tool. This study aims to investigate whether the same visual biases might be seen near remotely operated tools. Participants used tools—a handheld rake (Experiment 1), a remote-controlled drone (Experiment 2), a remote-controlled excavator (Experiment 3), or a handheld excavator (Experiment 4)—to rake sand for several minutes, then performed a target-detection task in which they made speeded responses to targets appearing near and far from the tool. In Experiment 1, participants detected targets appearing near the rake significantly faster than targets appearing far from the rake, replicating previous findings. We failed to find strong evidence of improved target detection near remotely operated tools in Experiments 2 and 3, but found clear evidence of near-tool facilitation in Experiment 4 when participants physically picked up the excavator and used it as a handheld tool. These results suggest that observers may not incorporate remotely operated tools into the body schema in the same manner as handheld tools. We discuss potential mechanisms that may drive these differences in embodiment between handheld and remote-controlled tools.

During stress, attentional capture by threatening stimuli may be particularly adaptive. Individuals are more efficient at identifying threatening faces in a crowd than identifying nonthreatening faces (e.g., Öhman et al., Journal of Experimental Psychology: General, 130(3): 466-478, 2001a, Öhman et al., Journal of Personality and Social Psychology, 80(3): 381-396, 2001b). However, under conditions of stress, when attention to threat may be most critical, cognitive processes are generally disrupted. The present study explored the attentional advantage of threatening stimuli under stressful conditions. We exposed participants to either high or low stress conditions during a visual search task displaying threatening and nonthreatening facial targets among distractors. Participants' accuracy, reaction times, and self-reported stress were measured. Stress introduced a speed-accuracy trade-off: participants in the high-stress condition were faster, but less accurate, than participants in the low-stress condition. Although both groups of participants showed relative performance advantages in detecting threatening compared with nonthreatening stimuli, this advantage was markedly larger for participants in the high-stress condition. This suggests that the established stress-mediated increase in the activity of the ventral neural network responsible for the reorienting of attention may have enhanced the ability to detect threatening stimuli or buffered the disruptive effects of stress on this process. Our findings highlight the potentially adaptive nature of stress disruption on attentional processes and align research on the anger superiority effect and automated attentional processes under stress.

Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic variants in the APC gene. Index patients with suspected FAP are usually investigated by APC coding region sequence and dosage analysis in a clinical diagnostic setting. The identification of an APC variant which is predicted to alter protein function enables predictive genetic testing to guide the management of family members. This report describes a 4-generation family with a phenotype consistent with FAP, but in which an APC variant had not been identified, despite testing. To explore this further, quantitative PCR (qPCR) was employed to assess APC transcription, demonstrating reduced levels of APC RNA. Next generation sequencing (NGS) identified the APC 5′UTR/ Exon 1 variant, c.-190 G>A, that had been reported previously in an another FAP family with APC allelic imbalance. Quantitative RNA studies and DNA sequencing of the APC promoters/ Exon 1 may be useful diagnostically for patients with suspected FAP when coding region variants cannot be identified.

Observers experience affordance-specific biases in visual processing for objects within the hands’ grasping space, but the mechanism that tunes visual cognition to facilitate action remains unknown. I investigated the hypothesis that altered vision near the hands is a result of experience-driven plasticity. Participants performed motion-detection and form-perception tasks—while their hands were either near the display, in atypical grasping postures, or positioned in their laps—both before and after learning novel grasp affordances. Participants showed enhanced temporal sensitivity for stimuli viewed near the backs of the hands after training to execute a power grasp using the backs of their hands (Experiment 1), but showed enhanced spatial sensitivity for stimuli viewed near the tips of their little fingers after training to use their little fingers to execute a precision grasp (Experiment 2). These results show that visual biases near the hands are plastic, facilitating processing of information relevant to learned grasp affordances.

Observers show biases in attention when viewing objects within versus outside of their hands' grasping space. While the hands' proximity to stimuli plays a key role in these effects, recent evidence suggests an observer's affordances for grasping actions also shape visual processing near the hands. The current study examined the relative contributions of proximity and affordances in introducing attentional biases in peripersonal space. Participants placed a single hand on a visual display and detected targets appearing near or far from the hand. Across conditions, the hand was either free, creating an affordance for a grasping action, or immobilized using an orthosis, interfering with the potential to grasp. Replicating previous findings, participants detected targets appearing near the hand more quickly than targets appearing far from the hand. Immobilizing the hands did not disrupt this effect, suggesting that proximity alone is sufficient to facilitate target detection in peripersonal space.

Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.

Observers experience biases in visual processing for objects within easy reach of their hands; these biases may assist them in evaluating items that are candidates for action. I investigated the hypothesis that hand postures that afford different types of actions differentially bias vision. Across three experiments, participants performed global-motion-detection and global-form-perception tasks while their hands were positioned (a) near the display in a posture affording a power grasp, (b) near the display in a posture affording a precision grasp, or (c) in their laps. Although the power-grasp posture facilitated performance on the motion-detection task, the precision-grasp posture instead facilitated performance on the form-perception task. These results suggest that the visual system weights processing on the basis of an observer’s current affordances for specific actions: Fast and forceful power grasps enhance temporal sensitivity, whereas detail-oriented precision grasps enhance spatial sensitivity.

Background and Aims\ud \ud Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, with 5% developing cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score--incorporating polyp number, size, dysplasia, and histology--for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP.\ud \ud \ud Methods\ud \ud A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff and St Mark's Hospital, London) from 2011 to 2014.\ud \ud \ud Results\ud \ud Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (p=0.013) and FAP (p=0.002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP.\ud \ud \ud Conclusions\ud \ud Chromoendoscopy improved the diagnostic yield of adenomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis.

People physically distance themselves from competitors and the disliked and cooperate less with those who are further away. We examine whether social interaction can also impact the space people perceive between themselves and others by measuring the influence of competitive dynamics on visual perception. In two experiments, participants played a ball toss game until they reached a target score. In Experiment 1, a confederate stood across the room from the participant and either a) played the same game competitively, b) played the same game cooperatively, or c) observed the participant without playing, while in Experiment 2, two participants played the same versions of the game with each other. After the game, participants provided an estimate of the distance between themselves and the other player. Participants in Experiment 1 who competed with the confederate consistently judged her to be more distant than participants who cooperated with the confederate or played alone. In Experiment 2, players who lost the competition perceived more distance between themselves and their opponents than did players who won, suggesting that the experience of losing a competition drives this perceptual distancing. These findings demonstrate the power of a socially distancing interaction to create perceptual distance between people.

Objects that serve as extensions of the body can produce a sensation of embodiment, feeling as if they are a part of us. We investigated the characteristics that drive an object's embodiment, examining whether cast-body shadows, a purely visual stimulus, are embodied. Tools are represented as an extension of the body when they enable observers to interact with distant targets, perceptually distorting space. We examined whether perceptual distortion would also result from exposure to cast-body shadows in two separate distance estimation perceptual matching tasks. If observers represent cast-body shadows as extensions of their bodies, then when these shadows extend toward a target, it should appear closer than when no shadow is present (Experiment 1). This effect should not occur when a non-cast-body shadow is cast toward a target (Experiment 2). We found perceptual distortions in both cast-body shadow and tool-use conditions, but not in our non-cast-body shadow condition. These results suggest that, although cast-body shadows do not enable interaction with objects or provide direct tactile feedback, observers nonetheless represent their shadows as if they were a part of them.

When people manipulate a moving object, such as writing with a pen or driving a car, they experience their actions as intimately related to the object’s motion, that is they perceive control. Here, we tested the hypothesis that observers would feel more control over a moving object if an unrelated task drew attention to a location to which the object subsequently moved. Participants steered an object within a narrow path and discriminated the color of a flash that appeared briefly close to the object. Across two experiments, participants provided higher ratings of perceived control when an object moved over a flash’s location than when an object moved away from a flash’s location. This result suggests that we use the location of spatial attention to determine the perception of control. If an object goes where we are attending, we feel like we made it go there.

Objects in peripersonal space are of great importance for interaction with the sensory world. A variety of research exploring sensory processing in peripersonal space has produced extensive evidence for altered vision near the hands. However, visual representations of the peripersonal space surrounding the feet remain unexplored. In a set of four experiments, we investigated whether observers experience biases in visual processing for objects near the feet that mirror the alterations associated with near-hand space. Participants performed attentional-cueing tasks in which they detected targets appearing (1) near or far from a single visible foot, (2) near one of two visible feet, (3) near or far from a nonfoot visual anchor, or (4) near or far from an occluded foot. We found a temporal cost associated with detecting targets appearing far from a visible foot, but no biases were associated with targets appearing near versus far from either a nonfoot visual anchor or an occluded foot. These results provide the first evidence suggesting that objects within stepping or kicking distance are processed differently from objects outside of peripersonal foot space.

Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P=0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (P

Neurofibromatosis type 1, (NF1) is a complex, autosomal dominant disorder characterized by benign and malignant tumors which result from NF1 gene mutations. The molecular mechanisms that underlie NF1 tumorigenesis are still poorly understood although inactivation of other modifying loci in conjunction with NF1 mutations is postulated to be involved. These modifying loci may include deficiencies in mismatch repair genes and elements involved in cell cycle regulation (TP53, RB1, and CDKN2A). We have analyzed the somatic mutations in 89 cutaneous neurofibromas derived from three unrelated NF1 patients with high tumor burden, by loss of heterozygosity (LOH) analysis of the NF1, TP53, RB1, and CDKN2A genes, by assessing microsatellite instability (MSI), by direct sequencing of the NF1, TP53, and several mismatch repair (MMR) genes and by multiplex ligation-dependent probe amplification of the NF1 and TP53 genes. The aim was both to assess the possible clonality of these tumors and also to assess the involvement of other potential genetic loci in the development of these neurofibromas. Somatic NF1 mutations were identified in 57 (64%) of neurofibroma samples. Each mutation was distinct demonstrating the independent origin of each tumor. While somatic LOH of the TP53 gene was identified in four tumors, no specific deletions or sequence variations were identified. LOH of markers flanking the RB1 gene was also found in one tumor but no CDKN2A mutations were detected. Although evidence of MSI was seen in 21 tumors, no MMR gene alterations were identified. The identification of LOH involving TP53 and RB1 loci is a novel finding in benign cutaneous neurofibromas possibly demonstrating an alternative underlying molecular mechanism associated with the development of these benign tumors from this cohort of patients.

Can directed actions unconsciously influence higher order cognitive processing? We investigated how movement interventions affected participants' ability to solve a classic insight problem. The participants attempted to solve Maier's two-string problem while occasionally taking exercise breaks during which they moved their arms either in a manner related to the problem's solution (swing group) or in a manner inconsistent with the solution (stretch group). Although most of the participants were unaware of the relationship between their arm movement exercises and the problem-solving task, the participants who moved their arms in a manner that suggested the problem's solution were more likely to solve the problem than were those who moved their arms in other ways. Consistent with embodied theories of cognition, these findings show that actions influence thought and, furthermore, that we can implicitly guide people toward insight by directing their actions.

Previous research shows that directed actions can unconsciously influence higher-order cognitive processing, helping learners to retain knowledge and guiding problem solvers to useful insights (e.g. Cook, S. W., Mitchell, Z., & Goldin-Meadow, S. (2008). Gesturing makes learning last. Cognition, 106, 1047-1058; Thomas, L. E., & Lleras, A. (2007). Moving eyes and moving thought: on the spatial compatibility between eye movements and cognition. Psychonomic Bulletin and Review, 14, 663-668). We examined whether overt physical movement is necessary for these embodied effects on cognition, or whether covert shifts of attention are sufficient to influence cognition. We asked participants to try to solve Duncker's radiation problem while occasionally directing them, via an unrelated digit-tracking task, to shift their attention (while keeping their eyes fixed) in a pattern related to the problem's solution, to move their eyes in this pattern, or to keep their eyes and their attention fixed in the center of the display. Although they reported being unaware of any relationship between the digit-tracking task and the radiation problem, participants in both the eye-movement and attention-shift groups were more likely to solve the problem than were participants who maintained fixation. Our results show that by shifting attention in a pattern compatible with a problem's solution, we can aid participants' insight even in the absence of overt physical movements.

Grant and Spivey (2003) proposed that eye movement trajectories can influence spatial reasoning by way of an implicit eye-movement-to-cognition link. We tested this proposal and investigated the nature of this link by continuously monitoring eye movements and asking participants to perform a problem-solving task under free-viewing conditions while occasionally guiding their eye movements (via an unrelated tracking task), either in a pattern related to the problem's solution or in unrelated patterns. Although participants reported that they were not aware of any relationship between the tracking task and the problem, those who moved their eyes in a pattern related to the problem's solution were the most successful problem solvers. Our results support the existence of an implicit compatibility between spatial cognition and the eye movement patterns that people use to examine a scene.

People use facial appearance to predict social behavior, but can social context also influence face perception? Leveraging a link between competition and aggression, we investigated the effects of competitive interactions with confederates on participants’ performance in a face reconstruction task. Participants played a game either in competition or cooperation with confederates and were then asked to create facial portraits of these confederates by arranging their component features into their best estimate of an accurate configuration. Across 2 experiments, participants who played in a competitive context reconstructed faces in a more aggressive configuration—with higher width-to-height ratios—than did participants who played cooperatively or alone. This result demonstrates that the social perception of faces is not merely a feed-forward process, but instead that the social contexts in which people interact can shape memory for faces.

Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxia-inducible factor (HIF)1α, HIF2α, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1α ablated these oncogenic facets of STAT3. Implications: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1α/VEGF-A signaling axis is a viable treatment strategy. Mol Cancer Res; 13(7); 1149–60. ©2015 AACR.

Building on a well-established link between elevation and social power, we demonstrate that—when perceptual information is limited—subtle visual cues can shape people’s representations of others and, in turn, alter strategic social behavior. A cue to elevation (unrelated to physical size) provided by the placement of web cameras in a video chat biased individuals’ perceptions of a partner’s height (Experiment 1) and shaped the extent to which they made decisions in their own self-interest: participants tended to coordinate their behavior in a manner that benefitted the preferences of a partner pictured from a low camera angle during a game of asymmetric coordination (Experiment 2). Our results suggest that people are vulnerable to the influence of a limited viewpoint when forming representations of others in a manner that shapes their strategic choices.

Inhibition of return (IOR) has long been viewed as a foraging facilitator in visual search. We investigated the contribution of IOR in a task that approximates natural foraging more closely than typical visual search tasks. Participants in a fully immersive virtual reality environment manually searched an array of leaves for a hidden piece of fruit, using a wand to select and examine each leaf location. Search was slower than in typical IOR paradigms, taking seconds instead of a few hundred milliseconds. Participants also made a speeded response when they detected a flashing leaf that either was or was not in a previously searched location. Responses were slower when the flashing leaf was in a previously searched location than when it was in an unvisited location. These results generalize IOR to an approximation of a naturalistic visual search setting and support the hypothesis that IOR can facilitate foraging. The experiment also constitutes the first use of a fully immersive virtual reality display in the study of IOR.

Models of spatial updating attempt to explain how representations of spatial relationships between the actor and objects in the environment change as the actor moves. In allocentric models, object locations are encoded in an external reference frame, and only the actor's position and orientation in that reference frame need to be updated. Thus, spatial updating should be independent of the number of objects in the environment (set size). In egocentric updating models, object locations are encoded relative to the actor, so the location of each object relative to the actor must be updated as the actor moves. Thus, spatial updating efficiency should depend on set size. We examined which model better accounts for human spatial updating by having people reconstruct the locations of varying numbers of virtual objects either from the original study position or from a changed viewing position. In consistency with the egocentric updating model, object localization following a viewpoint change was affected by the number of objects in the environment.

Directed actions can play a causal role in cognition, shaping thought processes. What drives this cross-talk between action and thought? I investigated the hypothesis that representations in spatial working memory mediate interactions between directed actions and problem solving. Participants attempted to solve an insight problem while occasionally either moving their eyes in a pattern embodying the problem's solution or maintaining fixation. They simultaneously held either a spatial or verbal stimulus in working memory. Participants who moved their eyes in a pattern that embodied the solution were more likely to solve the problem, but only while also performing a verbal working memory task. Embodied guidance of insight was eliminated when participants were instead engaged in a spatial working memory task while moving their eyes, implying that loading spatial working memory prevented movement representations from influencing problem solving. These results point to spatial working memory as a mechanism driving embodied guidance of insight, suggesting that actions do not automatically influence problem solving. Instead, cross-talk between action and higher order cognition requires representations in spatial working memory.

Previous research has shown that attention is prioritized for the space near the hand, leading to faster detection of visual targets appearing close to one's own hand. In the present study, we examined whether observers are also facilitated in detecting targets presented near another's hand by having participants perform a Posner cueing task while sitting next to a friend. Across blocks, either the participant or the friend placed a hand next to one of the target locations. Our results robustly showed that participants detected targets appearing near their own hands more quickly than targets appearing away from their hands, replicating previous work demonstrating that spatial attention is prioritized near one's own hand (Experiments 1–4). No such attentional bias effects were found for targets appearing near the friend's hand, suggesting that spatial attention is not automatically prioritized near another's hand (Experiments 1 and 2). However, participants were faster to detect targets near the friend's hand following a joint action task, suggesting a shared body representation plays an influential role in biasing attention to the space near another's hand (Experiment 4).