Combined inhibition of XIAP and autophagy induces apoptosis and differentiation in acute myeloid leukaemia.

Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.

MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia.

BACKGROUND: The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. METHODS: Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. RESULTS: We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. CONCLUSIONS: Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.

The linear impact of visual working memory load on visual awareness: Evidence from motion-induced blindness.

Despite the close relationship between visual working memory (VWM) and visual awareness, the question of how these two constructs interact with each other is still under debate. The current study aimed to further address this issue by investigating whether and how visual awareness is influenced by VWM load. In Experiment 1, participants were asked to perform a motion-induced blindness (MIB) task while simultaneously memorizing different numbers of items in VWM. The results indicated that the latency of MIB was prolonged gradually as the VWM load increased, revealing a linear trend in the modulation effect of VWM load on visual awareness. Experiments 2 and 3 tested the other potential explanations and validated the initial finding by confirming that VWM load was indeed responsible for the observed effect on visual awareness. These findings have important implications for a better understanding of the relationship between VWM and visual awareness.

Consciousness can overflow report: Novel evidence from attribute amnesia of a single stimulus.

There is a long-standing debate on whether visual consciousness is confined to cognitive access measured by reportability, or whether it is rich and overflows reportability. Much of the debate in previous studies concentrated on whether information outside attentional focus could be consciously experienced and reportable. This study sought to address the debate from a new perspective, through testing whether fully attended supraliminal information is necessarily reportable with a variation of attribute amnesia. Participants were asked to judge the parity of a single number or whether a Chinese character referred to furniture. After several trials, they were unexpectedly asked to report the stimulus identity. The results consistently showed that participants could not correctly report the identity, indicating that fully attended information that was consciously perceived could sometimes overflow report. In addition to providing novel overflow evidence, these findings also have crucial implications in understanding the relationship between consciousness and working memory.

The postdictive effect of choice reflects the modulation of attention on choice.

Our conscious perception of the world is not an instantaneous, moment-by-moment construction. Rather, our perception of an event is influenced, over time, by information gained after the event; this is known as a postdictive effect. A recent study reported that this postdictive effect could occur even in choice. The present study sought to test whether the striking postdictive effect of choice reflects the modulation of attention on choice, by directly and systematically manipulating attention in two experiments. Specifically, Experiment 1 revealed that the robust postdictive effect of choice was almost completely eliminated when attentional bias was removed. More important, Experiment 2 demonstrated that the postdictive effect of choice could be modulated by directly manipulating participants' attention with a spatial cue, in particular, when the cue appeared at short time delays. These results suggest that choice could be considerably postdictively influenced by attention and this effect was most pronounced within a short time window wherein decision making was most likely in progress. The current study not only enables clarification of the mechanism of the newly discovered postdictive effect of choice, but also extends evidence of the modulation of attention on decision making.

Does attribute amnesia occur with the presentation of complex, meaningful stimuli? The answer is, "it depends".

Attribute amnesia (AA) is a recently reported phenomenon whereby participants are unable to report a salient attribute of a stimulus (e.g., the color or identity of a target letter) on which their attention has just been focused during a prior task. This counterintuitive effect has been repeatedly replicated with various simple stimuli such as digits and letters. The current study sought to explore boundaries of AA by investigating whether the phenomenon persists when participants encounter complex, meaningful stimuli (e.g., pictures) that have been shown to hold an advantage in cognitive processing and memory. In Experiments 1a-d, we examined whether AA was observed with different types of complex stimuli. In Experiments 2a-b and 3a-b, we linked the type of stimuli (simple vs. complex and meaningful stimuli) to the other two potential boundary factors of AA (i.e., repetitiveness of target stimulus and set effects of Einstellung) to see whether there were interactions between stimuli type and these two boundary factors. The results demonstrated that the AA effect was still consistently observed for complex stimuli in a typical AA paradigm wherein participants encountered many trials and the targets were repeated across trials. However, this effect only appeared for simple stimuli, but not for complex stimuli in two special cases: when target stimuli were never repeated through the experiment, or when the surprise test was placed on the first trial of the experiment. These findings have crucial implications in understanding the boundaries of the AA phenomenon.

Opposite ERP effects for conscious and unconscious semantic processing under continuous flash suppression.

We examined whether semantic processing occurs without awareness using continuous flash suppression (CFS). In two priming tasks, participants were required to judge whether a target was a word or a non-word, and to report whether the masked prime was visible. Experiment 1 manipulated the lexical congruency between the prime-target pairs and Experiment 2 manipulated their semantic relatedness. Despite the absence of behavioral priming effects (Experiment 1), the ERP results revealed that an N4 component was sensitive to the prime-target lexical congruency (Experiment 1) and semantic relatedness (Experiment 2) when the prime was rendered invisible under CFS. However, these results were reversed with respect to those that emerged when the stimuli were perceived consciously. Our findings suggest that some form of lexical and semantic processing can occur during CFS-induced unawareness, but are associated with different electrophysiological outcomes.

Beyond the SNARC effect: distance-number mapping occurs in the peripersonal space.

Estimating distance of objects relative to one's body is important for interaction with the environment. Given that distance is an interval of magnitude describing space, distance and the commonly used estimations of magnitude, i.e., numbers, may share a common representation system (the ATOM theory, Walsh in Trends Cogn Sci 7(11):483-488, 2003). The current study systematically examined the association between distance and number representations on both the sagittal and transverse axes on the transverse plane in the peripersonal space. Participants in Experiment 1 judged the parity of digits by pressing one of two buttons (both were in front of participants): One was near the body and the other away from it. We found that near responses were faster when paired with smaller numbers and far responses with larger numbers. When one button was set in front and the other in back in Experiment 2, no mapping was found. In Experiment 3, when both buttons were on the right side aligned with the transverse axis, small-near and large-far mapping were found. However, no such effect was found on the left side. These results suggest that numbers are mapped onto the whole transverse plane of the peripersonal space, not only a left-right oriented number line.

Cognitive style modulates conscious but not unconscious thought: Comparing the deliberation-without-attention effect in analytics and wholists.

Unconscious thought theory (UTT) suggests that conscious thinking is less effective in complex decision-making than unconscious thinking. However, little research has taken individual differences (e.g., cognitive style) into account. Using an adapted UTT paradigm, the present study compared the performances of individuals with a wholist or an analytic cognitive style in both conscious and unconscious thought conditions. After viewing information regarding four hypothetical phones, participants in the conscious thought condition deliberated for three minutes before rating the phones, while participants in the unconscious thought condition were distracted with a 2-back task for three minutes before rating. The results showed that wholists were equally good at differentiating good and bad phones after conscious or unconscious thought, whereas analytics performed well only when thinking unconsciously. The modulation effect of cognitive style appeared only in conscious thought. Implications for UTT and the understanding of cognitive style are discussed.

Bias or equality? Unconscious thought equally integrates temporally scattered information.

In previous experiments on unconscious thought, information was presented to participants in one continuous session; however, in daily life, information is delivered in a temporally partitioned way. We examined whether unconscious thought could equally integrate temporally scattered information when making overall evaluations. When presenting participants with information in two temporally partitioned sessions, participants' overall evaluation was based on neither the information in the first session (Experiment 1) nor that in the second session (Experiment 2); instead, information in both sessions were equally integrated to reach a final judgment. Conscious thought, however, overemphasized information in the second session. Experiments 3 and 4 further ruled out possible influencing factors including differences in the distributions of positive/negative attributes in the first and second sessions and on-line judgment. These findings suggested that unconscious thought can integrate information from a wider range of periods during an evaluation, while conscious thought cannot.

Hierarchical Constraints on the Distribution of Attention in Dynamic Displays.

Human vision is remarkably good at recovering the latent hierarchical structure of dynamic scenes. Here, we explore how visual attention operates with this hierarchical motion representation. The way in which attention responds to surface physical features has been extensively explored. However, we know little about how the distribution of attention can be distorted by the latent hierarchical structure. To explore this topic, we conducted two experiments to investigate the relationship between minimal graph distance (MGD), one key factor in hierarchical representation, and attentional distribution. In Experiment 1, we constructed three hierarchical structures consisting of two moving objects with different MGDs. In Experiment 2, we generated three moving objects from one hierarchy to eliminate the influence of different structures. Attention was probed by the classic congruent-incongruent cueing paradigm. Our results show that the cueing effect is significantly smaller when the MGD between two objects is shorter, which suggests that attention is not evenly distributed across multiple moving objects but distorted by their latent hierarchical structure. As neither the latent structure nor the graph distance was part of the explicit task, our results also imply that both the construction of hierarchical representation and the attention to that representation are spontaneous and automatic.

Enhancement of joint flanker effect in intergroup competition.

Representing the mental state of the partner lays the foundation for successful social interaction. While the representation of group members has been extensively studied, it is unclear how intergroup interactions affect it. In three experiments utilizing the joint flanker task, we found that competition between groups brought about a greater joint flanker effect (Experiment 1). Such phenomenon was not due to competition per se, as competition that occurred between individuals from different groups did not enhance the joint flanker effect (Experiment 2). Using the minimal grouping method to directly manipulate group entitativity, we found that the joint flanker effect was larger when participants perceived the group as being more closely connected; conversely, when they perceived the group as less close, the joint flanker effect was attenuated (Experiment 3). These results suggested that beliefs about the group may be key to how group competition enhanced the joint flanker effect. The potential cognitive mechanisms producing this phenomenon are fully discussed. Overall, our study is the first to explore the impact of intergroup interactions on the joint flanker effect and provides a new perspective on understanding the relationship between within-group representations and intergroup interactions.

Unconscious prioritization for face-to-face people.

One central question in the scientific and philosophical study of consciousness is regarding the scope of human consciousness. There is a lively debate as to whether high-level information integration is necessarily dependent on consciousness. This study presents a new form of unconscious integration based on the facingness between two individuals. Using a breaking continuous flash suppression paradigm, Experiments 1-3 found that two facing human heads got a privilege in breaking into awareness compared to nonfacing pairs. Experiments 4 and 5 demonstrated that the breakthrough difference between facing and nonfacing pairs could not be attributed to low-level or mid-level factors. Experiments 6, 7a, and 7b showed that the unconscious priority of facing pairs was significantly diminished when the holistic processing of the two agents was disrupted. Experiments 8-11 demonstrated that the advantage of facing pairs was only observable for human agents and not for daily objects, directional arrows, or nonhuman animals. These findings have critical implications for better understanding the scope of human consciousness and the origins of social vision. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Matrine induces autophagic cell death by triggering ROS/AMPK/mTOR axis and apoptosis in multiple myeloma.

Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a primary active compound of traditional Chinese medicinal herb Sophora flavescens Ait, has been found to have anti-tumor properties in various types of malignant tumors. Whether autophagy plays a crucial role in the anti-MM effect of matrine remain unknown. Herein, we found that matrine could trigger apoptosis and cell cycle arrest, and meanwhile induce autophagy in MM cells in vitro. We further ascertained the role of autophagy by using ATG5 siRNA or the autophagy inhibitor spautin-1, which partially reversed matrine's inhibitory effect on MM cells. Conversely, the combination of matrine with the autophagy inducer rapamycin enhanced their anti-tumor activity. These findings suggest that autophagy induced by matrine can lead to cell death in MM cells. Further mechanism investigation revealed that matrine treatment increased the levels of reactive oxygen species (ROS) and AMPKα1 phosphorylation and decreased the phosphorylation of mTOR in MM cells. Additionally, co-treatment with AMPKα1 siRNA or the ROS scavenger N-acetyl-1-cysteine weakened the increase in autophagy that was induced by matrine. Finally, we demonstrated a synergistic inhibitory effect of matrine and rapamycin against MM in a xenograft mouse model. Collectively, our findings provided novel insights into the anti-MM efficacy of matrine and suggest that matrine induces autophagy by triggering ROS/AMPK/mTOR axis in MM cells, and combinatorial treatment of matrine and rapamycin may be a promising therapeutic strategy against MM.

Remembering Sets: Capacity Limit and Time Limit of Ensemble Representations in Working Memory.

In a constantly changing visual environment, the ability to extract and store ensemble representations plays a crucial role in efficiently processing and remembering complex visual information. However, how working memory maintains these ensemble representations remains unclear. Therefore, the present study aimed to investigate the limits and characteristics of ensemble representations in working memory using a change detection paradigm. Participants were presented with multiple sets of circles grouped by spatial proximity and were asked to memorize the mean diameter of the circles in each set. Results showed that working memory could stably maintain mean sizes of approximately two sets for at least four seconds. Moreover, the memory performance of ensembles was not affected by the number of circles within a set, suggesting that individual details were not stored in working memory. These results suggest that the visual system can effectively store ensembles in working memory without preserving detailed individual information.

Generative visual common sense: Testing analysis-by-synthesis on Mondrian-style image.

The well-known Mondrian-style images, aside from being aesthetically amusing, also reflect the core principles of human vision in their viewing experience. First, when we see a Mondrian-style image consisting only of a grid and primary colors, we may automatically interpret its causal history such that it was generated by recursively partitioning a blank scene. Second, the image we observe is open to many possible ways of partitioning, and their probabilities of dominating the interpretation can be captured by a probabilistic distribution. Moreover, the causal interpretation of a Mondrian-style image can emerge almost spontaneously, not being tailored to any specific task. Using Mondrian-style images as a case study, we demonstrate the generative nature of human vision by showing that a Bayesian model based upon an image-generation task can support a wide range of visual tasks with little retraining. Our model, learned from human-synthesized Mondrian-style images, could predict human performance in the perceptual complexity ranking, capture the transmission stability when images were iteratively passed among participants, and pass a visual Turing test. Our results collectively show that human vision is causal such that we interpret an image from the angle of how it was generated. The success of generalization with little retraining suggests that generative vision constitutes a type of common sense that supports a wide range of tasks of different natures. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Completeness out of incompleteness: Inferences from regularities in imperfect information ensembles.

Handling imperfect information problems is fundamental to perception, learning, and decision-making. Ensemble perception may partially overcome imperfect information by providing global clues. However, if not all cluster elements are readily accessible, the observations required for computing statistics are incomplete. In this case, these elements' internal correlations (i.e., regularity) could serve as clues to elucidate the missing pieces. We thus investigated spatial regularity's role in ensemble perception under imperfect information situations created using partially occluded stimuli. In two experiments, we manipulated circle size (Experiment 1) and line orientation (Experiment 2) to linearly vary with its location; spatial regularity thus supplied clues for inferring information of the invisible parts. Participants estimated the mean of the targeted feature of the entire cluster, including visible and invisible parts. We observed robust biases toward the overall cluster in the estimations, implying the invisible parts were considered during ensemble perception. We proposed this effect could be understood as assessing evidence from visible parts to construct the missing parts. Experiment 3 employed a periodicity regularity to deter participants from using specific strategies, and consistent results were found. We then developed a generative model, the Regularity-Based Model, to simulate the inference process, which better captured the pattern of human outcomes than the comparative model. These findings indicate the visual system could use high-level structural information to infer scenes with incomplete information, thus producing more accurate ensemble representations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Intention beyond desire: Spontaneous intentional commitment regulates conflicting desires.

The human mind is a mosaic composed of multiple selves with conflicting desires. How can coherent actions emerge from such conflicts? Classical desire theory argues that rational action depends on maximizing the expected utilities evaluated by all desires. In contrast, intention theory suggests that humans regulate conflicting desires with an intentional commitment that constrains action planning towards a fixed goal. Here, we designed a series of 2D navigation games in which participants were instructed to navigate to two equally desirable destinations. We focused on the critical moments in navigation to test whether humans spontaneously commit to an intention and take actions that would be qualitatively different from those of a purely desire-driven agent. Across four experiments, we found three distinctive signatures of intentional commitment that only exist in human actions: "goal perseverance" as the persistent pursuit of an original intention despite unexpected drift making the intention suboptimal; "self-binding" as the proactive binding of oneself to a committed future by avoiding a path that could lead to many futures; and "temporal leap" as the commitment to a distant future even before reaching the proximal one. These results suggest that humans spontaneously form an intention with a committed plan to quarantine conflicting desires from actions, supporting intention as a distinctive mental state beyond desire. Additionally, our findings shed light on the possible functions of intention, such as reducing computational load and making one's actions more predictable in the eyes of a third-party observer.

Working-Memory-Guided Attention Competes with Exogenous Attention but Not with Endogenous Attention.

Recent research has extensively investigated working memory (WM)-guided attention, which is the phenomenon of attention being directed towards information in the external environment that matches the content stored in WM. While prior studies have focused on the potential influencing factors of WM-guided attention, little is known about the nature of it. This attention system exhibits characteristics of two classical distinct attention systems: exogenous attention and endogenous attention, as it can operate automatically like exogenous attention yet persist for a long time and be modulated by cognitive resources like endogenous attention. Thus, the current study aimed to explore the mechanism of WM-guided attention by testing whether it competed with exogenous attention, endogenous attention, or both. Two experiments were conducted within a classic WM-guided attention paradigm. Experiment 1 included an exogenous cue and revealed an interaction between WM-guided attention and exogenous attention. Experiment 2 replaced the exogenous cue with an endogenous cue and demonstrated that endogenous attention had no impact on WM-guided attention. These findings indicate that WM-guided attention shares mechanisms with exogenous attention to some extent while operating in parallel with endogenous attention.

Aging-related genes related to the prognosis and the immune microenvironment of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML), one of the common malignancies of the hematologic system, has progressively increased in incidence. Aging is present in both normal tissues and the tumor microenvironment. However, the relationship between senescence and AML prognosis is still not elucidated. METHODS: In this study, RNA sequencing data of AML were obtained from TCGA, and prognostic prediction models were established by LASSO-Cox analysis. Differences in immune infiltration between the different risk groups were calculated using the CIBERSORT and ESTIMATE scoring methods. The KEGG and GO gene enrichment and GSEA enrichment were also used to enrich for differential pathways between the two groups. Subsequently, this study collected bone marrow samples from patients and healthy individuals to verify the differential expression of uncoupling protein 2 (UCP2) in different populations. Genipin, a UCP2 protein inhibitor, was also used to examine its effects on proliferation, cell cycle, and apoptosis in AML cell lines in vitro. RESULTS: It showed that aging-related genes (ARGs) expression was correlated with prognosis. And there was a significant difference in the abundance of immune microenvironment cells between the two groups of patients at high risk and low risk. Subsequently, UCP2 expression was found to be elevated in AML patients. Genipin inhibits UCP2 protein and suppresses the proliferation of AML cell lines in vitro. CONCLUSION: ARGs can be used as a predictor of prognosis in AML patients. Moreover, suppressing UCP2 can reduce the proliferation of AML cell lines, alter their cell cycle, and promote apoptosis in vitro.