Antioxidant network-based signatures cluster glioblastoma into distinct redox-resistant phenotypes.

Introduction: Aberrant reactive oxygen species (ROS) production is one of the hallmarks of cancer. During their growth and dissemination, cancer cells control redox signaling to support protumorigenic pathways. As a consequence, cancer cells become reliant on major antioxidant systems to maintain a balanced redox tone, while avoiding excessive oxidative stress and cell death. This concept appears especially relevant in the context of glioblastoma multiforme (GBM), the most aggressive form of brain tumor characterized by significant heterogeneity, which contributes to treatment resistance and tumor recurrence. From this viewpoint, this study aims to investigate whether gene regulatory networks can effectively capture the diverse redox states associated with the primary phenotypes of GBM. Methods: In this study, we utilized publicly available GBM datasets along with proprietary bulk sequencing data. Employing computational analysis and bioinformatics tools, we stratified GBM based on their antioxidant capacities and evaluated the distinctive functionalities and prognostic values of distinct transcriptional networks in silico. Results: We established three distinct transcriptional co-expression networks and signatures (termed clusters C1, C2, and C3) with distinct antioxidant potential in GBM cancer cells. Functional analysis of each cluster revealed that C1 exhibits strong antioxidant properties, C2 is marked with a discrepant inflammatory trait and C3 was identified as the cluster with the weakest antioxidant capacity. Intriguingly, C2 exhibited a strong correlation with the highly aggressive mesenchymal subtype of GBM. Furthermore, this cluster holds substantial prognostic importance: patients with higher gene set variation analysis (GSVA) scores of the C2 signature exhibited adverse outcomes in overall and progression-free survival. Conclusion: In summary, we provide a set of transcriptional signatures that unveil the antioxidant potential of GBM, offering a promising prognostic application and a guide for therapeutic strategies in GBM therapy.

Evaluation of potential increase in photosynthetic efficiency of cassava (Manihot esculenta Crantz) plants exposed to elevated carbon dioxide.

Cassava (Manihot esculenta Crantz), an important tropical crop, is affected by extreme climatic events, including rising CO2 levels. We evaluated the short-term effect of elevated CO2 concentration (ECO2 ) (600, 800 and 1000ppm) on the photosynthetic efficiency of 14 cassava genotypes. ECO2 significantly altered gaseous exchange parameters (net photosynthetic rate (P n ), stomatal conductance (g s ), intercellular CO2 (C i ) and transpiration (E )) in cassava leaves. There were significant but varying interactive effects between ECO2 and varieties on these physiological characteristics. ECO2 at 600 and 800ppm increased the P n rate in the range of 13-24% in comparison to 400ppm (ambient CO2 ), followed by acclimation at the highest concentration of 1000ppm. A similar trend was observed in g s and E . Conversely, C i increased significantly and linearly across increasing CO2 concentration. Along with C i , a steady increase in water use efficiency [WUEintrinsic (P n /g s ) and WUEinstantaneous (P n /E )] across various CO2 concentrations corresponded with the central role of restricted stomatal activity, a common response under ECO2 . Furthermore, P n had a significant quadratic relationship with the ECO2 (R 2 =0.489) and a significant and linear relationship with C i (R 2 =0.227). Relative humidity and vapour pressure deficit during the time of measurements remained at 70-85% and ~0.9-1.31kPa, respectively, at 26±2°C leaf temperature. Notably, not a single variety exhibited constant performance for any of the parameters across CO2 concentrations. Our results indicate that the potential photosynthesis can be increased up to 800ppm cassava varieties with high sink capacity can be cultivated under protected cultivation to attain higher productivity.

An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade.

Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady-state and tumor-bearing conditions is lacking. Intravital imaging combined with immune phenotyping shows that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs by increasing the availability of the main egress signal sphingosine-1-phosphate. Single-cell RNA sequencing of tumor-draining LNs shows that loss of ATG5 remodels niche-specific LEC phenotypes involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC autophagy prevents recruitment of tumor-infiltrating T and natural killer cells and abrogates response to immunotherapy. Thus, an LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics.

Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh /AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.

Tolerance and adaptation mechanism of Solanaceous crops under salinity stress.

Solanaceous crops act as a source of food, nutrition and medicine for humans. Soil salinity is a damaging environmental stress, causing significant reductions in cultivated land area, crop productivity and quality, especially under climate change. Solanaceous crops are extremely vulnerable to salinity stress due to high water requirements during the reproductive stage and the succulent nature of fruits and tubers. Salinity stress impedes morphological and anatomical development, which ultimately affect the production and productivity of the economic part of these crops. The morpho-physiological parameters such as root-to-shoot ratio, leaf area, biomass production, photosynthesis, hormonal balance, leaf water content are disturbed under salinity stress in Solanaceous crops. Moreover, the synthesis and signalling of reactive oxygen species, reactive nitrogen species, accumulation of compatible solutes, and osmoprotectant are significant under salinity stress which might be responsible for providing tolerance in these crops. The regulation at the molecular level is mediated by different genes, transcription factors, and proteins, which are vital in the tolerance mechanism. The present review aims to redraw the attention of the researchers to explore the mechanistic understanding and potential mitigation strategies against salinity stress in Solanaceous crops, which is an often-neglected commodity.

Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.

Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.

Salinity responses and tolerance mechanisms in underground vegetable crops: an integrative review.

MAIN CONCLUSION: The present review gives an insight into the salinity stress tolerance responses and mechanisms of underground vegetable crops. Phytoprotectants, agronomic practices, biofertilizers, and modern biotechnological approaches are crucial for salinity stress management. Underground vegetables are the source of healthy carbohydrates, resistant starch, antioxidants, vitamins, mineral, and nutrients which benefit human health. Soil salinity is a serious threat to agriculture that severely affects the growth, development, and productivity of underground vegetable crops. Salt stress induces several morphological, anatomical, physiological, and biochemical changes in crop plants which include reduction in plant height, leaf area, and biomass. Also, salinity stress impedes the growth of the underground organs, which ultimately reduces crop yield. Moreover, salt stress is detrimental to photosynthesis, membrane integrity, nutrient balance, and leaf water content. Salt tolerance mechanisms involve a complex interplay of several genes, transcription factors, and proteins that are involved in the salinity tolerance mechanism in underground crops. Besides, a coordinated interaction between several phytoprotectants, phytohormones, antioxidants, and microbes is needed. So far, a comprehensive review of salinity tolerance responses and mechanisms in underground vegetables is not available. This review aims to provide a comprehensive view of salt stress effects on underground vegetable crops at different levels of biological organization and discuss the underlying salt tolerance mechanisms. Also, the role of multi-omics in dissecting gene and protein regulatory networks involved in salt tolerance mechanisms is highlighted, which can potentially help in breeding salt-tolerant underground vegetable crops.

The lysosome as a master regulator of iron metabolism.

Intracellular iron fulfills crucial cellular processes, including DNA synthesis and mitochondrial metabolism, but also mediates ferroptosis, a regulated form of cell death driven by lipid-based reactive oxygen species (ROS). Beyond their established role in degradation and recycling, lysosomes occupy a central position in iron homeostasis and integrate metabolic and cell death signals emanating from different subcellular sites. We discuss the central role of the lysosome in preserving iron homeostasis and provide an integrated outlook of the regulatory circuits coupling the lysosomal system to the control of iron trafficking, interorganellar crosstalk, and ferroptosis induction. We also discuss novel studies unraveling how deregulated lysosomal iron-handling functions contribute to cancer, neurodegeneration, and viral infection, and can be harnessed for therapeutic interventions.

Pre evaluation of cassava (Manihot esculenta Crantz) germplasm for genotypic variation in the identification of K efficient genotypes through different statistical tools.

Among the tropical tuber crops, cassava (Manihot esculenta Crantz) deserves special attention as regards to its higher biological efficiency in terms of dry matter production which incidentally implies to the higher amount of nutrient extraction from the soil resulting in better response to the application of manures and fertilizers. Among the major nutrients, Potassium (K) is considered as the key nutrient for cassava owing to its influence both in tuber yield and tuber quality. The above facts as well as the availability of sufficient cassava genotypes in the germplasm collection of ICAR-CTCRI made us to initiate research work to screen cassava germplasm including the pre breeding lines. The objective being to identify K efficient genotypes which can yield well under limited availability of K so that the external application of K can be reduced. This paper describes the wide variation noticed during the pre evaluation of 83 elite genotypes which was done as a prelude in the screening and identification of K efficient genotypes. The characters studied were tuber yield, tuber characters, plant dry matter percentage, plant K content, tuber quality (starch, cyanogenic glucosides) attributes, physiological efficiency and plant biometric characters. The variation among the genotypes for the above traits was assessed by making some yardstick for classification which in turn helped in determining the percent distribution of genotypes in each category. The variation among the genotypes were further affirmed through principal component analysis, wherein the first five components explained more than 77% of variability and the cluster analysis performed grouped these genotypes into five clusters. The biplot showed the traits which are closely linked to the genotypes. The dendrogram constructed indicated similar genotypes to that of the clusters to the extent of more than 50% revealing the association of members with similar traits in clusters and dendrograms. The study helped in establishing the drastic variation among the genotypes along with identification of six genotypes viz., Aniyoor, 7 Sahya (2), 7 III E3-5, W-19, CR 43-8, 6-6 for further detailed experimentation to identify K efficient genotypes.

Aspartic Aminopeptidase Is a Novel Biomarker of Aggressive Chronic Lymphocytic Leukemia.

Treatment of chronic lymphocytic leukemia has advanced substantially as our understanding of the kinase signal transduction pathways driven by the B cell receptor (BcR) has developed. Particularly, understanding the role of Bruton tyrosine kinase and phosphatidyl inositol 3 kinase delta in driving prosurvival signal transduction in chronic lymphocytic leukemia (CLL) cells and their targeting with pharmacological inhibitors (ibrutinib and idelalisib, respectively) has improved patient outcomes significantly. The kinase signaling pathway induced by the BcR is highly complex and has multiple interconnecting branches mediated by tyrosine and serine/threonine kinases activated downstream of the BcR. There is a high level of redundancy in the biological responses, with several BcR-signaling kinases driving nuclear factor kappa B activation or inducing antiapoptotic Bcl-2 genes. Accordingly, common gene targets of BcR-signaling kinases may serve as biomarkers indicating enhanced BCR-signaling and aggressive disease progression. This study used a gene expression correlation analysis of malignant B cell lines and primary CLL cells to identify genes whose expression correlated with BCR-signaling kinases overexpressed and/or overactivated in CLL, namely: AKT1, AKT2, BTK, MAPK1, MAPK3, PI3KCD and ZAP70. The analysis identified a 32-gene signature with a strong prognostic potential and DNPEP, the gene coding for aspartic aminopeptidase, as a predictor of aggressive CLL. DNPEP gene expression correlated with MAPK3, PI3KCD, and ZAP70 expression and, in the primary CLL test dataset, showed a strong prognostic potential. The inhibition of DNPEP with a pharmacological inhibitor enhanced the cytotoxic potential of idelalisib and ibrutinib, indicating a biological functionality of DNPEP in CLL. DNPEP, as an aminopeptidase, contributes to the maintenance of the free amino acid pool in CLL cells found to be an essential process for the survival of many cancer cell types, and thus, these results warrant further research into the exploitation of aminopeptidase inhibitors in the treatment of drug-resistant CLL.

Evaluation of photosynthetic efficiency of yam bean (Pachyrhizus erosus L.) at saturating photon flux density under elevated carbon dioxide.

The future CO2 concentration is projected to reach 900-1000 ppm levels by the end of twenty-first century, pertaining to global climatic changes. Consequences of climate change such as changes in mean climatic conditions, increasing extreme weather events, relentless increase in atmospheric CO2 concentration and increasing pest damage pose serious threats to agricultural productivity. An experiment was planned to assess the response of yam bean to elevated CO2, as it is of paramount importance to identify photosynthetically efficient climate-smart crops and varieties to meet future food demand. The net photosynthetic rate (P n ), stomatal conductance (g s ) and intercellular CO2 (C i ) of yam bean variety, Rajendra Misrikand-1 was recorded under elevated carbon dioxide (400-1000 ppm) and photon flux density (PPFD; 50-2000 µmol m-2 h-1) at 30 ± 2 °C, 70-80% relative humidity and 0.8-1.2 kPa vapour pressure deficit. The mean P n rate steadily increased at 200-1000 ppm owing to enhanced intercellular CO2. The same trend was observed in the case of intercellular CO2. However, contrasting results were recorded with regard to g s , which steadily decreased at ascending carbon dioxide concentrations. Further, P n had a significant (P < 0.001) linear correlation with the PPFD (R2 = 0.973). Yam bean was found to be responsive to elevated carbon dioxide as P n rate at 1000 ppm increased up to 23% relative to 400 ppm.

Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications.

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.