Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma.

Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.

Changes in electroencephalography microstates are associated with reduced levels of vigilance after sleep deprivation.

Total sleep deprivation (TSD) negatively affects cognitive functions, especially vigilance attention, but studies on vigilance changes in terms of electroencephalography (EEG) microstates after TSD are limited. This study investigates the impact of TSD on vigilance attention, EEG microstates and its relationship. Thirty healthy adult males completed a psychomotor vigilance task (PVT) before, 24 h after, and 36 h after TSD while their EEG was recorded during rest. Microstate analysis revealed significant changes in the occurrence and contribution of microstate class B after TSD. Moreover, changes in the probability of transitioning between microstate classes A and D were observed, correlating with decreased vigilance. Specifically, a positive correlation was found between transitioning from class B to class C and vigilance, while a trend of negative correlation was observed between transitioning between classes A and D and vigilance. These findings indicate abnormal activity in the salience network and dorsal attention network following sleep deprivation. TSD impairs vigilance attention, as demonstrated by the effects on EEG microstate class B and the transitions between classes A and D. The study suggests its potential as an early warning indicator for predicting vigilance attention after sleep deprivation.

Total Sleep Deprivation Triggers a Compensatory Mechanism During Conflict Monitoring Process: Evidence From Event-Related Potentials.

Sleep deprivation impairs cognitive function and is accompanied by a simultaneous compensatory effect, one of the brain's capacities to maintain function in emergency situations. However, the time course of the compensatory effect is unclear. In this study, 22 male participants completed a pronunciation working memory task that included congruent and incongruent stimuli trials with EEG recordings before and after total sleep deprivation (TSD). Behavioral performance analysis showed that after TSD, the participants' reaction time (RT) was shortened, but accuracy was reduced significantly. Analysis of event-related potential (ERP) results showed that the amplitude of N2 (an early visual ERP) was larger (i.e., more negative) after TSD than at baseline. A significant interaction between congruency and sleep condition was seen. Compared to that before TSD, the increase in amplitude of P3 (a stimulus-induced positive deflection component) under an incongruent stimulus was larger than that under a congruent stimulus after TSD. Moreover, a significant negative correlation was found between P3 amplitude and RT. Our results suggest that TSD impairs cognitive function. Meanwhile, the brain activates a compensatory mechanism after TSD, which is comprehensive during the conflict-detection and information-updating stages. This study provides a fresh viewpoint for understanding how TSD affects cognitive function.

Decrease in the P2 Amplitude of Object Working Memory after 8 h-Recovery Sleep Following 36 h-Total Sleep Deprivation: An ERP Study.

The impact of sleep deprivation on working memory can only be reversed by recovery sleep (RS). However, there are limited electrophysiological studies on the effect of RS on the improvement in working memory after sleep deprivation, and the changes in the early components of event-related potentials (ERPs) before and after RS are still unclear. Therefore, this study aims to explore the effects of RS on the earlier ERP components related to object working memory following 36 h of total sleep deprivation (TSD). Twenty healthy male participants performed an object working memory task after 36 h of TSD and after 8 h of RS. Electroencephalogram data were recorded accordingly while the task was performed. Repeated ANOVA showed that P2 amplitudes related to object working memory decreased significantly after 8 h of RS compared to after a 36 h period of TSD, but there was no significant difference from baseline (BS), which indicates a trend of recovery to the baseline state. An 8 h RS can partially improve impaired object working memory caused by TSD. However, a longer period of RS is needed for the complete recovery of cognitive function after a long period of TSD.

Total sleep deprivation reduces the table tennis anticipation performance of young men: A functional magnetic resonance imaging study.

This study explored whether and how sleep deprivation (SD) affects sport-related anticipation. Twenty table tennis players and 28 non-athletes completed a table tennis anticipation task before and after 36 h SD. Functional magnetic resonance imaging (fMRI) data were acquired simultaneously. The results showed that, compared with the non-athletes, table tennis players had higher neural efficiency, manifested by their higher anticipation accuracy and lower frontal lobe activation. SD impaired anticipation performance, accompanied by decreased activation of the occipital and temporal lobes. Compensatory activation occurred in the left hippocampus and orbital part of the right inferior frontal gyrus (IFG) after SD in the table tennis player group, but not in the non-athlete group. The decreased accuracy of non-athletes was positively correlated with decreased activation of orbital part of the right IFG. This study's findings improve the understanding of the cognitive neuroscience mechanisms by which SD affects sport-related anticipation.

C-reactive protein impairs immune response of CD8+ T cells via FcγRIIb-p38MAPK-ROS axis in multiple myeloma.

BACKGROUND: C-reactive protein (CRP) is a prototypical acute phase protein in humans with the function of regulating immune cells. Serum CRP levels are elevated in multiple myeloma (MM), associated with MM cell proliferation and bone destruction. However, its direct effects on T lymphocytes in MM have not been elucidated. METHODS: Public data sets were used to explore the correlation of CRP levels with immune cell infiltration and cytotoxicity score of CD8+ T cells in MM. In vitro, repeated freeze-thaw myeloma cell lines were taken as tumor antigens to load dendritic cells (DCs) derived from HLA-A*0201-positive healthy donors. MM-specific cytotoxic T cells (MM-CTL) were obtained from T lymphocytes of the corresponding donors pulsed with these DCs. B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells were manipulated by transfecting with lentivirus encoding an anti-BCMA single-chain variable fragment. Then T cells from healthy controls, MM-CTLs and BCMA CAR-T cells were exposed to CRP and analyzed for cell proliferation, cytotoxicity, immunophenotypes. CRP binding capacity to T cells before and after Fc gamma receptors IIb (FcγRIIb) blockage, p38 mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were also detected. In vivo, both normal C57BL/6J mice and the Vk*MYC myeloma mouse models were applied to confirm the impact of CRP on T cells. RESULTS: CRP levels were negatively correlated with cell-infiltration and cytotoxicity score of CD8+ T cells in MM. In vitro experiments showed that CRP inhibited T-cell proliferation in a dose-dependent manner, impaired the cytotoxic activity and upregulated expression of senescent markers in CD8+ T cells. In vivo results validated the suppressive role of CRP in CD8+ T cells. CRP could bind to CD8+ T cells, mainly to the naïve T subset, while the binding was dramatically decreased by FcγRIIb blockage. Furthermore, CRP resulted in increased phosphorylation of p38 MAPK, elevated levels of reactive oxygen species and oxidized glutathione in CD8+ T cells. CONCLUSIONS: We found that CRP impaired immune response of CD8+ T cells via FcγRIIb-p38MAPK-ROS signaling pathway. The study casted new insights into the role of CRP in anti-myeloma immunity, providing implications for future immunotherapy in MM.

CXCL10 Recruitment of γδ T Cells into the Hypoxic Bone Marrow Environment Leads to IL17 Expression and Multiple Myeloma Progression.

In multiple myeloma (MM), bone marrow stromal cells (BMSC) shape a unique niche within the bone marrow, promoting T-cell dysfunction and driving MM progression; however, the precise underlying mechanisms remain elusive. Here, we show that BMSC-mediated reprogramming of MM cells led to heightened production of CXCL10. CXCL10 orchestrated the recruitment of γδ T cells into the bone marrow, and this was observed in both the Vk*MYC and 5TGM1 mouse models of MM, as well as in patients experiencing refractory or relapsed MM. Furthermore, the dysfunctional γδ T cells in the MM bone marrow niche exhibited increased PD-1 expression and IL17 production. In the Vk*MYC mouse model, MM-associated bone lesions and mortality were markedly alleviated in Tcrd-/- mice, and MM disease progression could be rescued in these mice upon transplantation of γδ T cells expanded from wild-type mice, but not from Il17-/- mice. Mechanistically, the hypoxic microenvironment prevailing in the MM bone marrow niche stimulated the expression of steroid receptor coactivator 3 (SRC-3) in γδ T cells, which in turn interacted with the transcriptional factor RORγt, promoting Il17 transcription. Pharmacologic inhibition of SRC-3 utilizing SI-2 effectively suppressed Il17A expression in γδ T cells, leading to alleviation of MM progression in the murine models and enhancing the anti-multiple myeloma efficacy of bortezomib. Our results illuminated the bone marrow microenvironment's involvement in provoking γδ T-cell dysfunction throughout MM progression and suggest SRC-3 inhibition as a promising strategy to enhance the effectiveness of immunotherapies targeting γδ T cells.

Whole Blood-Derived circUSP10 Acts as a Diagnostic Biomarker in Patients With Early-Stage Non-Small-Cell Lung Cancer.

Accumulating evidence has indicated that differentially expressed noncoding circular RNAs (circRNAs) play essential roles in the occurrence and development of various types of cancer. Here, we aimed to identify and explore the diagnostic value of hsa_circ_0003026 (named circUSP10) in patients with early non-small-cell lung cancer (NSCLC). The differentially expressed circRNAs were screened from the microarray-based assay of human NSCLC tissues and their corresponding noncancerous tissues, and the candidate circRNAs were further verified in patients with NSCLC using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Circulating circUSP10 was isolated from whole blood of healthy people and patients with NSCLC and was detected by RT-qPCR. In addition, the diagnostic value of circUSP10 in early NSCLC was evaluated by receiver operating characteristic (ROC) curve analysis. We found that circUSP10 was upregulated in tumor tissues from patients with early NSCLC and associated with tumor size and tumor-node-metastasis (TNM) stage. Importantly, circUSP10 was obviously upregulated in the whole blood of patients with NSCLC. Additionally, whole blood-derived circUSP10 showed good diagnostic performance for screening early NSCLC and was relatively stable in blood under adverse conditions. These findings demonstrate that circUSP10 may act as a novel biomarker for the diagnosis of early-stage NSCLC, suggesting the potential of circUSP10 in RNA-based therapy for cancer.

Total sleep deprivation impairs visual selective attention and triggers a compensatory effect: evidence from event-related potentials.

Many studies have demonstrated the impairment of sustained attention due to total sleep deprivation (TSD). However, it remains unclear whether and how TSD affects the processing of visual selective attention. In the current study, 24 volunteers performed a visual search task before and after TSD over a period of 36 h while undergoing spontaneous electroencephalography. Paired-sample t-tests of behavioral performance revealed that, compared with baseline values, the participants showed lower accuracy and higher variance in response time in visual search tasks performed after TSD. Analysis of the event-related potentials (ERPs) showed that the mean amplitude of the N2-posterior-contralateral (N2pc) difference wave after TSD was less negative than that at baseline and the mean amplitude of P3 after TSD was more positive than that at baseline. Our findings suggest that TSD significantly attenuates attentional direction/orientation processing and triggers a compensatory effect in the parietal brain to partially offset the impairments. These findings provide new evidence and improve our understanding of the effects of sleep loss.

Reduced Resting-State EEG Power Spectra and Functional Connectivity after 24 and 36 Hours of Sleep Deprivation.

Total sleep deprivation (TSD) leads to cognitive decline; however, the neurophysiological mechanisms underlying resting-state electroencephalogram (EEG) changes after TSD remain unclear. In this study, 42 healthy adult participants were subjected to 36 h of sleep deprivation (36 h TSD), and resting-state EEG data were recorded at baseline, after 24 h of sleep deprivation (24 h TSD), and after 36 h TSD. The analysis of resting-state EEG at baseline, after 24 h TSD, and after 36 h TSD using source localization analysis, power spectrum analysis, and functional connectivity analysis revealed a decrease in alpha-band power and a significant increase in delta-band power after TSD and impaired functional connectivity in the default mode network, precuneus, and inferior parietal lobule. The cortical activities of the precuneus, inferior parietal lobule, and superior parietal lobule were significantly reduced, but no difference was found between the 24 h and 36 h TSD groups. This may indicate that TSD caused some damage to the participants, but this damage temporarily slowed during the 24 h to 36 h TSD period.

Recovery sleep attenuates impairments in working memory following total sleep deprivation.

Introduction: The detrimental effects of sleep deprivation (SD) on cognitive function and quality of life are well known, and sleep disturbances are a major physical and mental health issue worldwide. Working memory plays an important role in many complex cognitive processes. Therefore, it is necessary to identify strategies that can effectively counteract the negative effects of SD on working memory. Methods: In the present study, we utilized event-related potentials (ERPs) to investigate the restorative effects of 8 h of recovery sleep (RS) on working memory impairments induced by total sleep deprivation for 36 h. We analyzed ERP data from 42 healthy male participants who were randomly assigned to two groups. The nocturnal sleep (NS) group completed a 2-back working memory task before and after normal sleep for 8 h. The sleep deprivation (SD) group completed a 2-back working memory task before and after 36 h of total sleep deprivation (TSD) and after 8 h of RS. Electroencephalographic data were recorded during each task. Results: The N2 and P3 components-which are related to working memory-exhibited low-amplitude and slow-wave characteristics after 36 h of TSD. Additionally, we observed a significant decrease in N2 latency after 8 h of RS. RS also induced significant increases in the amplitude of the P3 component and in the behavioral indicators. Discussion: Overall, 8 h of RS attenuated the decrease in working memory performance caused by 36 h of TSD. However, the effects of RS appear to be limited.

Altered Postcentral Connectivity after Sleep Deprivation Correlates to Impaired Risk Perception: A Resting-State Functional Magnetic Resonance Imaging Study.

BACKGROUND: Previous studies revealed that sleep deprivation (SD) impairs risk perception and leads to poor decision-making efficiency. However, how risk perception is related to brain regions' communication after SD has not been elucidated. In this study, we investigated the neuropsychological mechanisms of SD-impaired risk perception. METHODS: Nineteen healthy male adults were recruited and underwent resting-state functional magnetic resonance imaging during a state of rested wakefulness and after nearly 36 h of total SD. They then completed the balloon analog risk task, which was used to measure the risk perception ability of risky decision-making. Regional homogeneity (ReHo) and voxel-wise functional connectivity were used to investigate neurobiological changes caused by SD. Correlation analysis was used to investigate the relationship between changes in ReHo, function, and risk perception. RESULTS: At the behavioral level, risk perception decreased after 36 h of SD. At the neural level, SD induced a significant increase in ReHo in the right postcentral gyrus and was positively correlated with risk perception changes. The functional connectivity between the right postcentral gyrus, left medial temporal gyrus, and right inferior temporal gyrus was enhanced. Critically, increased right postcentral gyrus and right inferior temporal gyrus connectivity positively correlated with changes in risk perception. CONCLUSIONS: SD impairs the risk perception associated with altered postcentral connectivity. The brain requires more energy to process and integrate sensory and perceptual information after SD, which may be one possible reason for decreased risk perception ability after SD.

Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance.

Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.

Total sleep deprivation selectively impairs motor preparation sub-stages in visual search task: Evidence from lateralized readiness potentials.

Introduction: Many studies have provided evidence of a damage effect triggered by total sleep deprivation (TSD). However, it remains unclear whether the motor preparation processing is affected by TSD. Methods: In the current study, 23 volunteers performed a stimulus-response compatibility visual search task before and after TSD while undergoing spontaneous electroencephalography (EEG). Results: Repeated-measures analysis of variance revealed that: Compared with that at baseline, the visual search task's accuracy decreased after TSD, while the response time variance increased significantly. The peak amplitude of the stimulus-locked lateralized readiness potential (LRP) induced by a compatible stimulus was significantly more negative than that induced by an incompatible stimulus before TSD, whereas this difference was not significant after TSD. However, when taking sleep status into consideration, there were no significant main or interaction effects on response-locked LRPs. Discussion: Our findings suggest that TSD damages visual search behavior, selectively impairs the earlier sub-stages of motor preparation (sensory integration). These findings will provide a new perspective for understanding the effects of sleep loss.

Decreased Functional Connectivity of Brain Networks in the Alpha Band after Sleep Deprivation Is Associated with Decreased Inhibitory Control in Young Male Adults.

Sleep deprivation leads to reduced inhibitory control in individuals. However, the underlying neural mechanisms are poorly understood. Accordingly, this study aimed to investigate the effects of total sleep deprivation (TSD) on inhibitory control and their neuroelectrophysiological mechanisms from the perspective of the time course of cognitive processing and brain network connectivity, using event-related potential (ERP) and resting-state functional connectivity techniques. Twenty-five healthy male participants underwent 36 h of TSD (36-h TSD), completing Go/NoGo tasks and resting-state data acquisition before and after TSD; their behavioral and electroencephalogram data were recorded. Compared to baseline, participants' false alarms for NoGo stimuli increased significantly (t = -4.187, p < 0.001) after 36-h TSD. ERP results indicated that NoGo-N2 negative amplitude increased and latency was prolonged (t = 4.850, p < 0.001; t = -3.178, p < 0.01), and NoGo-P3 amplitude significantly decreased and latency was prolonged (t = 5.104, p < 0.001; t = -2.382, p < 0.05) after 36-h TSD. Functional connectivity analysis showed that the connectivity of the default mode and visual networks in the high alpha band was significantly reduced after TSD (t = 2.500, p = 0.030). Overall, the results suggest that the negative amplitude increase in N2 after 36-h TSD may reveal that more attention and cognitive resources are invested after TSD; the significant decrease in P3 amplitude may indicate the impairment of advanced cognitive processing. Further functional connectivity analysis indicated impairment of the brain's default mode network and visual information processing after TSD.

All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma.

BACKGROUND: Immunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored. METHODS: The efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl /SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging. RESULTS: We report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo. CONCLUSION: This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now.

Dynamic hippocampal functional connectivity responses to varying working memory loads following total sleep deprivation.

Sleep loss with work overload can impact human cognitive performance. However, the brain's response to an increased working memory load following total sleep deprivation (TSD) remains unclear. In the present study, we focussed on the dynamic response of the hippocampus to increased working memory load before and after total sleep deprivation of 36 h. A total of 16 male participants completed a verbal working memory task under functional magnetic resonance imaging. After whole-brain activation analysis and region of interest analysis of the hippocampus, the generalised form of context-dependent psychophysiological interactions (gPPI) was used to analyse the hippocampal functional connectivity with the whole brain. The results revealed that as the working memory load increased within a small range, from 0-back to 1-back task, the left hippocampal functional connectivity decreased with the left supplementary motor area, left pars opercularis, left rolandic operculum, right superior frontal gyrus, bilateral precentral gyrus, and left middle cingulate cortex following total sleep deprivation compared with that observed in resting wakefulness. When the working memory load further increased from 1-back to 2-back task, the connectivity increased between the left hippocampus and the left superior parietal lobule as well as between the left hippocampus and right lingual gyrus after total sleep deprivation compared with that observed in resting wakefulness. Moreover, the left hippocampus gPPI effect on the left middle cingulate cortex and left superior parietal lobule could predict the behavioural test accuracy in 1-back and 2-back task, respectively, following total sleep deprivation. These findings indicated that increased working memory load after total sleep deprivation disrupts working memory processes. The brain reacts to these disruptions in a dynamic and flexible manner, involving not only brain activation but also hippocampus-related functional network connections.

The Lateralization of Spatial Cognition in Table Tennis Players: Neuroplasticity in the Dominant Hemisphere.

Spatial cognition facilitates the successful completion of specific cognitive tasks through lateral processing and neuroplasticity. Long-term training in table tennis induces neural processing efficiency in the visuospatial cognitive processing cortex of athletes. However, the lateralization characteristics and neural mechanisms of visual−spatial cognitive processing in table tennis players in non-sport domains are unclear. This study utilized event-related potentials to investigate differences in the spatial cognition abilities of regular college students (controls) and table tennis players. A total of 48 participants (28 controls; 20 s-level national table tennis players) completed spatial cognitive tasks while electroencephalography data were recorded. Task performance was better in the table tennis group than in the control group (reaction time: P < 0.001; correct number/sec: P = 0.043), P3 amplitude was greater in the table tennis group (P = 0.040), spatial cognition showed obvious lateralization characteristics (P < 0.001), table tennis players showed a more obvious right-hemisphere advantage, and the P3 amplitude in the right hemisphere was significantly greater in table tennis athletes than in the control group. (P = 0.044). Our findings demonstrate a right-hemisphere advantage in spatial cognition. Long-term training strengthened the visual−spatial processing ability of table tennis players, and this advantage effect was reflected in the neuroplasticity of the right hemisphere (the dominant hemisphere for spatial processing).

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma.

The bone marrow microenvironment in multiple myeloma (MM) is hypoxic and provides multi-advantages for the initiation of chemoresistance, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs), and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identified SENP1 as a key modifier of SRC-3 stability, as SENP1-mediated deSUMOylation attenuated the K11-linked polyubiquitination of SRC-3. SENP1 depletion in the SENP1fl/flCD19Cre/+ B cells showed impaired SRC3 stability, and knockdown of SENP1 in MM cells by CRISPR/cas9 sgRNA accelerated the degradation of SRC-3 and remarkably overcame the resistance to PIs. In the Vk*Myc and 5TGM1 mouse models as well as patient-derived xenograft (PDX) of myeloma, SENP1 inhibitor Momordin Ιc (Mc) increased the sensitivity to PIs in MM cells. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our findings suggest that hypoxia-induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.

Altered insular functional connectivity correlates to impaired vigilant attention after sleep deprivation: A resting-state functional magnetic resonance imaging study.

Objectives: This study used resting-state functional magnetic resonance imaging (rs-fMRI) scans to assess the dominant effects of 36 h total sleep deprivation (TSD) on vigilant attention and changes in the resting-state network. Materials and methods: Twenty-two healthy college students were enrolled in this study. Participants underwent two rs-fMRI scans, once in rested wakefulness (RW) and once after 36 h of TSD. We used psychomotor vigilance tasks (PVT) to measure vigilant attention. The region-of-interest to region-of-interest correlation was employed to analyze the relationship within the salience network (SN) and between other networks after 36 h of TSD. Furthermore, Pearson's correlation analysis investigated the relationship between altered insular functional connectivity and PVT performance. Results: After 36 h of TSD, participants showed significantly decreased vigilant attention. Additionally, TSD induced decreased functional connectivity between the visual and parietal regions, whereas, a significant increase was observed between the anterior cingulate cortex and insula. Moreover, changes in functional connectivity in the anterior cingulate cortex and insula showed a significant positive correlation with the response time to PVT. Conclusion: Our results suggest that 36 h of TSD impaired vigilant visual attention, resulting in slower reaction times. The decrease in visual-parietal functional connectivity may be related to the decrease in the reception of information in the brain. Enhanced functional connectivity of the anterior cingulate cortex with the insula revealed that the brain network compensation occurs mainly in executive function.