Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death.

TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.

The Brain's Topographical Organization Shapes Dynamic Interaction Patterns That Support Flexible Behavior Based on Rules and Long-Term Knowledge.

Adaptive behavior relies both on specific rules that vary across situations and stable long-term knowledge gained from experience. The frontoparietal control network (FPCN) is implicated in the brain's ability to balance these different influences on action. Here, we investigate how the topographical organization of the cortex supports behavioral flexibility within the FPCN. Functional properties of this network might reflect its juxtaposition between the dorsal attention network (DAN) and the default mode network (DMN), two large-scale systems implicated in top-down attention and memory-guided cognition, respectively. Our study tests whether subnetworks of FPCN are topographically proximal to the DAN and the DMN, respectively, and how these topographical differences relate to functional differences: the proximity of each subnetwork is anticipated to play a pivotal role in generating distinct cognitive modes relevant to working memory and long-term memory. We show that FPCN subsystems share multiple anatomical and functional similarities with their neighboring systems (DAN and DMN) and that this topographical architecture supports distinct interaction patterns that give rise to different patterns of functional behavior. The FPCN acts as a unified system when long-term knowledge supports behavior but becomes segregated into discrete subsystems with different patterns of interaction when long-term memory is less relevant. In this way, our study suggests that the topographical organization of the FPCN and the connections it forms with distant regions of cortex are important influences on how this system supports flexible behavior.

Brain structural and functional signatures of multi-generational family history of suicidal behaviors in preadolescent children.

Parent-child transmission of suicidal behaviors has been extensively studied, but the investigation of a three-generation family suicide risk paradigm remains limited. In this study, we aimed to explore the behavioral and brain signatures of multi-generational family history of suicidal behaviors (FHoS) in preadolescents, utilizing a longitudinal design and the dataset from Adolescent Brain and Cognitive DevelopmentSM Study (ABCD Study®), which comprised 4 years of data and includes a total of 9,653 preadolescents. Our findings revealed that multi-generational FHoS was significantly associated with an increased risk of problematic behaviors and suicidal behaviors (suicide ideation and suicide attempt) in offspring. Interestingly, the problematic behaviors were further identified as a mediator in the multi-generational transmission of suicidal behaviors. Additionally, we observed alterations in brain structure within superior temporal gyrus (STG), precentral/postcentral cortex, posterior parietal cortex (PPC), cingulate cortex (CC), and planum temporale (PT), as well as disrupted functional connectivity of default mode network (DMN), ventral attention network (VAN), dorsal attention network (DAN), fronto-parietal network (FPN), and cingulo-opercular network (CON) among preadolescents with FHoS. These results provide compelling longitudinal evidence at the population level, highlighting the associations between multi-generational FHoS and maladaptive behavioral and neurodevelopmental outcomes in offspring. These findings underscore the need for early preventive measures aimed at mitigating the familial transmission of suicide risk and reducing the global burden of deaths among children and adolescents.

Unveiling the core functional networks of cognition: An ontology-guided machine learning approach.

Deciphering the functional architecture that underpins diverse cognitive functions is fundamental quest in neuroscience. In this study, we employed an innovative machine learning framework that integrated cognitive ontology with functional connectivity analysis to identify brain networks essential for cognition. We identified a core assembly of functional connectomes, primarily located within the association cortex, which showed superior predictive performance compared to two conventional methods widely employed in previous research across various cognitive domains. Our approach achieved a mean prediction accuracy of 0.13 across 16 cognitive tasks, including working memory, reading comprehension, and sustained attention, outperforming the traditional methods' accuracy of 0.08. In contrast, our method showed limited predictive power for sensory, motor, and emotional functions, with a mean prediction accuracy of 0.03 across 9 relevant tasks, slightly lower than the traditional methods' accuracy of 0.04. These cognitive connectomes were further characterized by distinctive patterns of resting-state functional connectivity, structural connectivity via white matter tracts, and gene expression, highlighting their neurogenetic underpinnings. Our findings reveal a domain-general functional network fingerprint that pivotal to cognition, offering a novel computational approach to explore the neural foundations of cognitive abilities.

Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing.

Phosphorylation has been generally thought to activate the SR family of splicing factors for efficient splice-site recognition, but this idea is incompatible with an early observation that overexpression of an SR protein kinase, such as the CDC2-like kinase 1 (CLK1), weakens splice-site selection. Here, we report that CLK1 binds SR proteins but lacks the mechanism to release phosphorylated SR proteins, thus functionally inactivating the splicing factors. Interestingly, CLK1 overcomes this dilemma through a symbiotic relationship with the serine-arginine protein kinase 1 (SRPK1). We show that SRPK1 interacts with an RS-like domain in the N terminus of CLK1 to facilitate the release of phosphorylated SR proteins, which then promotes efficient splice-site recognition and subsequent spliceosome assembly. These findings reveal an unprecedented signaling mechanism by which two protein kinases fulfill separate catalytic features that are normally encoded in single kinases to institute phosphorylation control of pre-mRNA splicing in the nucleus.

Disruption of network hierarchy pattern in bulimia nervosa reveals brain information integration disorder.

The human brain works as a hierarchical organization that is a continuous axis spanning sensorimotor cortex to transmodal cortex (referring to cortex that integrates multimodal sensory information and participates in complex cognitive functions). Previous studies have demonstrated abnormalities in several specific networks that may account for their multiple behavioral deficits in patients with bulimia nervosa (BN), but whether and how the network hierarchical organization changes in BN remain unknown. This study aimed to investigate alterations of the hierarchy organization in BN network and their clinical relevance. Connectome gradient analyses were applied to depict the network hierarchy patterns of fifty-nine patients with BN and thirty-nine healthy controls (HCs). Then, we evaluated the network- and voxel-level gradient alterations of BN by comparing gradient values in each network and each voxel between patients with BN and HCs. Finally, the association between altered gradient values and clinical variables was explored. In the principal gradient, patients with BN exhibited reduced gradient values in dorsal attention network and increased gradient values in subcortical regions compared to HCs. In the secondary gradient, patients with BN showed decreased gradient values in ventral attention network and increased gradient values in limbic network. Regionally, the areas with altered principal or secondary gradient values in BN group were mainly located in transmodal networks, i.e., the default-mode and frontoparietal network. In BN group, the principal gradient values of right inferior frontal gyrus were negatively associated with external eating behavior. This study revealed the disordered network hierarchy patterns in patients with BN, which suggested a disturbance of brain information integration from attention network and subcortical regions to transmodal networks in these patients. These findings may provide insight into the neurobiological underpinnings of BN.

Necroptosis activates UPR sensors without disrupting their binding with GRP78.

Necroptosis is a form of regulated necrosis mediated by the formation of the necrosome, composed of the RIPK1/RIPK3/MLKL complex. Here, we developed a proximity ligation assay (PLA) that allows in situ visualization of necrosomes in necroptotic cells and in vivo. Using PLA assay, we show that necrosomes can be found in close proximity to the endoplasmic reticulum (ER). Furthermore, we show that necroptosis activates ER stress sensors, PERK, IRE1α, and ATF6 in a RIPK1-RIPK3-MLKL axis-dependent manner. Activated MLKL can be translocated to the ER membrane to directly initiate the activation of ER stress signaling. The activation of IRE1α in necroptosis promotes the splicing of XBP1, and the subsequent incorporation of spliced XBP1 messenger RNA (mRNA) into extracellular vesicles (EVs). Finally, we show that unlike that of a conventional ER stress response, necroptosis promotes the activation of unfolded protein response (UPR) sensors without affecting their binding of GRP78. Our study reveals a signaling pathway that links MLKL activation in necroptosis to an unconventional ER stress response.

Removal and reduction mechanism of Cr (VI) in Leersia hexandra Swartz constructed wetland-microbial fuel cell coupling system.

Cr (VI) is extremely harmful to both the environment and human health, and it can linger in the environment for a very long period. In this research, the Leersia hexandra Swartz constructed wetland-microbial fuel cell (CW-MFC) system was constructed to purify Cr (VI) wastewater. By comparing with the constructed wetland (CW) system, the system electricity generation, pollutants removal, Cr enrichment, and morphological transformation of the system were discussed. The results demonstrated that the L. hexandra CW-MFC system promoted removal of pollutants and production of electricity of the system. The maximum voltage of the system was 499 mV, the COD and Cr (VI) removal efficiency was 93.73% and 97.00%. At the same time, it enhanced the substrate and L. hexandra ability to absorb Cr and change it morphologically transformation. Additionally, the results of XPS and XANES showed that the majority of the Cr in the L. hexandra and substrate was present as Cr (III). In the L. hexandra CW-MFC system, Geobacter also functioned as the primary metal catabolic reducing and electrogenic bacteria. As a result, L. hexandra CW-MFC system possesses the added benefit of removing Cr (VI) while producing energy compared to the traditional CW system.

Utility-Driven End-to-End Network Slicing for Diverse IoT Users in MEC: A Multi-Agent Deep Reinforcement Learning Approach.

Mobile Edge Computing (MEC) is crucial for reducing latency by bringing computational resources closer to the network edge, thereby enhancing the quality of services (QoS). However, the broad deployment of cloudlets poses challenges in efficient network slicing, particularly when traffic distribution is uneven. Therefore, these challenges include managing diverse resource requirements across widely distributed cloudlets, minimizing resource conflicts and delays, and maintaining service quality amid fluctuating request rates. Addressing this requires intelligent strategies to predict request types (common or urgent), assess resource needs, and allocate resources efficiently. Emerging technologies like edge computing and 5G with network slicing can handle delay-sensitive IoT requests rapidly, but a robust mechanism for real-time resource and utility optimization remains necessary. To address these challenges, we designed an end-to-end network slicing approach that predicts common and urgent user requests through T distribution. We formulated our problem as a multi-agent Markov decision process (MDP) and introduced a multi-agent soft actor-critic (MAgSAC) algorithm. This algorithm prevents the wastage of scarce resources by intelligently activating and deactivating virtual network function (VNF) instances, thereby balancing the allocation process. Our approach aims to optimize overall utility, balancing trade-offs between revenue, energy consumption costs, and latency. We evaluated our method, MAgSAC, through simulations, comparing it with the following six benchmark schemes: MAA3C, SACT, DDPG, S2Vec, Random, and Greedy. The results demonstrate that our approach, MAgSAC, optimizes utility by 30%, minimizes energy consumption costs by 12.4%, and reduces execution time by 21.7% compared to the closest related multi-agent approach named MAA3C.

Characteristics of white matter alterations along fibres in patients with bulimia nervosa: A combined voxelwise and tractography study.

Accumulating evidence supports the hypothesis that white matter (WM) abnormalities are involved in the pathophysiology of bulimia nervosa (BN); however, findings from in vivo neuroimaging studies have been inconsistent. We aimed to investigate the possible brain WM alterations, including WM volume and microstructure, in patients with BN. We recruited 43 BN patients and 31 healthy controls (HCs). All participants underwent structural and diffusion tensor imaging. Differences in WM volume and microstructure were evaluated using voxel-based morphometry, tract-based spatial statistics, and automated fibre quantification analysis. Compared with HCs, BN patients showed significantly decreased fractional anisotropy in the middle part of the corpus callosum (nodes 31-32) and increased mean diffusivity in the right cranial nerve V (CN V) (nodes 27-33 and nodes 55-88) and vertical occipital fasciculus (VOF) (nodes 58-85). Moreover, we found decreased axial diffusivity in the right inferior fronto-occipital fasciculus (node 67) and increased radial diffusivity in the CN V (nodes 22-34 and nodes 52-89) and left VOF (nodes 60-66 and nodes 81-85). Meanwhile, WM microstructural changes were correlated with patients' clinical manifestations. We did not find any significant differences in WM volume and the main WM fibre bundle properties between BN patients and HCs. Taken together, these findings provide that BN shows significant brain WM reorganization, but primarily in microstructure (part of WM fibre bundle), which is not sufficient to cause changes in WM volume. The automated fibre quantification analysis could be more sensitive to detect the subtle pathological changes in a point or segment of the WM fibre bundle.

Improving Cooperative Interactions Between Halogenated Aromatic Additives and Aromatic Side Chain Acceptors for Realizing 19.22% Efficiency Polymer Solar Cells.

Processing additive plays an important role in the standard operation procedures for fabricating top performing polymer solar cells (PSCs) through efficient interactions with key photovoltaic materials. However, improving interaction study of acceptor materials to high performance halogenated aromatic additives such as diiodobenzene (DIB) is a widely neglected route for molecular engineering toward more efficient device performances. In this work, two novel Y-type acceptor molecules of BTP-TT and BTP-TTS with different aromatic side chains on the outer positions are designed and synthesized. The resulting aromatic side chains significantly enhanced the interactions between the acceptor molecules and DIB through an arene/halogenated arene interaction, which improved the crystallinity of the acceptor molecules and induced a polymorph with better photovoltaic performances. Thus, high power conversion efficiencies (PCEs) of 18.04% and 19.22% are achieved in binary and ternary blend devices using BTP-TTS as acceptor and DIB as additive. Aromatic side chain engineering for improving additive interactions is proved to be an effective strategy for achieving much higher performance photovoltaic materials and devices.

The role of functional and structural properties of the nucleus accumbens subregions in eating behavior regulation of bulimia nervosa.

OBJECTIVE: Although studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. This study investigated the structural and functional properties of NAc in patients with BN. METHOD: Based on the resting-state functional MRI and high-resolution anatomical T1-weighted imaging data acquired from 43 right-handed BN patients and 40 sex-, age- and education-matched right-handed healthy controls (HCs), the group differences in gray matter volume (GMV) and fractional amplitude of low-frequency fluctuation (fALFF) in slow-4 and -5 bands and functional connectivity (FC) of NAc subregions (core and shell) were compared. The relationships between MRI and clinical data were explored in the BN group. RESULTS: Compared with HCs, BN patients showed preserved GMV, decreased fALFF in slow-5 band of the left NAc core and shell, decreased FC between left NAc core and right caudate, and increased FC between all NAc subregions and frontal regions, between all NAc subregions (except the right NAc core) and the supramarginal gyrus (SMG), and between right NAc shell and left middle temporal gyrus. FC between the NAc and SMG was correlated with emotional eating behaviors. DISCUSSION: Our study revealed preserved GMV, local neuronal activity reduction and functional network reorganization of the NAc in BN. The functional network reorganization of the NAc mainly occurred in the frontal cortex and was correlated with emotional eating behavior. These findings may provide novel insights into the BN using NAc as an entry point. PUBLIC SIGNIFICANCE: Although studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. We used a multimodal MRI technique to systematically investigate structural and functional alterations in NAc subregions of BN patients and explored the associations between such alterations and maladaptive eating behaviors, hoping to provide novel insights into BN.

The disruption of white matter integrity of systemic striatal circuits in alcohol-dependent males with physiological cue reactivity.

Alcohol dependence (AD) is a chronic and relapsing disorder. Conditioned cues associated with the rewarding properties of drugs could trigger motivational/physiological reactions and render subjects vulnerable to relapse. Striatal circuit dysfunction has been implicated in alcohol addiction behaviours. However, little is known about the striatal tracts structural connectivity changes underlying cue induced reactivity in AD. In our present study, we recruited 51 patients with AD; 31 individuals had physiological response. We used seed-based classification by probabilistic tractography with nine target masks to explore the white matter integrity of striatal circuits in physiological responders (N = 31), non-responders (N = 20), and healthy controls (N = 27). Compared with healthy controls, physiological responders showed lower fractional anisotropy (FA) and/or higher mean diffusivity in the striatum-dorsolateral prefrontal cortex (dlPFC), striatum-ventral lateral prefrontal cortex, striatum-supplementary motor area (SMA), and striatum-insular. Considering age and smoking are potential nuisances to diffusion parameters, an analysis of covariance also was conducted and similar results were found. We also found the cue-induced physiological response was negatively associated with the FA of the striatum-SMA (r = -0.287; p = 0.045) and left striatum-dlPFC (r = -0.253; p = 0.079) in AD. In our study, we found abnormal integrity of striatal circuit structural connectivity in AD with physiological cue reactivity, especially trajectory from prefrontal cortex and insular. We also found the FA of striatal tracks was negatively associated with the degree of cue reactivity. Our findings provide further evidence for reduced white matter integrity of striatal circuits for cue reactivity in male individuals with AD.

Partial Segregation of Bi and Microvoid Formation on a Pure Cu Substrate After Solid-Solid Reactions.

With the trend of technology development and carbon reduction, reducing the process temperature to prevent greenhouse effects is of great urgency. The back-end process of semiconductors is increasingly important because of the limitation of Moore's Law. High-temperature bonding is serious for semiconductor packages, which induces high cost and device damage. One of the critical ways to reduce the process temperature is to adopt low-temperature solders. In this study, we utilize the low-temperature solder Sn58Bi to achieve energy savings and device protection. The interfacial reactions between Sn58Bi and Cu after reflow and aging reactions were investigated. The solubility of Bi in Sn influences the Bi segregation at the interface. Partial Bi segregation, microvoids, and uneven Cu3Sn were observed at the interface after aging. There is no doubt that the aforementioned structures are unfavorable for solder joint strength.

The restorative effects of short-term exposure to nature in immersive virtual environments (IVEs) as evidenced by participants' brain activities.

Short-term exposure to nature has excellent potential to be used as a public health intervention measure. Nevertheless, the physiological and psychological mechanisms of this health benefit are still unclear. In this study, we intend to verify the effects of short-term exposure to nature on psychological functioning and to explore the underlying mechanism through experiments conducted in immersive virtual environments (IVEs). Participants were randomly exposed to videos of an urban forest and an indoor environment in IVEs. Before and after the exposure, a participant's self-perceived stress and cognitive performance were measured using the PSS-14 form and the Stroop task, respectively. Their brain activities during the exposure were measured using the electroencephalogram (EEG). The PSS-14 and the Stroop task results confirmed the benefits of stress reduction and cognitive performance improvements from short-term nature exposure. At the same time, rhythmic brain activities during nature exposure indicated better attentional states. The electrodes around the parietal region detected significantly stronger power spectral density of the theta band than other bands. Also, participants showed high functional connectivity among different brain parts during nature exposure, which revealed better cognitive flexibility. The topographic pattern of the differences in functional connectivity overlapped well with the default mode network (DMN)-a "task-negative" network active during the resting state. The overlap indicated a lower cognitive processing load when exposing to nature. Our results support the hypothesis that nature's restorative effects mainly come from effortless processing in natural environments.

Uncovering neural pathways underlying bulimia nervosa: resting-state neural connectivity disruptions correlate with maladaptive eating behaviors.

PURPOSE: Bulimia nervosa (BN) is characterized by recurrent binge-eating episodes and inappropriate compensatory behaviors. This study investigated alterations in resting-state surface-based neural activity in BN patients and explored correlations between brain activity and eating behavior. METHODS: A total of 26 BN patients and 28 healthy controls were enrolled. Indirect measurement of cerebral cortical activity and functional connectivity (FC) analyses were performed in Surfstat. A principal component analysis (PCA) model was used to capture the commonalities within the behavioral questionnaires from the BN group. RESULTS: Compared with the healthy control group, the BN group showed decreased surface-based two-dimensional regional homogeneity in the right superior parietal lobule (SPL). Additionally, the BN group showed decreased FC between the right SPL and the bilateral lingual gyrus and increased FC between the right SPL and the left caudate nucleus and right putamen. In the FC-behavior association analysis, the second principal component (PC2) was negatively correlated with FC between the right SPL and the left caudate nucleus. The third principal component (PC3) was negatively correlated with FC between the right SPL and the left lingual gyrus and positively correlated with FC between the right SPL and the right lingual gyrus. CONCLUSION: We revealed that the right SPL undergoes reorganization with respect to specific brain regions at the whole-brain level in BN. In addition, our results suggest a correlation between brain reorganization and maladaptive eating behavior. These findings may provide useful information to better understand the neural mechanisms of BN. LEVEL OF EVIDENCE: V, descriptive study.

Multi-channel higher-order OAM generation and switching based on a mode selective interferometer.

A multi-channel orbital angular momentum (OAM) mode generation and switching scheme is proposed and demonstrated based on an in-fiber mode selective interferometer (MSI), which is formed in a four-mode fiber. The MSI consists of two strong modulated long-period fiber gratings (LPFGs), which realizes the mode selected coupling between a target mode pair. With the optimized structural parameters, the MSI can couple a launched LP01 (or OAM0) into a desired higher-order azimuthal mode (HAM, LPl1 or OAM±l, l≥1) at multiple wavelength channels and generate the HAM with high-purity. To verify this concept, we fabricate two LPFGs in a four-mode fiber with designed distance and hence realize a MSI which can generate the second-order HAM (OAM2 or LP21) at 17 wavelength channels. The mode conversion efficiency is more than 90% at 17 wavelengths and the corresponding mode purity is no less than 97%, respectively. In addition, we also demonstrate that the selected mode pair (OAM0 and OAM2) can be switched at multiple channels by changing the state of the MSI. This MSI can also be used as a wavelength band-rejection filter on different spatial modes and find potential applications in optical communications and sensing.

Mediating role of impaired wisdom in the relation between childhood trauma and psychotic-like experiences in Chinese college students: a nationwide cross-sectional study.

BACKGROUND: The association between childhood trauma (CT) and psychotic-like experiences (PLEs) is well-established. Many previous studies have recognized wisdom as a protective factor for mental health, but its role in the relation between CT and PLEs remains unknown. We aimed to investigate the mediating effect of wisdom in the above association among Chinese college students. METHODS: We conducted a nationwide survey covering 9 colleges across China and recruited a total of 5873 students using online questionnaires between September 14 and October 18, 2021. Convenience sampling was adopted. We employed the San Diego Wisdom Scale (SD-WISE), the Childhood Trauma Questionnaire (CTQ-28), and the 15-item Positive Subscale of the Community Assessment of Psychic Experiences (CAPE-15) to measure the wisdom, CT and PLEs, respectively. Descriptive, correlation, and mediation analysis were utilized. RESULTS: The positive correlation between CT and PLEs was well-replicated among college students (Pearson's r = 0.30, p < 0.001). Wisdom was negatively associated with CT (Pearson's r = - 0.46, p < 0.001) and frequency of PLEs (Pearson's r = - 0.25, p < 0.001). Total wisdom scores partially mediated the relationship between cumulative childhood trauma, neglect, abuse and PLEs, separately. The mediated model respectively explained 21.9%, 42.54% and 18.27% of the effect of CT on PLEs. Our model further suggested that childhood trauma could be related to PLEs through decreasing the following wisdom components: decisiveness, emotional regulation and prosocial behavior. CONCLUSION: For the first time, our results suggested that impaired wisdom played a role in the translation from childhood adversity to subclinical psychotic symptoms, implicating wisdom as a possible target for early intervention for psychosis among young individuals. Longitudinal work is warranted to verify the clinical implications.

Analysis of EZH2 Genetic Variants on Triple-Negative Breast Cancer Susceptibility and Pathology.

Triple-negative breast cancer (TNBC) is the third most common female cancer in Taiwan. EZH2 plays an important role in cancer development through transcriptional repression by chromatin remodeling. However, the expression of EZH2 in breast cancer is highly correlated with tumorigenesis, and patient survival is not matched to TNBC. Furthermore, it has not been determined if specific EZH2 genetic variants are associated with breast cancer risk. In this paper, we evaluated the survival of different types of breast cancer. The results indicated that a lower expression of EZH2 led to poor survival of TNBC patients. Therefore, we aimed at studying the relationship between genetic polymorphisms of EZH2 and susceptibility to TNBC in Taiwan. Four single-nucleotide polymorphisms (SNPs) of EZH2 (rs6950683, rs2302427, rs3757441, and rs41277434) were analyzed by real-time PCR genotyping in 176 patients with TNBC and 1000 cancer-free controls. The results showed that TNBC patients under 60 years old who carried a TC or CC genotype at EZH2 rs6950683 and re3757441 had a tumor size of 20 mm or smaller (T1). Thus, this study is the first to examine the age and mutant genes associated with EZH2 SNPs in TNBC progression and development in Taiwan.

Chaperone-mediated autophagy is involved in the execution of ferroptosis.

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.