Multisensory perception constrains the formation of object categories: a review of evidence from sensory-driven and predictive processes on categorical decisions.

Although object categorization is a fundamental cognitive ability, it is also a complex process going beyond the perception and organization of sensory stimulation. Here we review existing evidence about how the human brain acquires and organizes multisensory inputs into object representations that may lead to conceptual knowledge in memory. We first focus on evidence for two processes on object perception, multisensory integration of redundant information (e.g. seeing and feeling a shape) and crossmodal, statistical learning of complementary information (e.g. the 'moo' sound of a cow and its visual shape). For both processes, the importance attributed to each sensory input in constructing a multisensory representation of an object depends on the working range of the specific sensory modality, the relative reliability or distinctiveness of the encoded information and top-down predictions. Moreover, apart from sensory-driven influences on perception, the acquisition of featural information across modalities can affect semantic memory and, in turn, influence category decisions. In sum, we argue that both multisensory processes independently constrain the formation of object categories across the lifespan, possibly through early and late integration mechanisms, respectively, to allow us to efficiently achieve the everyday, but remarkable, ability of recognizing objects. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

Longitudinal grip strength is associated with susceptibility to the Sound Induced Flash Illusion in older adults.

The precision of temporal multisensory integration is associated with specific aspects of physical functioning in ageing, including gait speed and incidents of falling. However, it is unknown if such an association exists between multisensory integration and grip strength, an important index of frailty and brain health and predictor of disease and mortality in older adults. Here, we investigated whether temporal multisensory integration is associated with longitudinal (eight-year) grip strength trajectories in a large sample of 2,061 older adults (mean age = 64.42 years, SD = 7.20; 52% female) drawn from The Irish Longitudinal Study on Ageing (TILDA). Grip strength (kg) for the dominant hand was assessed with a hand-held dynamometer across four testing waves. Longitudinal k-means clustering was applied to these data separately for sex (male, female) and age group (50-64, 65-74, 75+ years). At wave 3, older adults participated in the Sound Induced Flash Illusion (SIFI), a measure of the precision of temporal audio-visual integration, which included three audio-visual stimulus onset asynchronies (SOAs): 70, 150 and 230 ms. Results showed that older adults with a relatively lower (i.e., weaker) grip strength were more susceptible to the SIFI at the longer SOAs compared to those with a relatively higher (i.e., stronger) grip strength (p <.001). These novel findings suggest that older adults with relatively weaker grip strength exhibit an expanded temporal binding window for audio-visual events, possibly reflecting a reduction in the integrity of the central nervous system.

Older adults with slow sit to stand times show reduced temporal precision of audio-visual integration.

Sustained integration of sensory inputs over increased temporal delays is associated with reduced cognitive and physical functioning in older adults and adverse outcomes such as falls. Here, we explored the relationship between multisensory integration and a clinically relevant measure of balance/postural control; Sit-to-Stand Time, the efficiency with which an older adult can transition between a seated and a standing posture. We investigated whether temporal multisensory integration was associated with performance on the Five-Times Sit-to-Stand Test (FTSST) in a large sample of 2556 older adults (mean age = 63.62 years, SD = 7.50; 55% female) drawn from The Irish Longitudinal Study on Ageing (TILDA). K-means clustering was applied to FTSST data, yielding three clusters characterised by fast (mean = 10.88 s; n = 1122), medium (mean = 14.34 s; n = 1133) and slow (mean = 18.97 s; n = 301) sit-to-stand times. At wave 3 of TILDA, older adults participated in the Sound Induced Flash Illusion (SIFI), a measure of the precision of temporal audio-visual integration, which included three audio-visual stimulus onset asynchronies (SOAs): 70, 150 and 230 ms. Older adults with the slowest sit-to-stand times were more susceptible to the SIFI at the longest SOA (230 ms) compared to the shortest SOA (70 ms) relative to those with the fastest times (p = 0.02). Older adults who take longer to repeatedly transition from a seated to a standing posture exhibit an expanded temporal binding window for audio-visual events, supporting a link between multisensory perception and balance/postural control in ageing.

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance. PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel. RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent. CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Self-reported vividness of tactile imagery for object properties and body regions: An exploratory study.

Mental imagery ability has been examined principally in the visual domain. Despite evidence for tactile mental representations in the absence of direct stimulation, this ability is poorly understood. We investigated tactile imagery for both active and passive tasks in a large sample (N = 118). Vividness of imagery was tested across two different tasks: somatosensory imagery (of body sensitivity) and tactile imagery (of object properties) in all participants. Evidence for vivid imagery across tactile and somatosensory dimensions was found with a positive, albeit weak, correlation in imagery strength between dimensions. Imagery ratings varied across objects and object properties in the tactile imagery task and across body sites in the somatosensory imagery task. These findings shed light on the capacity for, and characteristics of, tactile mental imagery in the general population and suggest that the ability to experience vivid tactile mental images may mediate performance across a number of perceptual tasks.

The rubber hand illusion is influenced by self-recognition.

Susceptibility to the Rubber Hand Illusion (RHI) demonstrates that body ownership can be modulated by visuotactile inputs. In contrast to body-like images, other objects cannot be embodied suggesting that crossmodal interactions on body ownership are based on a 'goodness-of-fit' mechanism relative to one's own body. However, it is not clear whether visual self-recognition influences susceptibility to the RHI, although evidence for individual differences in the perceptual body image on the RHI suggests that this may be the case. We investigated the role of self-recognition on the subjective experience of the RHI and measured proprioceptive drift and onset time of the RHI between two groups, one with the ability to identify an image of their own hand and the other without this ability. A typical RHI response was found overall with no group difference in the subjective experience of the RHI. However, a larger proprioceptive drift and an earlier onset time for the RHI was found for the non-recognisers than the self-recognition group. Our findings provide evidence for a link between a visual representation of one's own body in long-term memory and plasticity of the body representation.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism.

BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

Distinctive voices enhance the visual recognition of unfamiliar faces.

Several studies have provided evidence in favour of a norm-based representation of faces in memory. However, such models have hitherto failed to take account of how other person-relevant information affects face recognition performance. Here we investigated whether distinctive or typical auditory stimuli affect the subsequent recognition of previously unfamiliar faces and whether the type of auditory stimulus matters. In this study participants learned to associate either unfamiliar distinctive and typical voices or unfamiliar distinctive and typical sounds to unfamiliar faces. The results indicated that recognition performance was better to faces previously paired with distinctive than with typical voices but we failed to find any benefit on face recognition when the faces were previously associated with distinctive sounds. These findings possibly point to an expertise effect, as faces are usually associated to voices. More importantly, it suggests that the memory for visual faces can be modified by the perceptual quality of related vocal information and more specifically that facial distinctiveness can be of a multi-sensory nature. These results have important implications for our understanding of the structure of memory for person identification.

Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes.

Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.

Effects of rosiglitazone and linoleic acid on human preadipocyte differentiation.

BACKGROUND: Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand-activated transcription factor known to be central to both adipose tissue development and insulin action. Growth of adipose tissue requires differentiation of preadipocytes with acquisition of specific cellular functions including insulin sensitivity, leptin secretion and the capacity to store triglyceride. Dietary fatty acids and members of the thiazolidinedione class of compounds have been reported to influence adipogenesis at the transcriptional level. Here, we compare the effects of a dietary fatty acid, linoleic acid, and a thiazolidinedione, rosiglitazone, on biochemical and functional aspects of human preadipocyte differentiation in vitro. MATERIALS AND METHODS: Human omental and subcutaneous preadipocytes were subcultured 2-3 times and subsequently differentiated for 21 days in the presence of either linoleic acid or rosiglitazone. Differentiation was assessed using a number of biochemical and functional parameters. RESULTS: Omental and subcutaneous preadipocytes differentiated in the presence of linoleic acid showed marked cytoplasmic triacylglycerol accumulation however, no biochemical markers of differentiation (LPL expression, G3PDH gene expression and enzyme activity and leptin expression or secretion) were detected. In contrast, treatment of these cells with rosiglitazone induced full biochemical differentiation as judged by all markers assessed, despite comparatively little lipid accumulation. The rosiglitazone effects were subcutaneous depot-specific. Cells treated with linoleic acid showed decreased glucose uptake cf rosiglitazone-treated cells. A luciferase reporter assay demonstrated that rosiglitazone potently activates h-peroxisome proliferator activated receptor gamma while linoleic acid had no effect. CONCLUSIONS: These studies demonstrate that (a) human preadipocytes have the potential to accumulate triacylglycerol irrespective of their stage of biochemical differentiation; (b) while omental preadipocytes are refractory to biochemical differentiation in vitro, they are able to accumulate triacylglycerol; and (c) rosiglitazone and linoleic acid may exert their effects via different biochemical pathways.

Viewpoint dependence in visual and haptic object recognition.

On the whole, people recognize objects best when they see the objects from a familiar view and worse when they see the objects from views that were previously occluded from sight. Unexpectedly, we found haptic object recognition to be viewpoint-specific as well, even though hand movements were unrestricted. This viewpoint dependence was due to the hands preferring the back "view" of the objects. Furthermore, when the sensory modalities (visual vs. haptic) differed between learning an object and recognizing it, recognition performance was best when the objects were rotated back-to-front between learning and recognition. Our data indicate that the visual system recognizes the front view of objects best, whereas the hand recognizes objects best from the back.

A neural basis for general intelligence.

Universal positive correlations between different cognitive tests motivate the concept of "general intelligence" or Spearman's g. Here the neural basis for g is investigated by means of positron emission tomography. Spatial, verbal, and perceptuo-motor tasks with high-g involvement are compared with matched low-g control tasks. In contrast to the common view that g reflects a broad sample of major cognitive functions, high-g tasks do not show diffuse recruitment of multiple brain regions. Instead they are associated with selective recruitment of lateral frontal cortex in one or both hemispheres. Despite very different task content in the three high-g-low-g contrasts, lateral frontal recruitment is markedly similar in each case. Many previous experiments have shown these same frontal regions to be recruited by a broad range of different cognitive demands. The results suggest that "general intelligence" derives from a specific frontal system important in the control of diverse forms of behavior.

Recognizing unfamiliar faces: the effects of distinctiveness and view.

Three experiments are reported in which the effects of viewpoint on the recognition of distinctive and typical faces were explored. Specifically, we investigated whether generalization across views would be better for distinctive faces than for typical faces. In Experiment 1 the time to match different views of the same typical faces and the same distinctive faces was dependent on the difference between the views shown. In contrast, the accuracy and latency of correct responses on trials in which two different faces were presented were independent of viewpoint if the faces were distinctive but were view-dependent if the faces were typical. In Experiment 2 we tested participants' recognition memory for unfamiliar faces that had been studied at a single three-quarter view. Participants were presented with all face views during test. Finally, in Experiment 3, participants' were tested on their recognition of unfamiliar faces that had been studied at all views. In both Experiments 2 and 3 we found an effect of distinctiveness and viewpoint but no interaction between these factors. The results are discussed in terms of a model of face representation based on an inter-item similarity in which the representations are view specific.

Stimulus context and view dependence in object recognition.

The effect of stimulus factors such as interobject similarity and stimulus density on the recognition of objects across changes in view was investigated in five experiments. The recognition of objects across views was found to depend on the degree of interobject similarity and on stimulus density: recognition was view dependent when both interobject similarity and stimulus density were high, irrespective of the familiarity of the target object. However, when stimulus density or interobject similarity was low recognition was invariant to viewpoint. It was found that recognition was accomplished through view-dependent procedures when discriminability between objects was low. The findings are discussed in terms of an exemplar-based model in which the dimensions used for discriminating between objects are optimised to maximise the differences between the objects. This optimisation process is characterised as a perceptual 'ruler' which measures interobject similarity by stretching across objects in representational space. It is proposed that the 'ruler' optimises the feature differences between objects in such a way that recognition is view invariant but that such a process incurs a cost in discriminating between small feature differences, which results in view-dependent recognition performance.

The American Journal of Ophthalmology 1862-1864.

The American Journal of Ophthalmology was the first specialty periodical to be published in the Western hemisphere; the first issue appeared in New York City July 1862. Its editor and publisher was Julius Homberger, M.D., aged 22 years, who had emmigrated from Germany in January 1861. Six issues were published the first year and The Journal ceased publication after two issues in 1864. Possibly, the American Ophthalmological Society, the first national medical specialty society, was founded in 1864 in a reaction to Homberger, his journal, and his strong belief that specialists, but not other practitioners, should be permitted to advertise their skills. In 1866, Homberger submitted his resignation to the American Medical Association, which he had served a secretary of the Section on Surgery, 1864-1865. His resignation was refused and he was expelled from membership in 1868. He moved to New Orleans to practice ophthalmology in 1867, and died in 1872. The second series of The Journal began in St. Louis in 1884 with Adolf Alt, A graduate of Heidelberg University, who trained in ophthalmology in New York City, with Hermann Knapp, founder, editor, and publisher of the Archives of Ophthalmology. In 1918, the current third series of the American Journal of Ophthalmology, consolidated five ophthalmic publications, with Edward Jackson of Denver as editor.

The effect of depth rotation on object identification.

Five experiments are reported in which the time to verify the name of different three-dimensional common objects shown rotated in depth was investigated. Views of computer-generated images of elongated objects rotated in steps of 30 degrees along six axes of rotation were used as stimuli. A significant main effect of view was found in all experiments. This effect was initially attributed to the relatively slower verification times to the end-on views of objects but further analysis revealed that views 30 degrees off the end-on views were significantly slower to verify than other views. Objects with gravitational uprights yielded the same effects as objects without gravitational uprights. The results were not dependent on practice with the stimuli prior to the experiment or on repeated exposure of the views during the experiment. Also, there was no benefit found for the identification of shaded over silhouetted images of objects when shown in more-conventional views but unconventional views were more recognisable when shaded than when silhouetted. Last, initial verification times for familiar views of a set of novel objects were faster than for unfamiliar views even when the views were unconventional. With practice on unfamiliar views, however, the same function relating view to verification time found for familiar objects was found for the novel objects. The results suggest that for recognition purposes visual memory stores discrete views of objects but it characteristically favours a canonical range of views of elongated objects that are based on the salient geometry of the objects so that more unconventional or foreshortened views are less readily recognised.

The origins of the National Eye Institute 1933-1968. The Fifth Charles B. Snyder Lecture.

Many organizations and individuals prompted the authorization of the National Eye Institute by the United States Congress. The United States Marine Hospital and Public Health Service established a Laboratory of Hygiene in 1887, which became the research center of the National Institute of Health in 1930. The Albert D. and Mary Lasker Medical Foundation was mainly responsible for the 1945 conversion of the American Society for the Control of Cancer to the American Cancer Society, dedicated to medical research. Mildred Weisenfeld, a patient with retinitis pigmentosa, founded The Fight for Sight! in 1946 to provide funds for eye research. The Laskers invited Miss Weisenfeld to testify in support of a National Institute of Neurology, and her appeal was so persuasive that it emerged as the National Institute of Neurological Diseases and Blindness. Congressman John Fogarty and Senator Lister Hill directed the attention of the Congress and the public to the need for the Federal support of medical research. In 1960 Jules Stein, the legendary founder of the Music Corporation of America (MCA), established a new philanthropy, Research to Prevent Blindness, which provided skilled leadership in detailing the need for research in blinding disease and obtaining Congressional and Presidential approval of a new institute. The Committee for Research in Ophthalmology and Blindness was instrumental in bringing the groups interested in the welfare of the blind into harmony with groups concerned with medical research in blinding disease. The Association of University Professors of Ophthalmology was the first medical society to support the need for a National Eye Institute. The National Eye Institute was formally approved 8 August 1968 and celebrated its 25th anniversary in 1993.