Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy. Deleting N-linked glycosylation gene ALG3 in mouse cancer cells substantially attenuates their growth in mice in a manner depending on cytotoxic T cells. Furthermore, ALG3 inhibition or N-linked glycosylation inhibitor tunicamycin treatment synergizes with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer. Mechanistically, we found that inhibiting ALG3 induced deficiencies of post-translational N-linked glycosylation modification and led to excessive lipid accumulation through sterol-regulated element-binding protein (SREBP1)-dependent lipogenesis in cancer cells. N-linked glycosylation deficiency-mediated lipid hyperperoxidation induced immunogenic ferroptosis of cancer cells and promoted a pro-inflammatory microenvironment, which boosted anti-tumor immune responses. In human subjects with cancer, elevated levels of ALG3 expression in tumor tissues are associated with poor patient survival. Taken together, we reveal an unappreciated role of ALG3 in regulating tumor immunogenicity and propose a potential therapeutic strategy for enhancing cancer immunotherapy.

Historical variability of cotton yield and response to climate and agronomic management in Xinjiang, China.

Cotton is the primary fibre crop in the world with high economic value, and its yield can be affected by climate and agronomic management. Xinjiang, the largest cotton-producing province in China, contributes to approximately 90 % of the national and over 20 % of global production. Earlier studies focused on cotton yield variability and/or drivers on the site scale, for only one to several counties or cities within Xinjiang, in several years before 2000, or provincial production for a short period. It remains poorly understood how and why cotton yields change in Xinjiang. This study analyzes the spatiotemporal variability of cotton yields at the provincial and county (73 counties) levels from 1989 to 2017 using yield statistics, and identifies the dominant climate and agronomic management factors as well as their optimal ranges, historical states, and interaction effects using the geographical detector method (Geodetector). The results show that the Xinjiang cotton yield has increased markedly over the past decades, with the long-term trend outweighing the interannual variability. High yields are mostly found in southern and northwestern Xinjiang. Yield has increased significantly in over 95.6 % of cotton-planting areas, primarily in the west. Nitrogen fertilization is the leading driver of cotton yield changes, mainly impacting long-term trends. The combination of nitrogen fertilization and agricultural mechanization enhances the explanatory power in a bivariate way and is the strongest in the interaction effect between factors. Temperature variability has the greatest influence on detrended yield variability, and the explanatory power is enhanced and the highest when combined with precipitation. In addition, historical states of these factors are generally lower than their optimal ranges, indicating potential for cotton yield enhancement through improved agronomic management practices and in the context of global warming. This study could enhance understanding of cotton Xinjiang yield variability and drivers, and provides scientific guidance for local cotton cultivation.

In Situ Synthesis of an Immune-Checkpoint Blocker from Engineered Bacteria Elicits a Potent Antitumor Response.

Immune-checkpoint blockade (ICB) reinvigorates T cells from exhaustion and potentiates T-cell responses to tumors. However, most patients do not respond to ICB therapy, and only a limited response can be achieved in a "cold" tumor with few infiltrated lymphocytes. Synthetic biology can be used to engineer bacteria as controllable bioreactors to synthesize biotherapeutics in situ. We engineered attenuated Salmonella VNP20009 with synthetic gene circuits to produce PD-1 and Tim-3 scFv to block immunosuppressive receptors on exhausted T cells to reinvigorate their antitumor response. Secreted PD-1 and Tim-3 scFv bound PD-1+ Tim-3+ T cells through their targeting receptors in vitro and potentiated the T-cell secretion of IFN-γ. Engineered bacteria colonized the hypoxic core of the tumor and synthesized PD-1 and Tim-3 scFv in situ, reviving CD4+ T cells and CD8+ T cells to execute an antitumor response. The bacteria also triggered a strong innate immune response, which stimulated the expansion of IFN-γ+ CD4+ T cells within the tumors to induce direct and indirect antitumor immunity.

Bioengineered Artificial Extracellular Vesicles Presenting PD-L1 and Gal-9 Ameliorate New-Onset Type 1 Diabetes.

An important factor in the development of type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and galectin-9 (Gal-9), in ß-cells. Therefore, modulation of pancreas-infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating new-onset T1D. We genetically engineered macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict islet autoreactive T lymphocytes and protect ß-cells from destruction. Intriguingly, overexpression of Gal-9 stimulated macrophage polarization to the M2 phenotype with immunosuppressive attributes. Alternatively, both PD-L1- and Gal-9-presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhered to T cells via the interaction of programmed cell death protein 1/PD-L1 or T-cell immunoglobulin mucin 3/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T-cell apoptosis and splenic regulatory T (Treg) cell formation in vitro. Notably, PD-L1-Gal-9 aEVs efficaciously reversed new-onset hyperglycemia in NOD mice, prevented T1D progression, and decreased the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas, which together contributed to the preservation of residual ß-cell survival and mitigation of hyperglycemia.

Engineered Cell Membrane Vesicles Expressing CD40 Alleviate System Lupus Nephritis by Intervening B Cell Activation.

Immune intervention of B cell activation to blockade the production of autoantibodies provokes intense interest in the field of systemic lupus erythematosus (SLE) therapy development. Although the survival rate for SLE is improved, many patients die untimely. Engineered cell membrane vesicles manifest remarkable capacity of targeted drug delivery and immunomodulation of immune cells such as B cells. Herein, this work engineered cellular nanovesicles (NVs) presenting CD40 (CD40 NVs) that can blunt B cells and thus alleviate SLE. CD40 NVs disrupt the CD40/CD40 ligand (CD40L) costimulatory signal axis through the blockade of CD40L on CD4+ T cells. Therefore, the CD40 NVs restrain the generation of the germinal center structure and production of antibodies from B cells. Furthermore, immunosuppressive drug mycophenolate mofetil (MMF) is also encapsulated in the vesicles (MMF-CD40 NVs), which is employed to deplete immunocytes including B cells, T cells, and dendritic cells. Together, CD40 NVs are promising formulations for relieving autoimmunity and lupus nephritis in MRL/lpr mice.

Influence of atmospheric teleconnections on interannual variability of Arctic-boreal fires.

Fires across the Arctic-boreal zone (ABZ) play an important role in the boreal forest succession, permafrost thaw, and the regional and global carbon cycle and climate. These fires occur mainly in summer with large interannual variability. Previous studies primarily focused on the impacts of local surface climate and tropical El Niño-Southern Oscillation (ENSO). This study, for the first time, comprehensively investigates the influence of summer leading large-scale atmospheric teleconnection patterns in the Northern Hemisphere extra-tropics on interannual variability of ABZ fires. We use correlation and regression analysis of 1997-2019 multiple satellite-based products of burned area and observed/reanalyzed climate data. Results show that eight leading teleconnection patterns significantly affect 63 ± 2 % of burned areas across the ABZ. Western North America is affected by the East Pacific/North Pacific pattern (EP/NP) and the West Pacific pattern (WP); boreal Europe by the Scandinavia pattern (SCA); eastern North America, western and central Siberia, and southeastern Siberia by the North Atlantic Oscillation (NAO); and eastern Siberia /Russian Far East by the East Atlantic pattern (EA). NAO/EA induces lower-tropospheric drier northwesterly/northerly airflow passing through the east of boreal North America/Eurasia, which decreases surface relative humidity. Other teleconnections trigger a high-pressure anomaly, forcing downward motion that suppresses cloud formation and increases solar radiation reaching the ground to warm the surface air as well as brings drier air downward to reduce surface relative humidity. The drier and/or warmer surface air can decrease fuel wetness and thus increase burned area. Our study highlights the important role of the extra-tropical teleconnection patterns on ABZ fires, which is much stronger than ENSO that was thought to control interannual variability of global fires. It also establishes a theoretical foundation for ABZ fire prediction based on extra-tropical teleconnections, and has the potential to facilitate ABZ fire prediction and management.

Biosynthetic neoantigen displayed on bacteria derived vesicles elicit systemic antitumour immunity.

Neoantigens derived from mutant proteins in tumour cells could elicit potent personalized anti-tumour immunity. Nevertheless, the layout of vaccine vehicle and synthesis of neoantigen are pivotal for stimulating robust response. The power of synthetic biology enables genetic programming bacteria to produce therapeutic agents under contol of the gene circuits. Herein, we genetically engineered bacteria to synthesize fusion neoantigens, and prepared bacteria derived vesicles (BDVs) presenting the neoantigens (BDVs-Neo) as personalized therapeutic vaccine to drive systemic antitumour response. BDVs-Neo and granulocyte-macrophage colony-stimulating factor (GM-CSF) were inoculated subcutaneously within hydrogel (Gel), whereas sustaining release of BDVs-Lipopolysaccharide (LPS) and GM-CSF recruited the dendritic cells (DCs). Virtually, Gel-BDVs-Neo combined with the programmed cell death protein 1 (PD-1) antibody intensively enhanced proliferation and activation of tumour-infiltrated T cells, as well as memory T cell clone expansion. Consequently, BDVs-Neo combining with checkpoint blockade therapy effectively prevented tumour relapse and metastasis.

Holocene fire history in China: Responses to climate change and human activities.

Fire is an intrinsic feature of terrestrial ecosystems as well as a key Earth system process that significantly influences ecosystem patterns, the carbon cycle, and climate. Although local and regional paleofires across China have been investigated, the history of these phenomena at the national scale as well as possible drivers remain unknown. This study investigated spatiotemporal patterns in fire activity across China based on 107 individual site charcoal records. The aim of this work was to discuss the possible impact of climate and human activities on fire in China. Results showed that fire activities across China declined gradually overall between the early Holocene (12 ka BP) and the middle Holocene (7.3 ka BP) but then sharply increased in occurrence after 7.3 ka BP. Data showed that although regional fire activities did not vary synchronously, more events tended to occur in the late Holocene and there were relative less in the early-to-middle Holocene. These changes in Holocene fire activity closely mirrored millennial scale moisture variations across China. Intensified human activities over the last 3 ka might also be responsible for a sharp increase in fire activity. Variable trends in fire activities within regions might also be attributed to large-scale climatic controls modulated by local factors, which determined burn likelihood. This study enhances our insights into the fire history of China and may help to provide improved future projections for such phenomena given current climate change.

Climate influence on the 2019 fires in Amazonia.

Amazonia experienced unusually devastating fires in August 2019, leading to huge regional and global environmental and economic losses. The increase in fires has been largely attributed to anthropogenic deforestation, but anomalous climate conditions could also have contributed. This study investigates the climate influence on Amazonia fires in August 2019 and underlying mechanisms, based on statistical correlation and multiple linear regression analyses of 2001-2019 satellite-based fire products and multiple observational or reanalyzed climate datasets. Positive fire anomalies in August 2019 were mainly located in southern Amazonia. These anomalies were mainly driven by low precipitation and relative humidity, which increased fuel dryness and contributed to 38.9 ± 9.5% of the 2019 anomaly in pyrogenic carbon emissions over the southern Amazonia. The dry conditions were associated with southerly wind anomalies over southern Amazonia that suppressed the climatological southward transport of water vapor originating from the Atlantic. The southerly wind anomalies were caused by the combination of a Gill-type cyclonic response to the warmer North Atlantic sea surface temperature (SST), and enhancement of the Walker and Hadley circulations over South America due to the colder SST in the eastern Pacific, and a mid-latitude wave train triggered by the warmer condition in the western Indian Ocean. Our study highlights, for the first time, the important role of Indian Ocean SST for fires in Amazonia. It also reveals how cold SST anomalies in the tropical eastern Pacific link the warm phase of the El Niño-Southern Oscillation (ENSO) in the preceding December-January to the dry-season fires in Amazonia. Our findings can develop theoretical basis of global tropical SST-based fire prediction, and have potential to improve prediction skill of extreme fires in Amazonia and thus to take steps to mitigate their impacts which is urgency given that dry conditions led to the extreme fires are becoming common in Amazonia.

A Calcium-Related Immune Signature in Prognosis Prediction of Patients With Glioma.

Background: Immune checkpoint inhibitors have been successfully used in a variety of tumors, however, the efficacy of immune checkpoint blockade therapy for patients with glioma is limited. In this study, we tried to clarify gene expression signatures related to the prognosis of gliomas and construct a signature to predict the survival of patients with gliomas. Methods: Calcium-related differential expressed genes (DEGs) between gliomas and normal brain tissues were comprehensively analyzed in two independent databases. Univariate, multivariate Cox regression analysis and proportional hazards model were used to identify the prognostic of calcium-related risk score signature. The CIBERSORT algorithm and association analysis were carried out to evaluate the relationship between calcium-related signature and characteristic clinical features, tumor-infiltrating immune cell signatures as well as immune checkpoint molecules in glioma. A nomogram model was developed for predicting the overall survival for patients with gliomas. Results: We found the intersection of 415 DEGs between gliomas and normal brain tissues, and identified that an eighteen calcium-related gene panel was significantly enriched in these DEGs. A calcium-related signature derived risk score was developed to divide patients into high- and low-risk groups. Low levels of calcium-related gene expression in high-risk score cases were accompanied with worse outcomes of patients. Calcium-related risk scores were significantly associated with characteristic clinical features, immune infiltrating signatures of tumor microenvironment, and exhausted T cell markers including programmed cell death 1 (PD-1), lymphocyte activating 3 (LAG3), and T cell membrane protein 3 (TIM-3), which contribute to an adverse therapeutic effect of immunotherapy. Calcium-related signature risk score was considered as an independent prognostic parameter to predict the of overall survival of patients with gliomas in nomogram model. Conclusion: Our study demonstrated that calcium signaling pathway is highly associated with immunosuppression of gliomas and overall survival of patients. Targeting the calcium signaling pathway might be a new strategy to reverse the immunosuppressive microenvironment of gliomas and improve the efficacy of glioma immunotherapy.