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Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function 1 – 4 . However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer—an aggressive malignancy that is refractory to standard treatments and current immunotherapies 5 – 8 —induces endoplasmic reticulum stress and activates the IRE1α–XBP1 arm of the unfolded protein response 9 , 10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N -linked protein glycosylation defects in T cells, which triggered IRE1α–XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N -linked protein glycosylation, abrogating IRE1α–XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α–XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts. In human and mouse models of ovarian cancer, endoplasmic reticulum stress and the activation of the IRE1α–XBP1 pathway decreases the metabolic fitness of T cells and limits their anti-tumour functions.

Thymocytes must undergo positive selection to survive and emigrate to the periphery as mature T cells. Glimcher and colleagues identify CHMP5 as a TCR-sensitive regulator of positive selection that acts by preventing oxidation and degradation of the pro-survival protein Bcl-2. The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function.sup.1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer--an aggressive malignancy that is refractory to standard treatments and current immunotherapies.sup.5-8--induces endoplasmic reticulum stress and activates the IRE1[alpha]-XBP1 arm of the unfolded protein response.sup.9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1[alpha]-XBP1 activation that suppressed mitochondrial activity and IFN[gamma] production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1[alpha]-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1[alpha]-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.

Precise mechanisms underlying interleukin-7 (IL-7)-mediated tumor invasion remain unclear. Thus, we investigated the role of IL-7 in tumor invasiveness using metastatic prostate cancer PC-3 cell line derivatives, and assessed the potential of IL-7 as a clinical target using a Janus kinase (JAK) inhibitor and an IL-7-blocking antibody. We found that IL-7 stimulated wound-healing migration and invasion of PC-3 cells, increased phosphorylation of signal transducer and activator of transcription 5, Akt, and extracellular signal-regulated kinase. On the other hand, a JAK inhibitor and an IL-7-blocking antibody decreased the invasiveness of PC-3 cells. IL-7 increased tumor sphere formation and expression of epithelial–mesenchymal transition (EMT) markers. Importantly, lentiviral delivery of IL-7Rα to PC-3 cells significantly increased bone metastasis in an experimental murine metastasis model compared to controls. The gene expression profile of human prostate cancer cells from The Cancer Genome Atlas revealed that EMT pathways are strongly associated with prostate cancers that highly express both IL-7 and IL-7Rα. Collectively, these data suggest that IL-7 and/or IL-7Rα are promising targets of inhibiting tumor metastasis.

Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.

Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection.

Concepts of non-volatile memory to replace conventional flash memory have suffered from low material reliability and high off-state current, and the use of a thick, rigid blocking oxide layer in flash memory further restricts vertical scale-up. Here, we report a two-terminal floating gate memory, tunnelling random access memory fabricated by a monolayer MoS 2 /h-BN/monolayer graphene vertical stack. Our device uses a two-terminal electrode for current flow in the MoS 2 channel and simultaneously for charging and discharging the graphene floating gate through the h-BN tunnelling barrier. By effective charge tunnelling through crystalline h-BN layer and storing charges in graphene layer, our memory device demonstrates an ultimately low off-state current of 10 −14  A, leading to ultrahigh on/off ratio over 10 9 , about ∼10 3 times higher than other two-terminal memories. Furthermore, the absence of thick, rigid blocking oxides enables high stretchability (>19%) which is useful for soft electronics. Traditional non-volatile memories suffer from poor scalability in the vertical direction due to the use of a bulky oxide layer. Here, the authors develop a tunnelling random access memory using a vertical heterostructure composed of atomically thin molybdenum disulfide, boron nitride and graphene.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7 -dependent formation of a “secretory phagophore (SP)” and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

Immunoglobulin A (IgA) nephropathy (IgAN) is a prevalent primary glomerulonephritis with progressive potential. Early identification of high-risk patients is critical; however, current clinical and pathological markers are limited. This study aimed to identify epigenetic biomarkers in circulating CD8⁺ T cells that discriminate IgAN patients with different disease severity. Seventeen patients with biopsy-proven IgAN were stratified into early- and late-stage groups based on kidney function. CD8⁺ T cells were isolated and analyzed using transposase-accessible chromatin sequencing (ATAC-Seq) to assess chromatin accessibility. Differentially accessible regions (DARs) were identified and selected biomarkers were additionally analyzed with ATAC-qPCR. In total, 279 DARs were identified, of which 122 were selected as stage-specific biomarkers. CD8⁺ T cells from the early-stage group exhibited higher chromatin accessibility, and t -SNE showed a clear separation between the stages. Deconvolution analysis revealed the enrichment of naïve CD8⁺ T cells in the early-stage group and terminally differentiated effector memory CD8⁺ T cells in the late-stage group. Motif analysis uncovered distinct regulatory signatures: ETS1 , LEF1 , and RUNX2 in the early-stage, EOMES , TBX21 , and IRF4 in the late stage. Receiver operating characteristic (ROC) analysis showed strong discriminatory power of the top biomarkers, enhanced by a composite weighted score. ATAC-qPCR confirmed the chromatin accessibility patterns observed using ATAC-Seq. This study defined stage-specific chromatin landscapes in the circulating CD8⁺ T cells of patients with IgAN and identified non-invasive epigenetic biomarkers associated with different disease severity, which may be utilized in early risk stratification and personalized management.

Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.