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The whole warps the sum of its parts: Gestalt-defined group mean size biases memory for individual objects

Despite our rich perceptual experience, the visual system is severely limited in capacity to simultaneously represent only a few objects in detail. In fact, attention and visual short-term memory (VSTM) are restricted to about four individual objects [1-3]. The visual system maintains our illusion of stable, complete perception by capitalizing on structure and redundancy inherent in the surrounding environment [4-10]. For example, previous work in our lab [11] demonstrated that the visual system relies on Gestalt-grouping principles like proximity, connectedness, and common region (Figure 1b in Design Plan) to organize information into meaningful chunks, summarized in average representations capturing their overall statistical properties. Gestalt-grouping and perceptual averaging likely boost attention and VSTM capacity well beyond the “four-item limit” by warping memory for individual items toward the means of Gestalt-defined groups, circumventing needs to represent individual objects. We plan to test this proposal using a psychophysical index of warping from averaging11 in conjunction with a well-established neural proxy of VSTM capacity, the Contralateral Delay Activity (CDA) [12]. CDA amplitude is typically used to measure capacity for four or fewer objects [13,14], and many investigations of perceptual averaging employ sets of only a few objects that can easily be individually encoded [15-17], raising the question of whether this sort of processing is naturally used when it would not be advantageous, or whether such “short-cuts” are only taken when necessary to represent collections that exceed VSTM capacity. Figure 1a in the Design Plan illustrates a CDA paradigm in which encephalographic (EEG) activity is recorded while the observer is cued to attend one side of an upcoming study display while remaining fixated in the centre. Observers’ task is to remember the sizes of the circles on the cued side of the study display over a blank retention interval. Study circles are ungrouped, or grouped into two, large-mean/small-mean sets, according to the Gestalt principles of proximity, connectedness, or common region (Figure 1b in the Design Plan). Importantly, half the circles are presented in both large and small mean size sets, such that “groups” are defined only by Gestalt grouping. Unbeknownst to participants, the test circles are always the same physical size. However, when the test was a member of large mean size Gestalt-defined set, participants tend to remember/adjust it larger than when it was a member of the small mean size set. The psychophysical index of averaging is therefore given by extent to which they adjust circles in the test display to the remembered sizes of the circles in the corresponding locations in the study display versus the average size of the Gestalt-defined group [11]. Groups of circles on the unattended side have equal mean sizes, with all other visual information held constant. Therefore, resultant EEG activity contralateral to the attended side, time-locked to the onset of study display (the CDA) indexes VSTM load, such that amplitude over the blank retention interval increases proportionally with the amount of information held in VSTM (Figure 1c in the Design Plan). There will be two baseline conditions, where only two circles are present in the study displays. Study circles will either be identical sizes, representing the grand mean in the Gestalt conditions, or different sizes, one representing the large Gestalt-defined group mean size and one representing the small mean size. We will manipulate Gestalt-groupings and study display set size (4 or 16 items). We will measure participants’ test circle adjustments and concomitant CDA amplitudes. References: 1. Luck, S. J., & Vogel, E. K. (1997). The capacity of visual working memory for features and conjunctions. Nature, 390, 279–281. https://doi.org/10.1038/36846 2. Pylyshyn, Z. W., & Storm, R. W. (1988). Tracking multiple independent targets: Evidence for a parallel tracking mechanism. Spatial Vision, 3, 179–197. https://doi.org/10.1163/156856888x00122 3. Cowan, N. (2001). The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behavioral & Brain Sciences, 24, 87-114. https://doi.org/10.1017/S0140525X01003922 4. Alvarez, G. A. (2011). Representing multiple objects as an ensemble enhances visual cognition. Trends in Cognitive Sciences, 15, 122–131. https://doi.org/10.1016/j.tics.2011.01.003 5. Ariely, D. (2001). Seeing sets: Representation by statistical properties. Psychological Science, 12, 157–162. https://doi.org/10.1111/1467-9280.00327 6. Brady, T.F. & Alvarez, G.A. (2011). Hierarchical encoding in visual working memory: ensemble statistics bias memory for individual items. Psychological Science, 22(3), 384-392. https://doi.org/10.1177/0956797610397956 7. Brady, T. F., & Tenenbaum, J. B. (2013). A probabilistic model of visual working memory: Incorporating higher order regularities into working memory capacity estimates. Psychological Review, 120(1), 85–109. https://doi.org/10.1037/a0030779 8. Corbett, J.E., & Munneke, J. (2019). Statistical stability and set size exert distinct influences on visual search. Attention, Perception, & Psychophysics, 40 Years of Feature Integration: Special Issue in Memory of Anne Treisman, 82(2), 832-839. https://doi.org/10.3758/s13414-019-01905-2 9. Kersten, D. (1987). Predictability and redundancy of natural images. Journal of the Optical Society of America A, Optics, Image & Science, 4, 2395–2400. https://doi.org/10.1364/JOSAA.4.002395 10. Wertheimer, M. (1938). Laws of organization in perceptual forms. In W. D. Ellis (Ed.), A source book of Gestalt psychology (p. 71–88). Kegan Paul, Trench, Trubner & Company. https://doi.org/10.1037/11496-005 11. Corbett, J. E. (2017). The whole warps the sum of its parts: Gestalt- defined-group mean size biases memory for individual objects. Psychological Science, 28(1), 12–22. https://doi.org/10.1177/0956797616671524 12. Vogel, E.K., & Machizawa, M.R. (2004). Neural activity predicts individual differences in visual working memory capacity. Nature, 428, 748-751. https://doi.org/10.1038/nature02447 13. Gao, Z., Xu, X., Chen, Z., Yin, J., Shen, M., & Shui, R. (2011). Contralateral delay activity tracks object identity information in visual short term memory. Brain Research, 1406, 30–42. https://doi.org/10.1016/j.brainres.2011.06.049 14. Peterson, D. J., Gozenman, F., Arciniega, H., & Berryhill, M. E. (2015). Contralateral delay activity tracks the influence of Gestalt grouping principles on active visual working memory representations. Attention, Perception, & Psychophysics, 77, 2270–2283. https://doi.org/10.3758/s13414-015-0929-y 15. Chong, S. C., & Treisman, A. (2003). Representation of statistical properties. Vision Research, 43, 393-404. https://doi.org/10.1016/S0042-6989(02)00596-5 16. Haberman, J., & Whitney, D. (2007). Rapid extraction of mean emotion and gender from sets of faces. Current Biology, 17, 751–753. https://doi.org/10.1016/j.cub.2007.06.039 17. Marchant, A.P., Simons, D.J. & de Fockert, J.W. (2013). Ensemble representations: Effects of set size and item heterogeneity on average size perception. Acta Psychologica, 142(2). 245-250. https://doi.org/10.1016/j.actpsy.2012.11.002

Additional file 1: Supplementary Figure 1. CsA impairs MSC suppression of T cell proliferation in vitro. MSC were seeded (1 × 104 per well) into a 96 well round bottom plate followed by the addition of anti-CD3/CD28 bead (1 × 104 per well) activated CFSE labelled PBMCs (5 × 104 per well). Some groups were cultured in the presence of CsA (100, 500 or 1000 ng/ml). On day four, cells were harvested and stained with anti-CD3 and 7AAD viability dye to analyse CD3+ proliferation by flow cytometry. Statistical analysis was carried out using one way ANOVA Multiple Tukey comparison test and unpaired student t-test where *

Supplemental material, CorbettSupplementalMaterial for “It’s Not a Tumor”: A Framework for Capitalizing on Individual Diversity to Boost Target Detection by Jennifer E. Corbett and Jaap Munneke in Psychological Science

The immunomodulatory ability of mesenchymal stromal cells (MSC) make them an ideal cellular therapy for inflammatory diseases such as acute Graft versus Host Disease (aGvHD). Cyclosporine (CsA) is an immunosuppressive drug commonly used as prophylaxis and treatment of aGvHD. However, oral bioavailability of CsA is suboptimal. The elucidation of MSC and CsA interactions will be beneficial as aGvHD patients in clinics would have undergone prophylaxis involving CsA immunosuppression and MSC may be administered alongside CsA therapy. The key goals of this thesis were to (1) investigate the direct interactions of MSC and CsA and elucidate the mechanisms by which these interactions occur in vitro and in vivo, and (2) establish the efficacy of a novel and more clinically applicable CsA treatment, by means of optimal targeted delivery, in a humanised model of aGvHD. This study has defined the direct interactions of MSC and CsA, identifying MSC activation and timing of CsA as being crucial for beneficial immunosuppressive functions. We proposed a mechanism by which CsA regulated IFNγ signalling in MSC through suppressor of cytokine signaling 1 (SOCS1) inhibition resulting in the enhancement of MSCγ suppression of CD3+ T cells and increased indoleamine 2,3-deoxygenase (IDO). For the first time, we have shown that a novel CsA formulation, SmPill® provided safe and superior efficacy in comparison to routinely used CsA drugs, Neoral® and Sandimmune® IV in a humanised model of aGvHD. We have shown this enhanced efficacy using pre-clinical survival studies, histopathology and cytokine analysis and hypothesise that this enhancement over these conventional CsA drugs is mediated through targeted delivery to systemic and GI tissues. Therefore, making it a highly attractive candidate for routine clinical use for aGvHD treatment. Moreover, we have investigated the interactions of MSC with SmPill® and Sandimmune® IV in a humanised model of aGvHD. We have shown that 1) CsA therapies did not impair MSC efficacy in aGvHD 2) Sandimmune® IV can be efficacious with both resting and licensed MSC therapy and 3) MSC but not MSCγ hamper SmPill® efficacy. Overall, this thesis has furthered our knowledge of MSC interactions with CsA in vitro and in vivo and presented translational pre-clinical results demonstrating the efficacy of a novel CsA formulation alone and in combination with MSC therapy for aGvHD.

Accurate knowledge of aerosol size and composition is important for the understanding of their effects on both the atmosphere and the health of those who inhale them. Ultrafine aerosols (0.25 nm to 10 nm radius) and small clusters (2 molecules to 0.25 nm radius) can only be detected down to radii of a few nanometers and no chemical information is provided. A photoion spectrometer was previously built and is used to dope clusters and ultrafine aerosols with Na atoms. The subsequent Na-cluster complexes are then ionized by a UV laser. This technique is currently believed to be the softest ionization method available. Calculations were done to predict the efficiency of this system because a direct comparison with other systems cannot be made over the complete size range. These calculations include, the probability of a particle colliding with a Na atom in the oven, the average lifetime of Na-cluster complexes and their photoionization efficiency. Calculations in this thesis focus on the collision probability and include predictions as to the most efficient temperature of the Na oven for Na pick up. The temperature of the Na oven was also found to experimentally agree with the calculations, because the vapor pressure of Na plays a significant role in the collision probability. Characterization of the sodium doping technique was done through experiments comparing direct XUV ionization with UV ionization of small Na doped clusters. The fragmentation of acetic acid clusters was characterized for the monomer and oligomers up to the tetramer. It was found that up to two acetic acid molecules evaporated from the clusters. The Na doping technique also reveals a significant difference in the size distribution as seen by UV and XUV laser ionization for large dimethyl ether and acetic acid clusters, and a smaller yet visible difference for large water clusters. Different UV wavelengths were also investigated including wavelengths above and below the ionization energy of a lone Na atom. The Na doping technique was found to be a softer technique than direct ionization with XUV light, because no fragmentation of molecules occurred and evaporation was minimized.