Effects of canonical color, luminance, and orientation on sustained inattentional blindness for scenes.

Whether scene gist perception occurs automatically and unconsciously has been the subject of much debate. In addition to demonstrating a new method that adapts the Mack and Rock (1998) inattentional blindness cross procedure to allow for sustained inattentional blindness over a large number of trials, we report evidence from a series of experiments that shows that canonical scene features reduce inattentional blindness to scenes by facilitating the extraction of scene gist. When attentional demands are high, the combination of canonical color, canonical luminance, and canonical orientation reduces rates of inattentional blindness. However, when attentional demands are reduced, canonical features are independently sufficient to facilitate gist extraction and to capture attention. These results demonstrate that canonical color, canonical luminance, and canonical orientation all contribute to scene gist perception, and that when attentional demands are high, only highly canonical stimuli are sufficient to capture attention.

A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans.

Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

Scene incongruity and attention.

Does scene incongruity, (a mismatch between scene gist and a semantically incongruent object), capture attention and lead to conscious perception? We explored this question using 4 different procedures: Inattention (Experiment 1), Scene description (Experiment 2), Change detection (Experiment 3), and Iconic Memory (Experiment 4). We found no differences between scene incongruity and scene congruity in Experiments 1, 2, and 4, although in Experiment 3 change detection was faster for scenes containing an incongruent object. We offer an explanation for why the change detection results differ from the results of the other three experiments. In all four experiments, participants invariably failed to report the incongruity and routinely mis-described it by normalizing the incongruent object. None of the results supports the claim that semantic incongruity within a scene invariably captures attention and provide strong evidence of the dominant role of scene gist in determining what is perceived.

No iconic memory without attention.

The experiments reported extend the findings of our earlier paper, (Mack, Erol, & Clarke, 2015) and allow us to reject Bachmann and Aru's critique of our conclusion (2015) that IM requires attention. They suggested our manipulations, which diverted attention from a letter reporting task in a dual task procedure where the task-cue occurred after the array disappeared, might only have affected access to IM and not the "existence of the phenomenal experience". By further decreasing the probability of reporting letters to only 10% and adding a final trial in which the letter matrix was either completely absent or distorted, we found more than half our subjects were unaware of its absence, or distortion i.e., were inattentionally blind. We take this as powerful evidence against the existence of any phenomenal experience component of iconic memory and consistent with the view that iconic memory demands attention and that conscious perception does as well.

Reply to Bachmann and Aru.

A reply to the Bachmann and Aru (2015) critique of our paper (Mack, Erol, & Clarke, 2015) in which we rebut their criticisms and argue once again that our results support our view that iconic memory requires attention.

Iconic memory is not a case of attention-free awareness.

Whether or not awareness entails attention is a much debated question. Since iconic memory has been generally assumed to be attention-free, it has been considered an important piece of evidence that it does not (Koch & Tsuchiya, 2007). Therefore the question of the role of attention in iconic memory matters. Recent evidence (Persuh, Genzer, & Melara, 2012), suggests that iconic memory does depend on attention. Because of the centrality of iconic memory to this debate, we looked again at the role of attention in iconic memory using a standard whole versus partial report task of letters in a 3×2 matrix. We manipulated attention to the array by coupling it with a second task that was either easy or hard and by manipulating the probability of which task was to be performed on any given trial. When attention was maximally diverted from the matrix, participants were able to report less than a single item, confirming the prior results and supporting the conclusion that iconic memory entails attention. It is not an instance of attention-free awareness.

Iconic memory for the gist of natural scenes.

Does iconic memory contain the gist of multiple scenes? Three experiments were conducted. In the first, four scenes from different basic-level categories were briefly presented in one of two conditions: a cue or a no-cue condition. The cue condition was designed to provide an index of the contents of iconic memory of the display. Subjects were more sensitive to scene gist in the cue condition than in the no-cue condition. In the second, the scenes came from the same basic-level category. We found no difference in sensitivity between the two conditions. In the third, six scenes from different basic level categories were presented in the visual periphery. Subjects were more sensitive to scene gist in the cue condition. These results suggest that scene gist is contained in iconic memory even in the visual periphery; however, iconic representations are not sufficiently detailed to distinguish between scenes coming from the same category.

Genome-wide copy number variation analysis of a Branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, hearing loss and renal dysmorphology. Although haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients. In this study, we used high-resolution array-based comparative genomic hybridization on 32 BOR probands negative for coding-sequence and splice-site mutations in known BOR-causing genes to identify potential disease-causing genomic rearrangements. Of the >1,000 rare and novel copy number variants we identified, four were heterozygous deletions of EYA1 and several downstream genes that had nearly identical breakpoints associated with retroviral sequence blocks, suggesting that non-allelic homologous recombination seeded by this recombination hotspot is important in the pathogenesis of BOR. A different heterozygous deletion removing the last exon of EYA1 was identified in an additional proband. Thus, in total five probands (14 %) had deletions of all or part of EYA1. Using a novel disease-gene prioritization strategy that includes network analysis of genes associated with other deletions suggests that SHARPIN (Sipl1), FGF3 and the HOXA gene cluster may contribute to the pathogenesis of BOR.

How effective is the cognitive interview when used with adults with intellectual disabilities specifically with conversation recall?

BACKGROUND: The cognitive interview (CI) has been shown to increase correct memory recall of a diverse range of participant types, without an increase in the number of incorrect or confabulated details. However, it has rarely been examined for use with adults with intellectual disability. MEASURES AND METHOD: This study compared the memory recall of twenty-one adults with a mild intellectual disability (ID) (IQ 70-50) and twenty-one adults from the general population (GP). Participants viewed a film of a staged distraction theft and were interviewed using either the CI or the structured interview (SI). RESULTS: The CI, when compared to the SI, enhanced the correct recall of person, action and conversation (gist) detail for both participant types, without increasing the number of incorrect or confabulated details reported. The ID group reported significantly less correct information than the GP regardless of the interview used. CONCLUSION: The findings suggest that the CI can enable adults with intellectual disability to provide a fuller picture about an experienced event. Implications of this research are discussed.

TNXB mutations can cause vesicoureteral reflux.

Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.

Red blood cell supernatant potentiates LPS-induced proinflammatory cytokine response from peripheral blood mononuclear cells.

Allogeneic blood transfusion has an immunomodulatory capacity on its recipients through accumulation of immunologically active substances with blood storage, and prestorage leukoreduction reduces many of these mediators. We investigated lipopolysaccharide (LPS)-induced cytokine response of peripheral blood mononuclear cells (PBMCs) exposed to packed red blood cell (PRBC) supernatants from leukoreduced (LR) or non-leukoreduced (NLR) units with variable duration of storage. PRBC units were collected with or without leukoreduction on Day 0 before routine storage. The plasma fraction (supernatant) was isolated from LR and NLR units after 1 day (D1) or 42 days (D42) of storage and exposed to PBMCs versus control media for 24 h, then with LPS for an additional 24 h. Cell supernatants were analyzed for IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha by cytokine bead array. IL-1beta, TNF-alpha, and IL-6 were significantly elevated in PRBC groups versus control. D42 NLR PRBC supernatant significantly increased secretion of IL-1beta and IL-6 compared to D1 NLR PRBC supernatant. LR significantly attenuated the cytokine response of IL-1beta. Thus, PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs. This response is accentuated with storage duration and partially attenuated with leukoreduction. These findings may partially explain the immune activation seen clinically after blood transfusion.

Regulation of c-Ret in the developing kidney is responsive to Pax2 gene dosage.

During kidney development, Pax2 and Pax8 are expressed very early in the mammalian nephric duct and both precede the expression of receptor tyrosine kinase, c-Ret. However, in Pax2-/- mutant mice, expression of c-Ret is lost after embryonic day 10.5. As the Ret/Gdnf pathway is necessary for renal development and there is a temporal and spatial relationship of Pax2 and c-Ret expression in the developing genito-urinary system, we postulate that Pax2 is necessary for c-Ret expression in the developing kidney. In vitro, Pax2 protein is capable of physically interacting with a c-RET promoter, and both Pax2 and Pax8 can activate the expression of a reporter gene driven by the c-RET promoter. Compound heterozygous null mice (Pax2+/-: Ret+/-) display an increased incidence of unilateral and bilateral renal agenesis, and smaller kidneys with fewer nephrons. Furthermore, the expression of Gdnf is reduced 2-3-fold, whereas c-Ret expression is reduced 9-47-fold in Pax2 heterozygous embryonic kidneys as detected by real-time quantitative RT (QRT)-PCR. The data demonstrate that Pax2 plays an integral role in the initiation and maintenance of the Ret/Gdnf pathway by not only activating the ligand of the pathway, but by also enhancing the expression of the pathway receptor Ret. The effects of reduced Pax2 gene dosage are thus amplified resulting in a haploinsufficient phenotype.

Melanoma skews dendritic cells to facilitate a T helper 2 profile.

BACKGROUND: Patients with progressing melanoma have a circulating cytokine profile reflecting a T helper cell type 2 (Th2) imbalance, while patients responding to therapy favor a Th1 profile. The aim of this study was to determine the role of circulating dendritic cells (DCs) in mediating this imbalance. METHODS: Isolated human peripheral blood mononuclear cells (PBMCs) were exposed to cell-free melanoma-conditioned medium (MCM) or control fibroblast-conditioned medium before stimulation. In separate experiments, isolated circulating DCs were exposed to MCM before addition of T cells. DC maturation and function were determined. Mixed leukocyte response T-cell proliferation was quantified and supernatants were assayed for Th1 (interleukin [IL]-2 and interferon gamma) and Th2 (IL-4, IL-5, and IL-10) cytokines. RESULTS: PBMCs exposed to MCM produced significantly more Th2-type cytokines (IL-4, IL-5, and IL-10) over time than those exposed to control medium. DCs exposed to MCM before addition of T cells, produced a similar pattern of a sustained longer term Th2 response after an initial burst of IL-2. Exposure to MCM did not significantly affect DC maturation or IL-12 production. T-cell proliferation did not change significantly in the mixed leukocyte response, however, the percentage of viable CD4+ T cells in the MCM-treated group was significantly less than control (37 vs 50%, P < .05). CONCLUSIONS: Exposure of PBMCs to melanoma produces a Th2-type cytokine profile, which may be, in part, facilitated by DCs.

Melanoma inhibits macrophage activation by suppressing toll-like receptor 4 signaling.

BACKGROUND: Activated macrophages defend against tumors by secreting cytokines to recruit secondary immune cells, presenting antigen to T cells, and by direct tumor cytotoxicity. Peritoneal macrophages harvested from melanoma-bearing mice are less cytotoxic to melanoma cells, and produce less superoxide, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha) than those from nontumor-bearing mice. Similar impairment of macrophage activation occurs in vitro using media harvested from cultured melanoma cells. Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. We hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling. STUDY DESIGN: Melanoma conditioned media (MCM) was generated from B16 melanoma cells. Peritoneal macrophages from TLR-4 competent or TLR-4 incompetent mice were exposed to control or MCM for 24 hours; then stimulated with lipopolysaccharide. TNF-alpha secretion, TNF-alpha mRNA production, nuclear factor-kappaB (NF-kappaB) activation, and TLR-4 surface expression were measured. RESULTS: Peritoneal macrophages exposed to MCM produced considerably less TNF-alpha in response to stimulus than controls (691 pg/mL versus 2,066 pg/mL, p < 0.001). TNF-alpha production by TLR-4 incompetent macrophages was not affected by MCM (454 pg/mL versus 480 pg/mL). Stimulated TNF-alpha mRNA and activated NF-kappaB were decreased in MCM treated C57BL/6 macrophages (by 38% and 33%, respectively). TLR-4 surface expression, however, was not decreased by exposure to MCM. CONCLUSIONS: Melanoma inhibits macrophage activation by suppressing TLR-4 signaling downstream of the TLR-4 receptor.