Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.

Mitophagy, the selective autophagic process that specifically degrades mitochondria, serves as a vital regulatory mechanism for eliminating damaged mitochondria and maintaining cellular balance. Emerging research underscores the central role of mitophagy in the initiation, advancement, and treatment of cancer. Mitophagy is widely acknowledged to govern mitochondrial homeostasis in hematopoietic stem cells (HSCs), influencing their metabolic dynamics. In this article, we integrate recent data to elucidate the regulatory mechanisms governing mitophagy and its intricate significance in the context of leukemia. An in-depth molecular elucidation of the processes governing mitophagy may serve as a basis for the development of pioneering approaches in targeted therapeutic interventions.

Identifying patients with cognitive motor dissociation using resting-state temporal stability.

Using task-dependent neuroimaging techniques, recent studies discovered a fraction of patients with disorders of consciousness (DOC) who had no command-following behaviors but showed a clear sign of awareness as healthy controls, which was defined as cognitive motor dissociation (CMD). However, existing task-dependent approaches might fail when CMD patients have cognitive function (e.g., attention, memory) impairments, in which patients with covert awareness cannot perform a specific task accurately and are thus wrongly considered unconscious, which leads to false-negative findings. Recent studies have suggested that sustaining a stable functional organization over time, i.e., high temporal stability, is crucial for supporting consciousness. Thus, temporal stability could be a powerful tool to detect the patient's cognitive functions (e.g., consciousness), while its alteration in the DOC and its capacity for identifying CMD were unclear. The resting-state fMRI (rs-fMRI) study included 119 participants from three independent research sites. A sliding-window approach was used to investigate global and regional temporal stability, which measured how stable the brain's functional architecture was across time. The temporal stability was compared in the first dataset (36/16 DOC/controls), and then a Support Vector Machine (SVM) classifier was built to discriminate DOC from controls. Furthermore, the generalizability of the SVM classifier was tested in the second independent dataset (35/21 DOC/controls). Finally, the SVM classifier was applied to the third independent dataset, where patients underwent rs-fMRI and brain-computer interface assessment (4/7 CMD/potential non-CMD), to test its performance in identifying CMD. Our results showed that global and regional temporal stability was impaired in DOC patients, especially in regions of the cingulo-opercular task control network, default-mode network, fronto-parietal task control network, and salience network. Using temporal stability as the feature, the SVM model not only showed good performance in the first dataset (accuracy = 90%), but also good generalizability in the second dataset (accuracy = 84%). Most importantly, the SVM model generalized well in identifying CMD in the third dataset (accuracy = 91%). Our preliminary findings suggested that temporal stability could be a potential tool to assist in diagnosing CMD. Furthermore, the temporal stability investigated in this study also contributed to a deeper understanding of the neural mechanism of consciousness.

Decoding subject's own name in the primary auditory cortex.

Current studies have shown that perception of subject's own name (SON) involves multiple multimodal brain regions, while activities in unimodal sensory regions (i.e., primary auditory cortex) and their interaction with multimodal regions during the self-processing remain unclear. To answer this, we combined multivariate pattern analysis and dynamic causal modelling analysis to explore the regional activation pattern and inter-region effective connection during the perception of SON. We found that SON and other names could be decoded from the activation pattern in the primary auditory cortex. In addition, we found an excitatory effect of SON on connections from the anterior insula/inferior frontal gyrus to the primary auditory cortex, and to the temporoparietal junction. Our findings extended the current knowledge of self-processing by showing that primary auditory cortex could discriminate SON from other names. Furthermore, our findings highlighted the importance of influence of the insula on the primary auditory cortex during self-processing.

Using the attribute amnesia paradigm to test the automatic memory advantage of person names.

Person names, which hold within them extensive meaning, such as gender and cultural information, play an essential role in our social interaction. The intentional memory advantage of person names has been proved, but whether the automatic memory advantage of them exists remains unclear. In order to explore this question, we used a paradigm called attribute amnesia that allows us to test the automatic memory of person names in a working memory task. In Experiment 1, we adopted a classic attribute amnesia paradigm including 11 pre-surprise trials requiring participants to report the location of the target (person names or animal names) among three distractors and one surprise trial requiring them to unexpectedly report the identity of the target. The results showed that the identity report accuracy of person names in the surprise test was significantly better than that of animal names that served as a control group. Experiment 2 replicated Experiment 1 but increased the number of pre-surprise trials that could reduce the report accuracy of surprise test according to previous studies. The results revealed that the accuracy of the surprise test of person names decreased significantly, and showed no significant difference from that of animal names. These results suggest that there exists an automatic memory advantage of person names in working memory; however, such an automatic memory advantage effect could be reduced after participants learn to stop automatically encoding the attended but no-need-to-report person names through experiencing sufficient trials.

MDM2 inhibition-mediated autophagy contributes to the pro-apoptotic effect of berberine in p53-null leukemic cells.

AIMS: Berberine (BBR) is reported to induce apoptosis and inhibit migration of leukemic cells, but the underlying pharmacological mechanisms have not been fully revealed. This study aims to investigate the possible mechanisms from the perspective of autophagy. MAIN METHODS: P-53-null leukemic cell lines Jurkat and U937 were used for the in vitro study. MDC staining was used for observation of autophagy in leukemic cells, and Western blot analysis was for determination of the expression levels of autophagy-associated proteins. Apoptosis of the leukemic cells was detected by flow cytometry. Cellular location of MDM2 was observed with immunofluorescence staining. Ubiquitination of MDM2 was assessed by immunoprecipitation. Male 6-8-week-old NOD/SCID mice were used for evaluating the effect of BBR on chemotherapy sensitivity in vivo. KEY FINDINGS: BBR induced autophagy in p53-null leukemic cells, which was inhibited by autophagy inhibitors 3-methyladenine. 3-methyladenine also inhibited BBR-induced apoptosis in leukemic cells. In addition, BBR not only decreased MDM2 mRNA expression, but also enhanced MDM2 self-ubiquitination in leukemic cells. Forced overexpression of MDM2 reversed the effect of BBR on autophagy and apoptosis. Furthermore, BBR promoted doxorubicin-induced autophagy and cell death in the leukemic cells and overexpression of MDM2 suppressed these effects. In vivo, BBR combined with doxorubicin achieved better therapeutic effect than doxorubicin alone. SIGNIFICANCE: MDM2 inhibits autophagy and apoptosis in leukemic cells in a p53-independent manner. BBR induces autophagy in p53-null leukemic cells through downregulating MDM2 expression at both transcriptional and post-transcriptional levels, which may contribute to the anti-cancer effect of BBR in leukemia.

CircCDYL Serves as a New Biomarker in Mantle Cell Lymphoma and Promotes Cell Proliferation.

INTRODUCTION: Mantle cell lymphoma (MCL) is a rare subtype of B-cell lymphoma. Circular (circ) RNA is a member of the non-coding RNA family. However, clinical references to circRNAs in MCL are not clear. METHODS: In this study, we detected the expression level of circCDYL in the plasma of MCL patients compared to healthy donors by the quantitative reverse transcription polymerase chain reaction. The diagnostic value of circCDYL was determined using a receiver operating characteristic (ROC) curve. We constructed a circCDYL short hairpin RNA plasmid and infected the MCL cell line, Z138, to detect its effect on cell proliferation. RESULTS: CircCDYL was high expressed in the plasma of MCL patients. The ROC curve showed that circCDYL had diagnostic value (area under the curve (AUC) = 0.856). Functionally, circCDYL knockdown inhibited MCL cell proliferation. We conducted bioinformatics analyses and identified a circCDYL-micro (mi)RNA-mRNA/long non-coding (lnc)RNA network, highlighted by five miRNAs (hsa-miR-129-5p, hsa-miR-3163, hsa-miR-4662a-5p, hsa-miR-101-3p, and hsa-miR-186-5p), three lncRNAs (MALAT1, NEAT1, and XIST), and five mRNAs (NOTCH1, FMR1, ABCB1, TWIST1, and VEGFA). CONCLUSION: These findings indicate that circ-CDYL might serve as a potential diagnostic biomarker in clinical practice.