Long-term memory for distractors: Effects of involuntary attention from working memory.

In a visual search task, attention to task-irrelevant distractors impedes search performance. However, is it maladaptive to future performance? Here, I showed that attended distractors in a visual search task were better remembered in long-term memory (LTM) in the subsequent surprise recognition task than non-attended distractors. In four experiments, participants performed a visual search task using real-world objects of a single color. They encoded color in working memory (WM) during the task; because each object had a different color, participants directed their attention to the WM-matching colored distractor. Then, in the surprise recognition task, participants were required to indicate whether an object had been shown in the earlier visual search task, regardless of its color. The results showed that attended distractors were remembered better in LTM than non-attended distractors (Experiments 1 and 2). Moreover, the more participants directed their attention to distractors, the better they explicitly remembered them. Participants did not explicitly remember the color of the attended distractors (Experiment 3) but remembered integrated information with object and color (Experiment 4). When the color of the distractors in the recognition task was mismatched with the color in the visual search task, LTM decreased compared to color-matching distractors. These results suggest that attention to distractors impairs search for a target but is helpful in remembering distractors in LTM. When task-irrelevant distractors become task-relevant information in the future, their attention becomes beneficial.

Visual mental imagery of atypical color objects attracts attention to an imagery-matching object.

Mental imagery attracts attention to imagery-matching stimuli. However, it remains unknown whether voluntarily imagined atypical color also attracts attention to a stimulus that matches the imagery when the imagined stimuli are color-diagnostic objects, which are strongly associated with typical color. This study investigated whether people can voluntarily imagine atypical colors of such objects and attend to imagery-matching stimuli. Participants in the imagery group were instructed to imagine an atypical color of the black-white objects according to the instructed color or voluntarily selected color, whereas participants in the control group were instructed to attend to the objects without any instruction of imagery. Thereafter, they detected a color target in a visual search task. Results revealed that participants in the imagery group directed attention to the imagery-matching atypical color, not to the original color of the object in the search. Meanwhile, participants in the control group did not demonstrate any attentional guidance. These results suggest that voluntarily imagining atypical color can attenuate mental representations of the original color imagery and change attention to a stimulus that matches imagery.

Usefulness of cell block examination for the cytological diagnosis of thoracic SMARCA4-deficient undifferentiated tumor: A case report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm showing undifferentiated or rhabdoid morphology that significantly involves the thorax of adults. It has been reported as SMARCA4-deficient thoracic sarcoma or SMARCA4-deficient non-small cell lung carcinoma according to the findings of immunohistochemical and genetic studies. We report a case of thoracic SMARCA4-UT for which cell block analysis and immunohistochemical staining were useful for the final diagnosis. A 51-year-old man had a chief complaint of left back pain and visited our hospital for further examination. Cytological examination of a left pleural effusion was performed and we also made a cell block of the pleural effusion. Cytological examination revealed polyhedral to round tumor cells. The tumor cells appeared singly or formed loosely cohesive clusters. The nuclei were round to oval, enlarged, and sometimes eccentric with prominent nucleoli with irregular borders. The nuclear chromatin was unevenly distributed. The cytoplasm was vacuolar to eosinophilic. There were no characteristic structures of tumor cells. The cell block revealed many single or loosely cohesive round to epithelioid cells. Some tumor cells often exhibited eccentrically located nuclei and lightly eosinophilic cytoplasm, showing a rhabdoid morphology. On immunohistochemistry, the tumor cells were positive for SOX-2 and they demonstrated significantly reduced SMARCA4 (BRG1) expression; SMARCA2 (BRM) and SMARCB1 (INI1) expression were retained. Accordingly, we made a diagnosis of SMARCA4-UT. This case demonstrates the importance of performing histological and immunohistochemical analysis using cell blocks for immediate diagnosis.

Novel rapid immunohistochemistry using an alternating current electric field identifies Rac and Cdc42 activation in human colon cancer FFPE tissues.

It is important to determine the activation status of Rac and Cdc42 in cancer tissues for the prediction of metastasis and patient prognosis. However, it has been impossible to detect their spatial activation on formalin-fixed paraffin embedded (FFPE) surgical specimens thus far. Here, we established a novel detection technique for activated Rac/Cdc42 in human colon cancer FFPE tissues by using a p21-activated kinase (PAK)-Rac binding domain (RBD) detection probe fused with glutathione S-transferase (GST), designated GST-PAK-RBD, and novel rapid-immunohistochemistry (R-IHC) systems using noncontact alterating-current electric field mixing, although there is a technical limitation in that it may not distinguish between Rac members and Cdc42. In 50 cases of colon cancer, various activation patterns of Rac/Cdc42 were observed, which were designated plasma membrane, cytoplasm, mixed pattern, and polarized distribution. The activity was striking in the invasive fronts of tumors and significantly correlated with tumor invasion properties evaluated by TNM classification. Of note, in tissue microarray (TMA) samples, 29 of 33 cases demonstrated higher Rac1/Cdc42 activity in the tumor area than the corresponding normal mucosa. In addition, positive correlations were detected between Rac/Cdc42 activity and clinicopathological factors such as venous and lymphatic vessel invasion. These results suggest that understanding Rac and Cdc42 activations in cancer tissues would be valuable as an option for molecular therapy as personalized medicine.

De novo development of proteolytically resistant therapeutic peptides for oral administration.

The oral administration of peptide drugs is hampered by their metabolic instability and limited intestinal uptake. Here, we describe a method for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases. By using phage display to screen large libraries of genetically encoded double-bridged peptides on protease-resistant fd bacteriophages, we generated a peptide inhibitor of the coagulation Factor XIa with nanomolar affinity that resisted gastrointestinal proteases in all regions of the gastrointestinal tract of mice after oral administration, enabling more than 30% of the peptide to remain intact, and small quantities of it to reach the blood circulation. We also developed a gastrointestinal-protease-resistant peptide antagonist for the interleukin-23 receptor, which has a role in the pathogenesis of Crohn's disease and ulcerative colitis. The de novo generation of targeted peptides that resist proteolytic degradation in the gastrointestinal tract should help the development of effective peptides for oral delivery.

Imprint cytology of biphenotypic sinonasal sarcoma of the paranasal sinus: A case report.

Biphenotypic sinonasal sarcoma (BSNS) is a rare low-grade spindle cell sarcoma that predominantly affects middle-aged women with multiple tumors in the sinonasal tract. BSNS shows biphenotypic expression of neural and myogenic markers on immunohistochemistry (IHC) with a specific chimeric PAX3-MAML3 fusion. The cytological features of BSNS have so far not been reported. Here, we describe a case of BSNS including findings of imprint cytology, histology, IHC, and genetic analysis. A 30-year-old woman presented with a nodular tumor that completely occupied the ethmoid sinus. The tumor was resected and submitted for imprint cytology, which revealed relatively bland spindle tumor cells that had mildly enlarged oval to spindle-shaped nuclei with fine nuclear chromatin and a thin nuclear rim in a clear background. Nucleoli were inconspicuous and there was no significant nuclear atypia and pleomorphism. These cytological findings were consistent with the histology of low-grade spindle cell sarcoma in BSNS. On IHC, the tumor cells were focally positive for S-100 protein and α-smooth muscle actin; nuclear ß-catenin expression was also seen. PAX3 split signals were detected in 52% of tumor cells by fluorescence in situ hybridization. Reverse transcriptase-polymerase chain reaction also identified a chimeric PAX3-MAML3 fusion gene. Based on these findings, we diagnosed the tumor as BSNS. Our findings revealed that a relatively bland spindle cell cytology with a clear background is a characteristic feature of BSNS. BSNS should therefore be differentiated from benign and bland-appearing malignant spindle cell tumors and the combination of cytology, histology, IHC, and genetic analysis facilitates the diagnosis of BSNS.

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.

Visual mental imagery influences attentional guidance in a visual-search task.

Visual mental imagery resembles visual working memory (VWM). Because both visual mental imagery and VWM involve the representation and manipulation of visual information, it was hypothesized that they would exert similar effects on visual attention. Several previous studies have demonstrated that working-memory representations guide attention toward a memory-matching task-irrelevant stimulus during visual-search tasks. Therefore, mental imagery may also guide attention toward imagery-matching stimuli. In the present study, five experiments were conducted to investigate the effects of visual mental imagery on visual attention during a visual-search task. Participants were instructed to visualize a color or an object clearly associated with a specific color, after which they were asked to detect a colored target in the visual-search task. Reaction times for target detection were shorter when the color of the target matched the imagined color, and when the color of the target was similar to that strongly associated with the imagined object, than when the color of the target did not match that of the mental representation. This effect was not observed when participants were not instructed to imagine a color. These results suggest that similar to VWM, visual mental imagery guides attention toward imagery-matching stimuli.

Attentional networks and visuospatial working memory capacity in social anxiety.

Social anxiety is associated with attentional bias and working memory for emotional stimuli; however, the ways in which social anxiety affects cognitive functions involving non-emotional stimuli remains unclear. The present study focused on the role of attentional networks (i.e. alerting, orienting, and executive control networks) and visuospatial working memory capacity (WMC) for non-emotional stimuli in the context of social anxiety. One hundred and seventeen undergraduates completed questionnaires on social anxiety. They then performed an attentional network test and a change detection task to measure visuospatial WMC. Orienting network and visuospatial WMC were positively correlated with social anxiety. A multiple regression analysis showed significant positive associations of alerting, orienting, and visuospatial WMC with social anxiety. Alerting, orienting networks, and high visuospatial WMC for non-emotional stimuli may predict degree of social anxiety.

Lost in distractors: Reduced Autobiographical Memory Specificity and dispersed activation spreading over distractors in working memory.

Studies on autobiographical memory retrieval highlight the prominence of rapid and direct access to a specific event memory. Because it has been believed that autobiographical memory retrieval mostly relies on an effortful generative process, there is little empirical evidence on the early stage of information processing that contributes to autobiographical memory specificity (AMS). Therefore, we investigated the associations between AMS and automatic activation of information stimulated by rapid presentation of emotional words. Study 1 involved a visual search task to assess activation of various distractors in working memory. Participants with reduced AMS showed a tendency to activate distractors that were not semantically associated with preceding cues. In Study 2, we manipulated the levels of AMS by using a computerized version of Memory Specificity Training (c-MeST) to observe the changes in the activation of distractors. Results showed that increases in AMS were associated with decreases in activation of cue-unassociated distractors. These findings suggest that reduced AMS can be characterized by dispersed activation spreading over semantically unassociated distractors in automatic information selection of working memory. Because we also found an association between depressive symptoms and AMS, the role of automatic information processing in the relation between reduced AMS and depression is discussed.

Unraveling the linguistic nature of specific autobiographical memories using a computerized classification algorithm.

In the present study, we explored the linguistic nature of specific memories generated with the Autobiographical Memory Test (AMT) by developing a computerized classifier that distinguishes between specific and nonspecific memories. The AMT is regarded as one of the most important assessment tools to study memory dysfunctions (e.g., difficulty recalling the specific details of memories) in psychopathology. In Study 1, we utilized the Japanese corpus data of 12,400 cue-recalled memories tagged with observer-rated specificity. We extracted linguistic features of particular relevance to memory specificity, such as past tense, negation, and adverbial words and phrases pertaining to time and location. On the basis of these features, a support vector machine (SVM) was trained to classify the memories into specific and nonspecific categories, which achieved an area under the curve (AUC) of .92 in a performance test. In Study 2, the trained SVM was tested in terms of its robustness in classifying novel memories (n = 8,478) that were retrieved in response to cue words that were different from those used in Study 1. The SVM showed an AUC of .89 in classifying the new memories. In Study 3, we extended the binary SVM to a five-class classification of the AMT, which achieved 64%-65% classification accuracy, against the chance level (20%) in the performance tests. Our data suggest that memory specificity can be identified with a relatively small number of words, capturing the universal linguistic features of memory specificity across memories in diverse contents.

Association between Social Anxiety and Visual Mental Imagery of Neutral Scenes: The Moderating Role of Effortful Control.

According to cognitive theories, verbal processing attenuates emotional processing, whereas visual imagery enhances emotional processing and contributes to the maintenance of social anxiety. Individuals with social anxiety report negative mental images in social situations. However, the general ability of visual mental imagery of neutral scenes in individuals with social anxiety is still unclear. The present study investigated the general ability of non-emotional mental imagery (vividness, preferences for imagery vs. verbal processing, and object or spatial imagery) and the moderating role of effortful control in attenuating social anxiety. The participants (N = 231) completed five questionnaires. The results showed that social anxiety was not necessarily associated with all aspects of mental imagery. As suggested by theories, social anxiety was not associated with a preference for verbal processing. However, social anxiety was positively correlated with the visual imagery scale, especially the object imagery scale, which concerns the ability to construct pictorial images of individual objects. Further, it was negatively correlated with the spatial imagery scale, which concerns the ability to process information about spatial relations between objects. Although object imagery and spatial imagery positively and negatively predicted the degree of social anxiety, respectively, these effects were attenuated when socially anxious individuals had high effortful control. Specifically, in individuals with high effortful control, both object and spatial imagery were not associated with social anxiety. Socially anxious individuals might prefer to construct pictorial images of individual objects in natural scenes through object imagery. However, even in individuals who exhibit these features of mental imagery, effortful control could inhibit the increase in social anxiety.

Psychometric properties of the written version of the autobiographical memory test in a japanese community sample.

The autobiographical memory test (AMT) is a widely used measure to assess the specificity of autobiographical memories. Reduced Autobiographical Memory Specificity (AMS) or increased overgeneralization of memories is considered as a cognitive hallmark of depression. Therefore, reduced AMS is the subject of much psychopathological research, and is a promising target for psychological interventions. Although considerable evidence has been gathered on the clinical relevance of reduced AMS over the past decades, studies on AMS have been mainly conducted in Western populations, and few have been conducted in Asian populations. This could be because of the unknown psychometric properties of the AMT given cultural and language differences. Therefore, the present study examined the psychometric properties of the AMT in a Japanese community sample (N=1240). Our data replicated that (a) the AMT has a uni-factorial structure; (b) AMS has a small but statistically significant negative correlation with depressive symptoms; (c) AMS shows a significant declining trend as a function of age, which influences the magnitude of the association between AMS and depressive symptoms in older adults. These findings suggest that the AMT has robust psychometric properties across different languages and cultural backgrounds.

Attention Moderates the Relationship Between Primary Psychopathy and Affective Empathy in Undergraduate Students.

Psychopathy is personality traits, which is consisted of primary psychopathy characterized by affective and interpersonal problems and secondary psychopathy characterized by behavioral problems. Prior researchers have suggested that people with psychopathy have peculiar attention, which prevents them from detecting information peripheral to their concern, and we hypothesized that this explains their low empathy. Based on these reasoning, the present study assessed whether attention moderates the relationship between psychopathy and affective empathy. Eighty-five undergraduates (40 men and 45 women; mean age = 19.8 years; SD = 1.6) completed the Levenson Self-Report Psychopathy Scale, the Interpersonal Reactivity Index, and a perceptual load task. Hierarchical regression showed that a significant moderation effect was found: primary psychopathy was negatively associated with affective empathy, among those with reduced interference from task-irrelevant stimuli under a medium level of perceptual load. Future study should need to replicate this finding with clinical population.

Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors.

The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen-antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20 by R-ICC for intraoperative diagnosis. R-ICC by AC electric field may become a substantial tool for compensating R-IHC and will be applied for broad antibodies in the future.

A case of cerebral astroblastoma with rhabdoid features: a cytological, histological, and immunohistochemical study.

Astroblastoma is a rare neuroepithelial neoplasm of unknown origin, usually occurring in children and young adults. Here we report a case of astroblastoma with uncommon features in an 18-year-old female. The tumor was a well-circumscribed cystic and solid mass with marked gadolinium enhancement in the right frontal lobe. Cytological examination showed polarized monopolar cells with diminished cohesiveness. Tumor cells possessed eccentric round to oval nuclei with abundant eosinophilic cytoplasm, sometimes having cytoplasmic processes. Histopathologically, the tumor showed perivascular pseudorosettes with prominent vascular sclerosis. Foam cells were frequently infiltrated around blood vessels and among tumor cells. In some areas, a solid growth pattern of plump tumor cells with abundant inclusion-like eosinophilic cytoplasm showing rhabdoid appearance was observed. The immunohistochemical study revealed strong and diffuse positivity for vimentin and epithelial membrane antigen. Tumor cells were focally positive for glial fibrillary acidic protein and cytokeratin AE1/AE3. Nuclear immunoreactivity for INI1 protein was evident. The Ki-67 labeling index was 10.8%. This tumor was finally diagnosed as low-grade astroblastoma and the patient had no evidence of recurrence without postoperative radiotherapy or chemotherapy during the last 6 months of follow-up. This report describes novel cytological, histopathological, and immunohistochemical features of the rare tumor.

Structure-Based Development of a Protein-Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6.

The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new opportunity for RA treatment and implications for structure-guided development of PPI inhibitors.

The influence of working memory on visual search for emotional facial expressions.

In visual search tasks, an angry face surrounded by happy faces is more rapidly detected compared with a happy face surrounded by angry faces. This is called the anger superiority effect. The anger superiority effect has been mainly related to automatic attentional effects, but top-down mechanisms may also influence this effect. In a series of studies, we investigated the influence of holding emotional information in working memory (WM) on the anger superiority effect. In multiple experiments, participants were generally faster to find an angry target with happy distractors compared to a happy target with angry distractors. However, this anger superiority effect was diminished when holding angry information in WM, whereas the effect was still observed when holding happy information. These effects were not observed when participants did not remember emotional information other than the color of the emotional stimuli. The data indicate that enhanced processing of distractor facial expressions was observed when they matched the content of WM, facilitating target detection. However, when the contents of WM and distractor faces differed, the processing of distractor faces and detection of a target face were delayed. These results suggest that the anger superiority effect is modulated by top-down effects of WM and that interactions between contents of WM and perception of facial expressions determine the enhancement or reduction of the anger superiority effect.

The influence of working memory on the anger superiority effect.

The anger superiority effect shows that an angry face is detected more efficiently than a happy face. However, it is still controversial whether attentional allocation to angry faces is a bottom-up process or not. We investigated whether the anger superiority effect is influenced by top-down control, especially working memory (WM). Participants remembered a colour and then searched for differently coloured facial expressions. Just holding the colour information in WM did not modulate the anger superiority effect. However, when increasing the probabilities of trials in which the colour of a target face matched the colour held in WM, participants were inclined to direct attention to the target face regardless of the facial expression. Moreover, the knowledge of high probability of valid trials eliminated the anger superiority effect. These results suggest that the anger superiority effect is modulated by top-down effects of WM, the probability of events and expectancy about these probabilities.

CD133 expression: a potential prognostic marker for non-small cell lung cancers.

BACKGROUND: CD133 is a membrane glycoprotein containing five transmembrane loops. Previous reports suggest that a CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal characteristics has biological features of a cancer stem cell. In addition, the presence of CD133-positive cells was associated with a significantly poorer prognosis for some solid tumors, compared to those with CD133-negative cells. However, the clinicopathological significance of CD133 in non-small cell lung cancer (NSCLC) remains controversial. METHODS: We conducted immunohistochemical assessment of 161 NSCLCs surgically resected at Hokkaido University Hospital between 1982 and 1994 to evaluate correlations between CD133 expression and various clinicopathological features. RESULTS: CD133 expression was significantly correlated with pathological stages (pStages) II, III, and IV for the various NSCLC types analyzed and was an independent factor for unfavorable prognosis in this population (hazard ratio = 3.157, P = 0.015). CONCLUSION: CD133 expression was correlated with pStage and was predictive of unfavorable prognosis in patients with pStages II, III, and IV NSCLC. These results suggest the possibility of using CD133 as a novel prognostic marker in these patients.