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.

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.

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).

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.

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 (AU)

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.

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).

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.

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.

Attentional biases and daily game craving dynamics: An ecological momentary assessment study.

Background and aims: Theories posit that the combination of external (e.g. cue exposure) and internal (e.g. attention biases) factors contributes to the development of game craving. Nevertheless, whether different components of attentional biases (namely, engagement bias and disengagement bias) play separate roles on game craving has not been fully elucidated. We aimed to examine the associations between two facets of attentional biases and game craving dynamics under a daily life setting. Methods: Participants (110 regular internet game players) accomplished the modified attentional assessment task in the laboratory, after which they entered a 10-day ecological momentary assessment (EMA) to collect data on their momentary game craving and occurrence of game-related events at five different time points per day. Results: We found that occurrence of game-related events was significantly associated with increased game craving. Moreover, attentional disengagement bias, instead of engagement bias, bore on the occasional level variations of game craving as moderating variables. Specifically, attentional disengagement bias, not engagement bias, was associated with a greater increase in game craving immediately after encountering a game-related event; however, neither attentional engagement bias nor disengagement bias was associated with the craving maintenance after a relatively long period. Discussion and conclusions: The present study highlights the specific attentional processes involved in game craving dynamics, which could be crucial for designing interventions for attentional bias modification (ABM) in Internet Gaming Disorder (IGD) populations.

Spontaneous perspective taking of an invisible person.

Observing the world from the perspective of others is one of the important foundational skills of social cognition. Visual perspective taking (VPT) is usually considered to have occurred when seeing another person. In researches on automatic VPT, a critical question is, does VPT occur merely based on another person's realistic perspective at the current moment, or does it also consider potential future perspectives? To examine the taking-a-potential-perspective assumption, the current study created a series of situations in which others are currently out of our sight (thus, extinguishing the information about the current perspective), with the possibility of returning and seeing a target from a different perspective than the participants, to test whether participants would spontaneously take the perspective of the temporarily invisible person. The experiments found that both the Level-1 and Level-2 VPT occurred for a person who was occluded from a participants' view, and VPT was more likely to occur when the person was more likely to return. These results suggest that people would not only spontaneously take others' current perspectives, but also the potential perspectives, thus future social interactions could be facilitated by the preprocessed perspectives of others. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Intrinsic neural activity predisposes susceptibility to a body illusion.

Susceptibility to the rubber hand illusion (RHI) varies. To date, however, there is no consensus explanation of this variability. Previous studies, focused on the role of multisensory integration, have searched for neural correlates of the illusion. But those studies have failed to identify a sufficient set of functionally specific neural correlates. Because some evidence suggests that frontal α power is one means of tracking neural instantiations of self, we hypothesized that the higher the frontal α power during the eyes-closed resting state, the more stable the self. As a corollary, we infer that the more stable the self, the less susceptible are participants to a blurring of boundaries-to feeling that the rubber hand belongs to them. Indeed, we found that frontal α amplitude oscillations negatively correlate with susceptibility. Moreover, since lower frequencies often modulate higher frequencies, we explored the possibility that this might be the case for the RHI. Indeed, some evidence suggests that high frontal α power observed in low-RHI participants is modulated by δ frequency oscillations. We conclude that while neural correlates of multisensory integration might be necessary for the RHI, sufficient explanation involves variable intrinsic neural activity that modulates how the brain responds to incompatible sensory stimuli.

More attention with less working memory: The active inhibition of attended but outdated information.

Attention has traditionally been regarded as a gateway to working memory, and almost all theoretical frameworks of attention and working memory assume that individuals always have a better memory for information that has received more attention. Here, we provide a series of counterintuitive demonstrations that show that paying more attention to a piece of information impedes, rather than enhances, the selection of this information into working memory. Experiments 1 to 5 provide converging evidence for an even weaker working memory trace of fully attended but outdated features, compared with baseline irrelevant features that were completely ignored. This indicates that the brain actively inhibits attended but outdated information to prevent it from entering working memory. Experiment 6 demonstrates that this inhibition processing is subject to executive control. These findings lead to a substantial reinterpretation of the relationship between attention and working memory.

The automatic processing of social information in working memory.

Working memory has been considered an active buffer for processing perceptual representations in a progressive manner, integrating information involuntarily to form structured mental representations. The automatic integration of objects' physical features in working memory has been well documented, although its social aspect remains unknown. The current study examines whether working memory would automatically process social information, that is, extract social information from memory content to form a higher-level social representation. Through four experiments, we demonstrate that participants could spontaneously infer personality traits when required to hold the social information implying others' traits in working memory, without the explicit goal of trait inference or awareness of the inference processes. Results show that participants mistook the memorized words for inferred trait words; such "errors" were then accumulated and amplified when the information was transmitted from person to person, during which the social information was briefly stored in working memory and reproduced after a short time. These findings indicate that working memory may automatically integrate social information into hierarchically structured mental representations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Implicit and Explicit Self-Identification as a Drug User in People Who Used Heroin and Methamphetamine.

Implicit and explicit self-identification as a drug user specific to the substance used (e.g., viewing oneself as a drinker) have been examined, as they relate to that drug use. However, studies have rarely explored whether identifying as a "drug user" differs implicitly and explicitly for people who use different drugs and how this identification relates to drug-use behaviors or abstinence. This study examined implicit and explicit self-identification as a "drug user" and their associations with drug-use behaviors and abstinence in people who used heroin (PWUH) and people who used methamphetamine (PWUM). Forty PWUH and 35 PWUM in a rehabilitation facility completed the single category implicit association test (SC-IAT), which evaluated implicit associations of a "drug user" with "self," and a measure of explicit self-identification as a "drug user." Prior drug-use behaviors and current abstinence duration of the participants were assessed. PWUH demonstrated stronger implicit "self + drug user" associations and higher levels of explicit self-identification as a "drug user" than PWUM. A higher frequency of drug use was associated with higher levels of explicit drug-user self-identity, and longer abstinence duration was positively related to stronger implicit "self + drug user" associations in PWUH. The drug type of heroin (vs. methamphetamine) participants used was associated with a higher frequency of use, which, in turn, predicted higher levels of explicit drug-user self-identity. Given that the PWUH group differs from the PWUM group in terms of implicit and explicit self-identification as "drug users," it would be more appropriate to address drug-user self-identity of individuals according to the substance they use rather than as a collective group.

The ROCK Tool: A Novel Method for the Structural Exploration of Schemata.

Information stored in the human memory is organized in the form of mental schemata. In this paper we report on the Reproduction of Categorical Knowledge (ROCK) tool, a novel method for uncovering the structure of mental schemata of memorized information. The tool applies serial reproduction and hierarchical clustering to magnify memory bias and uncover inner configurations of fragmented information, using strength of association. We conducted behavioral experiments to test the validity of the tool. Experiment 1a demonstrated that the schematic structure of personality traits uncovered by the ROCK tool highly matched those described by the Big Five theory. This finding was replicated in Experiment 1b, focusing on a lower-level personality dimension extroversion with results aligned with personality theories. Experiment 2 assessed the ROCK tool using artificial stimuli with a pre-defined structure, created using a Markov chain model. Participants acquired the structure of the stimuli through an implicit learning procedure, and the ROCK tool was used to assess their level of recall. The results showed that the learned structure was identical to the designed structure of the stimuli. The results from both studies suggest that the ROCK tool could effectively reveal the structure of mental schemata.