Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager.

Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE-sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation-that is, the removal of terminal sialic acid residues on glycans-at the BiTE-induced T-cell-tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE-sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers.

A Time-Local Weighted Transformation Recognition Framework for Steady State Visual Evoked Potentials Based Brain-Computer Interfaces.

Canonical correlation analysis (CCA), Multivariate synchronization index (MSI), and their extended methods have been widely used for target recognition in Brain-computer interfaces (BCIs) based on Steady State Visual Evoked Potentials (SSVEP), and covariance calculation is an important process for these algorithms. Some studies have proved that embedding time-local information into the covariance can optimize the recognition effect of the above algorithms. However, the optimization effect can only be observed from the recognition results and the improvement principle of time-local information cannot be explained. Therefore, we propose a time-local weighted transformation (TT) recognition framework that directly embeds the time-local information into the electroencephalography signal through weighted transformation. The influence mechanism of time-local information on the SSVEP signal can then be observed in the frequency domain. Low-frequency noise is suppressed on the premise of sacrificing part of the SSVEP fundamental frequency energy, the harmonic energy of SSVEP is enhanced at the cost of introducing a small amount of high-frequency noise. The experimental results show that the TT recognition framework can significantly improve the recognition ability of the algorithms and the separability of extracted features. Its enhancement effect is significantly better than the traditional time-local covariance extraction method, which has enormous application potential.

Highly Sensitive and Selective Defect WS2 Chemical Sensor for Detecting HCHO Toxic Gases.

The gas sensitivity of the W defect in WS2 (VW/WS2) to five toxic gases-HCHO, CH4, CH3HO, CH3OH, and CH3CH3-has been examined in this article. These five gases were adsorbed on the VW/WS2 surface, and the band, density of state (DOS), charge density difference (CDD), work function (W), current-voltage (I-V) characteristic, and sensitivity of adsorption systems were determined. Interestingly, for HCHO-VW/WS2, the energy level contribution of HCHO is closer to the Fermi level, the charge transfer (B) is the largest (0.104 e), the increase in W is more obvious than other adsorption systems, the slope of the I-V characteristic changes more obviously, and the calculated sensitivity is the highest. To sum up, VW/WS2 is more sensitive to HCHO. In conclusion, VW/WS2 has a great deal of promise for producing HCHO chemical sensors due to its high sensitivity and selectivity for HCHO, which can aid in the precise and efficient detection of toxic gases.

Delineation and authentication of ferroptosis genes in ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation, a critical support strategy for individuals enduring severe respiratory failure and general anesthesia, paradoxically engenders ventilator-induced lung injury (VILI). Ferrostatin-1 mitigates lung injury via ferroptosis inhibition, yet the specific ferroptosis genes contributing significantly to VILI remain obscure. METHODS: Leveraging the Gene Expression Omnibus database, we acquired VILI-associated datasets and identified differentially expressed genes (DEGs). To identify the hub genes, we constructed a protein-protein interaction network and used three parameters from CytoHubba. Consequently, we identified hub genes and ferroptosis genes as ferroptosis hub genes for VILI (VFHGs). We conducted enrichment analysis and established receiver operating characteristic (ROC) curves for VFHGs. Subsequently, to confirm the correctness of the VFHGs, control group mice and VILI mouse models, as well as external dataset validation, were established. For further research, a gene-miRNA network was established. Finally, the CIBERSORT algorithm was used to fill the gap in the immune infiltration changes in the lung during VILI. RESULTS: We identified 64 DEGs and 4 VFHGs (Il6,Ptgs2,Hmox1 and Atf3) closely related to ferroptosis. ROC curves demonstrated the excellent diagnostic performance of VFHGs in VILI. PCR and external dataset validation of the VILI model demonstrated the accuracy of VFHGs. Subsequently, the gene-miRNA network was successfully established. Ultimately, an Immune cell infiltration analysis associated with VILI was generated. CONCLUSIONS: The results emphasize the importance of 4 VFHGs and their involvement in ferroptosis in VILI, confirming their potential as diagnostic biomarkers for VILI.

Genetic, Clinical, and Pathologic Backgrounds of Children With X-Linked Alport Syndrome in China: A Monocenter Study.

Background. Characteristics of X-linked Alport syndrome (XLAS) in a cohort of Chinese children. Methods. This work is a retrospective study covering the clinical information, pathological data, and gene sequencing results of 32 cases with XLAS from 2011 to 2022. Results. Among these 32 patients, the youngest age of onset was 3 months. Renal biopsy was performed on 29 children. The lamellated glomerular basement membrane was observed in 19 children using electron microscopy (65.5%). Of the 26 samples tested, 73.1% were found to be negative for collagen-a5 under immunohistochemical staining, showing clinical significance. Next-generation sequencing (NGS) detected 27 pathogenic gene mutations. A total of 15.4% of patients carried de novo mutations. Conclusions. The boys with XLAS showed more typical pathological performance than the girls. Patients with severe mutation were more likely to have proteinuria and hearing impairment. Renal pathology combined with NSG is an important means of diagnosis of AS.

Immune characteristics of kidney transplant recipients with acute respiratory distress syndrome induced by COVID-19 at single-cell resolution.

BACKGROUND: COVID-19-induced acute respiratory distress syndrome (ARDS) can result in tissue damage and multiple organ dysfunction, especially in kidney transplant recipients (KTRs) receiving immunosuppressive drugs. Presently, single-cell research on COVID-19-induced ARDS is considerably advanced, yet knowledge about ARDS in KTRs is still constrained. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was performed to construct a comprehensive single-cell immune landscape of the peripheral blood mononuclear cells (PBMCs) of eight patients with COVID-19-induced ARDS, five KTRs with COVID-19-induced ARDS, and five healthy individuals. Subsequently, we conducted a comprehensive bioinformatics analysis, including cell clustering, enrichment analysis, trajectory analysis, gene regulatory network analysis, and cell-cell interaction analysis, to investigate the heterogeneity of the immune microenvironment in KTRs with ARDS. RESULT: Our study revealed that KTRs exhibit significant heterogeneity with COVID-19-induced ARDS compared with those of other individuals, with significant reductions in T cells, as well as an abnormal proliferation of B cells and monocytes. In the context of dual influences from immunosuppression and viral infection, KTRs exhibited more specific plasma cells, along with significant enrichment of dysfunctional GZMB and XAF1 double-positive effector T cells and IFI27-positive monocytes. Additionally, robust communication existed among T cells and monocytes in cytokine signaling. These effects impede the process of immune reconstitution in KTR patients. CONCLUSION: Our findings suggest that KTRs with COVID-19-induced ARDS show elevated antibody levels, impaired T cell differentiation, and dysregulation of innate immunity. In summary, this study provides a theoretical foundation for a comprehensive understanding of COVID-19-induced ARDS in KTRs.

Identification of cuproptosis-related biomarkers and analysis of immune infiltration in allograft lung ischemia-reperfusion injury.

Background: Allograft lung ischemia-reperfusion injury (ALIRI) is a major cause of early primary graft dysfunction and poor long-term survival after lung transplantation (LTx); however, its pathogenesis has not been fully elucidated. Cell death is a mechanism underlying ALIRI. Cuproptosis is a recently discovered form of programmed cell death. To date, no studies have been conducted on the mechanisms by which cuproptosis-related genes (CRGs) regulate ALIRI. Therefore, we explored the potential biomarkers related to cuproptosis to provide new insights into the treatment of ALIRI. Materials and methods: Datasets containing pre- and post-LTx lung biopsy samples and CRGs were obtained from the GEO database and previous studies. We identified differentially expressed CRGs (DE-CRGs) and performed functional analyses. Biomarker genes were selected using three machine learning algorithms. The ROC curve and logistic regression model (LRM) of these biomarkers were constructed. CIBERSORT was used to calculate the number of infiltrating immune cells pre- and post-LTx, and the correlation between these biomarkers and immune cells was analyzed. A competing endogenous RNA network was constructed using these biomarkers. Finally, the biomarkers were verified in a validation set and a rat LTx model using qRT-PCR and Western blotting. Results: Fifteen DE-CRGs were identified. GO analysis revealed that DE-CRGs were significantly enriched in the mitochondrial acetyl-CoA biosynthetic process from pyruvate, protein lipoylation, the tricarboxylic acid (TCA) cycle, and copper-transporting ATPase activity. KEGG enrichment analysis showed that the DE-CRGs were mainly enriched in metabolic pathways, carbon metabolism, and the TCA cycle. NFE2L2, NLRP3, LIPT1, and MTF1 were identified as potential biomarker genes. The AUC of the ROC curve for each biomarker was greater than 0.8, and the LRM provided an excellent classifier with an AUC of 0.96. These biomarkers were validated in another dataset and a rat LTx model, which exhibited good performance. In the CIBERSORT analysis, differentially expressed immune cells were identified, and the biomarkers were associated with the immune cells. Conclusion: NFE2L2, NLRP3, LIPT1, and MTF1 may serve as predictors of cuproptosis and play an important role in the pathogenesis of cuproptosis in ALIRI.

Elastohydrodynamic propulsion of a filament magnetically driven at both ends.

The elastohydrodynamic interaction between an elastic filament and its surrounding fluid was exploited to develop the first microswimmers. These flexible microswimmers are typically actuated magnetically at one end and their propulsion behavior is relatively well understood. In this work, we move beyond the traditional single-end actuation setup and explore the propulsion characteristics of an elastic filament driven by magnetic torques at both ends. We report the emergence of new modes of propulsion behaviors in different physical regimes, depending on the balance of elastic and viscous forces as well as the arrangement of the magnetic moments at the filament ends. In particular, under the same magnetic actuation, a filament driven at both ends can propel either forward or backward depending on its relative stiffness. Moreover, this new backward propulsion mode can generate a magnitude of propulsion that is unattainable by the traditional single-end actuation setup. We characterize these new propulsion behaviors and provide some physical insights into how they emerge from the complex interplay between viscous and elastic forces and magnetic actuation in various configurations. Taken together, these findings could guide the development of soft microrobots with enhanced propulsion performance and maneuverability for future biomedical applications.

Multiple thermocycles followed by LAMP with only two primers for ultrasensitive colorimetric viral RNA testing and tracking at single-base resolution.

Rapid, accurate and high throughput measurement of infectious viruses is an urgent need to prevent viral transmission. Loop-mediated isothermal amplification (LAMP) is an attractive isothermal amplification method for nucleic acid detection, especially for point-of-care (POC) testing, but it needs at least four primers and its sensitivity is also limited when integrating with visual detection methods. Herein, by designing only two primers to precisely recognize the four regions of the target, we developed a multiple thermocycles-based LAMP method (MTC-LAMP) for sensitive and specific testing and tracking of viral RNA. We also introduced a novel SYBR Green I (SG)-assisted stable colorimetric assay induced by the amplification products through the charge neutralization effect of positively charged SG toward gold nanoparticles (AuNPs). The ultralow nonspecific background of the double exponential amplification improved the detection sensitivity to near single-molecule level (1 aM, 3 copies in 5 µL solution), which was higher than RT-PCR and RT-LAMP. After adding AuNPs, a significant color difference between target and blank was immediately observed by naked eye. By introducing a peptide nucleic acid (PNA) clamp into our colorimetric MTC-LAMP assay, the specific distinguish of virus variants at single-base resolution was observed without the requirement of any equipment. This assay shows great potential for large-scale screening and tracking of the threatening viruses with ultrahigh sensitivity and pronounced colorimetric output, which is of great importance for pandemic control.

Longitudinal relationships between school assets, traditional bullying, and internet gaming disorder: the role of self-control and intentional self-regulation among Chinese adolescents.

Introduction: Although developmental assets have been proven to be enabling factors for both adolescent traditional bullying and internet gaming disorder (IGD), there is a lack of empirical evidence that has investigated the direct relationship between school assets and both of these problematic behaviors concurrently. Based on the positive youth development (PYD) perspective, the present study aimed to explore the relationship between school assets, intentional self-regulation (ISR), self-control, traditional bullying, and IGD among Chinese adolescents. Methods: A total of 742 middle school students (Mage = 13.88 years, SD = 1.99 years) were followed up to measure school assets, ISR, self-control, traditional bullying, and IGD in two waves that were separated by 5 months. Results: Structural equation modeling (SEM) indicated that T1 school assets negatively predicted T2 traditional bullying and T2 IGD. T1 self-control significantly mediated the relationships between T1 school assets and T2 traditional bullying, as well as between T1 school assets and T2 IGD. Additionally, T1 ISR strengthened the positive effect of T1 school assets on T1 self-control and further moderated the two mediating paths. Discussion: These findings show that plentiful school assets support the development of self-control and are more successful in reducing traditional bullying and IGD, particularly among students with higher ISR. As a result, schools should take measures to provide superior-quality assets for the positive development of youth, which will help to prevent and relieve traditional bullying and IGD in the school context.

Positive youth development attributes, mental disorder, and problematic online behaviors in adolescents: a longitudinal study amidst the COVID-19 pandemic.

Introduction: During the COVID-19 pandemic, adolescents have increasingly suffered from online problem behaviors and mental disorders. But little research has paid attention to the protective factors among adolescents. Therefore, the present study attempted to investigate the role of positive youth development (PYD) attributes in adolescents' depression, internet gaming disorder (IGD) and cyberbullying/victimization (CBV). Methods: A total of 995 Chinese adolescents (Mage = 15.97 years, SD = 0.77, 325 boys) from two public high schools in Hubei province were recruited to participate in the three-wave longitudinal study over the span of 1 year during the pandemic (Time 1: November, 2020; Time 2: May, 2021; Time 3: November, 2021). Results: T1 PYD attributes negatively predicted T2 depression and T3 online problematic behaviors. T2 depression positively predicted IGD at T3. T3 IGD significantly predicted greater involvement in T3 CBV, and vice versa. Moreover, depression and one online problem behavior mediated the relationships between PYD attributes and the other online problem behavior, separately and sequentially. Discussion: These findings demonstrated the protective role of PYD attributes in prevention of mental disorders and online problem behaviors among adolescents during the COVID-19 pandemic. Comprehensive measures should be taken to assist young people to develop more PYD attributes to promote healthy growth.

The Effect of Different Doses of Ciprofol in Patients with Painless Gastrointestinal Endoscopy.

Background: Ciprofol is currently used for painless gastrointestinal endoscopy and anesthesia induction. However, whether it is superior to propofol and its optimal dose remains unknown. Methods: A total of 149 patients, 63 males and 86 females, aged 18-80 years, BMI 18-28 kg/m2, ASA I-III, were divided randomly into four groups: propofol group (group P, n = 44), ciprofol 0.2mg/kg group (group C2, n = 38), ciprofol 0.3mg/kg group (group C3, n = 36) and ciprofol 0.4 mg/kg group (group C4, n = 31). Groups C2, C3 and C4 had injected IV with ciprofol 0.2, 0.3 and 0.4 mg/kg, respectively. Group P had injected IV with propofol 1.5mg/kg. The time for disappearance of the eyelash reflex, gastrointestinal endoscopy time, recovery time, and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score at awakening (T1), 15 minutes after awakening (T2) and 30 minutes after awakening (T3) were recorded. Results: Compared with group P, the time to fall asleep was significantly shortened, and the incidence of nausea and vomiting and injection pain was significantly lower in groups C2, C3 and C4 (P < 0.05). There was no significant difference in recovery time and recovery quality between each group (P > 0.05). Compared with group P and C4, the incidence of hypotension and respiratory depression was significantly lower in groups C2 and C3 (P < 0.05). Conclusion: The appropriate dose of ciprofol for painless gastrointestinal endoscopy is more advantageous than propofol in hemodynamics and respiratory stability, with less injection pain and nausea and vomiting, which is worthy of clinical promotion.

Effect of Sodium Bicarbonate Ringer's Solution on Intraoperative Blood Gas Analysis and Postoperative Recovery Time in Liver Transplantation: A Single-Center Retrospective Study.

BACKGROUND Sodium bicarbonate Ringer's solution (BRS) is the latest generation of balanced crystal solutions. BRS does not increase the liver burden, but its impact in liver transplantation is unclear. The aim of this study was to investigate the effect of BRS as a fluid therapy on intraoperative blood gas analysis and postoperative recovery time in orthotopic liver transplantation (LT) patients. MATERIAL AND METHODS The study included 101 patients who received classical in situ liver transplantation at the Second Affiliated Hospital of Guangxi Medical University from November 2019 to January 2022. The patients were divided into 2 groups according to the intraoperative fluid infusion: the BRS group and the sodium lactate Ringer's solution group (LRS group). Intraoperative blood gas analysis, including pH, base excess (BE), bicarbonate, and lactic acid levels of radial artery blood, were collected after induction (T0), 30 min before opening (T1), 30 min after no liver period (T2), 30 min after opening (T3), and at the end of the operation (T4). Postoperative ICU catheter time, ICU stay time, and total hospitalization days were also recorded and compared between the 2 groups. RESULTS Lactic acid levels were decreased significantly at T3 in the BRS group (P<0.05). ICU catheter time, ICU hospitalization days, and total hospitalization days were significantly shorter in the BRS group (P<0.05). CONCLUSIONS BRS can decrease the lactic acid level at 30 min after opening, reducing the postoperative recovery time. BRS is more effective than LRS in liver transplantation.

The relationship between parental neglect and cyberbullying perpetration among Chinese adolescent: The sequential role of cyberbullying victimization and internet gaming disorder.

Cyberbullying perpetration and victimization have been common public health issues that have impaired the development of adolescent physical and mental health. Abundant research has proven associations between negative parental factors and cyberbullying perpetration. However, there is a paucity of research exploring the impact of parental neglect on cyberbullying and its internal mechanisms. Based on the parental acceptance-rejection theory (PARTheory) and the general aggression model (GAM), the present study constructs a sequential mediation model in which parental neglect is related to adolescent cyberbullying perpetration through cyberbullying victimization and internet gaming disorder (IGD). Using random cluster sampling, a total of 699 middle school students (M age = 14.18 years, SD = 1.22, and 324 boys) were recruited from five schools in three provinces on mainland China. The participants completed questionnaires regarding parental neglect, cyberbullying perpetration, cyberbullying victimization, and IGD. The results of structural equation modeling indicated that parental neglect was positively associated with cyberbullying perpetration. The mediating effects of cyberbullying victimization and IGD in this relationship are significant both individually and jointly. The current findings have important implications for enlightening families and schools to pay particular attention to adolescents' experiences of parental neglect and provide them with timely feedback and assistance. This will contribute to the prevention and reduction of adolescent involvement in cyberbullying perpetration.

Evaluation and Use of Organs from Donors Poisoned by Organophosphorus Pesticide.

BACKGROUND The aim of this study was to explore the evaluation and use of donor organs from donors with brain death caused by acute severe organophosphorus pesticides and provide a basis for the use of such donor organs. MATERIAL AND METHODS Seven cases of brain dead donors caused by acute organophosphorus pesticide poisoning from January 2014 to December 2018 in the hospital were collected, and a retrospective analysis was made of the donors' age, race, physiological and pathological changes, donor organ function changes and the organ use, liver or kidney function recovery, and complications of the recipients. The 18 recipients were followed up until June 31, 2022. RESULTS We found that 71.42% of organ donors were male, and 71.42% of organ donors were under 50 years old. The main cause of death was respiratory failure caused by organophosphorus pesticide poisoning. The liver and kidney functions of 7 donors were damaged, and 3 livers could not be used due to severe functional damage, but the liver or kidney function of 18 recipients gradually recovered after transplantation. Delayed recovery of graft function occurred after transplantation accounted for 21.43%, and the grafts had good short-term to medium-term performance. CONCLUSIONS Although the function of organs from donor with brain death due to acute severe organophosphorus pesticide poisoning is seriously damaged, most of the organs can still be used for transplantation. Individualized functional maintenance according to the situation of donors is conducive to improving the quality of organs.

Resveratrol Prevents Vibrio vulnificus-Induced Sepsis by Attenuating Necroptosis.

Objective: This study investigated how the natural phytophenol and potent SIRT1 activator resveratrol (RSV) regulate necroptosis during Vibrio vulnificus (V. vulnificus)-induced sepsis and the potential mechanism. Methods: The effect of RSV on V. vulnificus cytolysin (VVC)-induced necroptosis was analyzed in vitro using CCK-8 and Western blot assays. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry and survival analyses were performed to elucidate the effect and mechanism of RSV on necroptosis in a V. vulnificus-induced sepsis mouse model. Results: RSV relieved necroptosis induced by VVC in RAW264.7 and MLE12 cells. RSV also inhibited the inflammatory response, had a protective effect on histopathological changes, and reduced the expression level of the necroptosis indicator pMLKL in peritoneal macrophages, lung, spleen, and liver tissues of V. vulnificus-induced septic mice in vivo. Pretreatment with RSV downregulated the mRNA of the necroptosis indicator and protein expression in peritoneal macrophages and tissues of V. vulnificus-induced septic mice. RSV also improved the survival of V. vulnificus-induced septic mice. Conclusion: Our findings collectively demonstrate that RSV prevented V. vulnificus-induced sepsis by attenuating necroptosis, highlighting its potency in the clinical management of V. vulnificus-induced sepsis.

Study on effect of collaborative governance participation willingness of online food delivery platform restaurants and consumers from perspective of control theory: Based on moderating effects of perceived risks.

The popularization of the Internet and the convenience of e-commerce are driving the online restaurant industry's rapid development of worldwide. However, serious information asymmetries in online food delivery (OFD) transactions not only aggravate food safety risks, resulting in simultaneous government and market failures, but also intensify consumers' perceived risks. This paper innovatively constructs a research framework for the governance participation willingness of OFD platform restaurants and consumers under the moderating effects of perceived risks from the perspective of control theory and then develops scales for analyzing the governance willingness of both restaurants and consumers. Using data collected through a survey, this paper explores the effect of control elements on governance participation by restaurants and consumers and analyzes the moderating effects of perceived food safety risks. Results showed that both government regulations and restaurant reputation (formal control elements) and online complaints and restaurant management response (informal control elements) can increase governance participation willingness among both platform restaurants and consumers. The moderating effects of perceived risks are partially significant. When the risks perceived by restaurants and consumers are strong, government regulation and online complaints can more effectively boost the governance participation willingness of restaurants and consumers, respectively. At this moment, consumers' willingness to pursue problem solving through online complaints is evidently enhanced. Accordingly, the perceived risks and the online complaints jointly motivate restaurants and consumers to participate in governance activities.

Halogenated Thermally Activated Delayed Fluorescence Materials for Efficient Scintillation.

Organic scintillators, materials with the ability to exhibit luminescence when exposed to X-rays, have aroused increasing interest in recent years. However, the enhancement of radioluminescence and improving X-ray absorption of organic scintillators lie in the inherent dilemma, due to the waste of triplet excitons and weak X-ray absorption during scintillation. Here, we employ halogenated thermally activated delayed fluorescence materials to improve the triplet exciton utilization and X-ray absorption simultaneously, generating efficient scintillation with a low detection limit, which is one order of magnitude lower than the dosage for X-ray medical diagnostics. Through experimental study and theoretical calculation, we reveal the positive role of X-ray absorption, quantum yields of prompt fluorescence, and intersystem crossing in promoting the radioluminescence intensity. This finding offers an opportunity to design diverse types of organic scintillators and expands the applications of thermally activated delayed fluorescence.

Chemoproteomic and Transcriptomic Analysis Reveals that O-GlcNAc Regulates Mouse Embryonic Stem Cell Fate through the Pluripotency Network.

Self-renewal and differentiation of embryonic stem cells (ESCs) are influenced by protein O-linked ß-N-acetylglucosamine (O-GlcNAc) modification, but the underlying mechanism remains incompletely understood. Herein, we report the identification of 979 O-GlcNAcylated proteins and 1340 modification sites in mouse ESCs (mESCs) by using a chemoproteomics method. In addition to OCT4 and SOX2, the third core pluripotency transcription factor (PTF) NANOG was found to be modified and functionally regulated by O-GlcNAc. Upon differentiation along the neuronal lineage, the O-GlcNAc stoichiometry at 123 sites of 83 proteins-several of which were PTFs-was found to decline. Transcriptomic profiling reveals 2456 differentially expressed genes responsive to OGT inhibition during differentiation, of which 901 are target genes of core PTFs. By acting on the core PTF network, suppression of O-GlcNAcylation upregulates neuron-related genes, thus contributing to mESC fate determination.

Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated. However, the role of EZH2 in T cell exhaustion remains under-explored. Here, using in vitro exhaustion models, we demonstrated that transient inhibition of EZH2 in T cells before the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetastat, delayed their dysfunctional progression and maintained T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells pre-treated with tazemetastat exhibited a superior response to anti-PD-1 blockade therapy after adoptive transfer. Collectively, these data unveil the potential of transient epigenetic reprogramming as a potential intervention to be combined with checkpoint blockade for immune therapy.