Transcriptional Reprogramming Research Articles

Physiochemical interaction between osmotic stress and a bacterial exometabolite promotes plant disease

Various microbes isolated from healthy plants are detrimental under laboratory conditions, indicating the existence of molecular mechanisms preventing disease in nature. Here, we demonstrated that application of sodium chloride (NaCl) in natural and gnotobiotic soil systems is sufficient to induce plant disease caused by an otherwise non-pathogenic root-derived Pseudomonas brassicacearum isolate (R401). Disease caused by combinatorial treatment of NaCl and R401 triggered extensive, root-specific transcriptional reprogramming that did not involve down-regulation of host innate immune genes, nor dampening of ROS-mediated immunity. Instead, we identified and structurally characterized the R401 lipopeptide brassicapeptin A as necessary and sufficient to promote disease on salt-treated plants. Brassicapeptin A production is salt-inducible, promotes root colonization and transitions R401 from being beneficial to being detrimental on salt-treated plants by disturbing host ion homeostasis, thereby bolstering susceptibility to osmolytes. We conclude that the interaction between a global change stressor and a single exometabolite from a member of the root microbiome promotes plant disease in complex soil systems.

Comprehensive transcriptomic and metabolomic analysis of porcine intestinal epithelial cells after PDCoV infection

IntroductionPorcine deltacoronavirus (PDCoV), an emerging swine enteropathogenic coronavirus with worldwide distribution, mainly infects newborn piglets with severe diarrhea, vomiting, dehydration, and even death, causing huge economic losses to the pig industry. However, the underlying pathogenic mechanisms of PDCoV infection and the effects of PDCoV infection on host transcripts and metabolites remain incompletely understood.MethodsThis study investigated a combined transcriptomic and metabolomic analysis of porcine intestinal epithelial cells (IPEC-J2) following PDCoV infection by LC/MS and RNA-seq techniques. A total of 1,401 differentially expressed genes and 254 differentially accumulated metabolites were detected in the comparison group of PDCoV-infected vs. mock-infected.Results and discussionWe found that PDCoV infection regulates gene sets associated with multiple signaling pathways, including the neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, MAPK signaling pathway, chemokine signaling pathway, ras signaling pathway and so on. Besides, the metabolomic results showed that biosynthesis of cofactors, nucleotide metabolism, protein digestion and absorption, and biosynthesis of amino acid were involved in PDCoV infection. Moreover, integrated transcriptomics and metabolomics analyses revealed the involvement of ferroptosis in PDCoV infection, and exogenous addition of the ferroptosis activator erastin significantly inhibited PDCoV replication. Overall, these unique transcriptional and metabolic reprogramming features may provide a better understanding of PDCoV-infected IPEC-J2 cells and potential targets for antiviral treatment.

Revisiting the Role of Sensors for Shaping Plant Research: Applications and Future Perspectives

Plant health monitoring is essential for understanding the impact of environmental stressors (biotic and abiotic) on crop production, and for tailoring plant developmental and adaptive responses accordingly. Plants are constantly exposed to different stressors like pathogens and soil pollutants (heavy metals and pesticides) which pose a serious threat to their survival and to human health. Plants have the ability to respond to environmental stressors by undergoing rapid transcriptional, translational, and metabolic reprogramming at different cellular compartments in order to balance growth and adaptive responses. However, plants’ exceptional responsiveness to environmental cues is highly complex, which is driven by diverse signaling molecules such as calcium Ca2+, reactive oxygen species (ROS), hormones, small peptides and metabolites. Additionally, other factors like pH also influence these responses. The regulation and occurrence of these plant signaling molecules are often undetectable, necessitating nondestructive, live research approaches to understand their molecular complexity and functional traits during growth and stress conditions. With the advent of sensors, in vivo and in vitro understanding of some of these processes associated with plant physiology, signaling, metabolism, and development has provided a novel platform not only for decoding the biochemical complexity of signaling pathways but also for targeted engineering to improve diverse plant traits. The application of sensors in detecting pathogens and soil pollutants like heavy metal and pesticides plays a key role in protecting plant and human health. In this review, we provide an update on sensors used in plant biology for the detection of diverse signaling molecules and their functional attributes. We also discuss different types of sensors (biosensors and nanosensors) used in agriculture for detecting pesticides, pathogens and pollutants.

Downregulation of HNF4A enables transcriptomic reprogramming during the hepatic acute-phase response.

The hepatic acute-phase response is characterized by a massive upregulation of serum proteins, such as haptoglobin and serum amyloid A, at the expense of liver homeostatic functions. Although the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has a well-established role in safeguarding liver function and its cistrome spans around 50% of liver-specific genes, its role in the acute-phase response has received little attention so far. We demonstrate that HNF4A binds to and represses acute-phase genes under basal conditions. The reprogramming of hepatic transcription during inflammation necessitates loss of HNF4A function to allow expression of acute-phase genes while liver homeostatic genes are repressed. In a pre-clinical liver organoid model overexpression of HNF4A maintained liver functionality in spite of inflammation-induced cell damage. Conversely, HNF4A overexpression potently impaired the acute-phase response by retaining chromatin at regulatory regions of acute-phase genes inaccessible to transcription. Taken together, our data extend the understanding of dual HNF4A action as transcriptional activator and repressor, establishing HNF4A as gatekeeper for the hepatic acute-phase response.

Correction to: Salinity Acclimation Induces Reduced Energy Metabolism, Osmotic Pressure Regulation and Transcriptional Reprogramming in Hypotrichida

Correction to: Salinity Acclimation Induces Reduced Energy Metabolism, Osmotic Pressure Regulation and Transcriptional Reprogramming in Hypotrichida

Effects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis

SPI1 was recently reported as a genetic risk factor for Alzheimer’s disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

A dual regulatory role of the arbuscular mycorrhizal master regulator RAM1 in tomato.

The REQUIRED FOR ARBUSCULAR MYCORRHIZATION1 (RAM1) transcription factor from the GRAS family is well-known by its role as a master regulator of the arbuscular mycorrhizal (AM) symbiosis in dicot and monocot species, being essential in the transcriptional reprograming for the development and functionality of the arbuscules. In tomato, SlGRAS27 is the putative ortholog of RAM1 (here named SlRAM1), but has not yet been characterized. A reduced colonization of the root and an impaired arbuscule formation were observed in the SlRAM1 silenced plants, confirming the functional conservation of the RAM1 ortholog in tomato . However, unexpectedly, SlRAM1 overexpressing (UBIL:SlRAM1) plants also showed a decreased mycorrhizal colonization. Analysis of non-mycorrhizal UBIL:SlRAM1 roots revealed an overall regulation of AM-related genes and a reduction of strigolactone biosynthesis. Moreover, the external application of the strigolactone analogue GR244DO almost completely reversed the negative effects of SlRAM1 overexpression on the frequency of mycorrhization. However, it only partially recovered the pattern of arbuscule distribution observed in control plants. Our results strongly suggest that SlRAM1 has a dual regulatory role during mycorrhization and, apart from its recognized action as a positive regulator of arbuscule development, SlRAM1 is also involved in different mechanisms for the negative regulation of mycorrhization, including the repression of strigolactone biosynthesis.

OsEIL2 balances rice immune responses against (hemi)biotrophic and necrotrophic pathogens via the salicylic acid and jasmonic acid synergism.

Plants typically activate distinct defense pathways against various pathogens. Heightened resistance to one pathogen often coincides with increased susceptibility to another pathogen. However, the underlying molecular basis of this antagonistic response remains unclear. Here, we demonstrate that mutants defective in the transcription factor ETHYLENE-INSENSITIVE 3-LIKE 2 (OsEIL2) exhibited enhanced resistance to the biotrophic bacterial pathogen Xanthomonas oryzae pv oryzae and to the hemibiotrophic fungal pathogen Magnaporthe oryzae, but enhanced susceptibility to the necrotrophic fungal pathogen Rhizoctonia solani. Furthermore, necrotroph-induced OsEIL2 binds to the promoter of OsWRKY67 with high affinity, leading to the upregulation of salicylic acid (SA)/jasmonic acid (JA) pathway genes and increased SA/JA levels, ultimately resulting in enhanced resistance. However, biotroph- and hemibiotroph-induced OsEIL2 targets OsERF083, resulting in the inhibition of SA/JA pathway genes and decreased SA/JA levels, ultimately leading to reduced resistance. Our findings unveil a previously uncharacterized defense mechanism wherein two distinct transcriptional regulatory modules differentially mediate immunity against pathogens with different lifestyles through the transcriptional reprogramming of phytohormone pathway genes.

Abstract PO3-24-12: CRIPTO-regulated extracellular vesicles mediate heterotypic cellular crosstalk in triple negative breast cancers

Abstract Tumor progression involves the dynamic interaction between various cell types within the tumor microenvironment. Fibroblasts, which normally participate in wound healing, exhibit reciprocal communication with breast cancer cells that contributes to tumor cell plasticity and heterogeneity. Gaining insights into the molecular mechanisms underlying cell-to-cell communication, which drive cellular plasticity and play a pivotal role in breast cancer progression and metastasis, has the potential to unlock novel avenues for targeted therapeutic interventions. The small GPI-adaptor protein CRIPTO is a key player in this context. CRIPTO orchestrates the activity of TGF-β and growth factor-like signaling pathways that activate c-Src/MEK/AKT. CRIPTO is expressed during mammary development, wound healing, and breast cancer but is largely undetectable in homeostatic tissue, making it a promising therapeutic target. Our previous studies have demonstrated that the activity of CRIPTO is contingent upon cellular stress, with pronounced influence within pro-fibrotic, hypoxic domains of tumors. Importantly, we have shown that inhibition of CRIPTO using the soluble recombinant protein antagonist A4Fc effectively impedes the progression of triple negative breast cancer (TNBC) in murine xenograft models. Building upon these findings, we have been dissecting CRIPTO‘s role in coordinating fibroblast activation and cell-state reprogramming in TNBC. Notably, we have found that inhibition of CRIPTO with A4Fc suppresses cancer associated fibroblast (CAF) activation and collagen remodeling in vivo. And, by modeling tumor cell:fibroblast crosstalk using in vitro organoid co-cultures, we have demonstrated CRIPTO expression in tumor cells is necessary for extracellular vesicle (EV) uptake by fibroblasts, their SMAD pathway activation and their priming for reciprocal signaling back to tumor cells to for transcriptional reprogramming and cellular invasion. The significance of these findings lies in their potential to pave the way for the development of new therapies specifically targeting crucial tumor cell:fibroblast crosstalk mechanisms at primary and metastatic sites. Plasticity targeting therapies are urgently needed in the treatment of TNBC and other malignancies, and hold great promise for improving patient outcomes. Citation Format: David Freeman, Benjamin Spike, Brooke Gates. CRIPTO-regulated extracellular vesicles mediate heterotypic cellular crosstalk in triple negative breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-12.

Single Cell RNA-Sequencing Uncover the Molecular Determinants of Sexual Dimorphism in Renal Potassium Regulation

Background: Women are more prone to hypokalemia than men, which exposes them to a higher risk of hypokalemia-induced disorders. We have previously shown the response to potassium (K+) deficiency in mice parallels the human condition, with females exhibiting more severe hypokalemia than males upon dietary K+ deficiency. Here, we investigated the molecular underpinnings of this sexual dimorphism. Methods: The renal adaptations to K+ deficiency were analyzed in Wild-type (WT) male and female mice. Animals were randomized to a control or K+-free diet for 8 days. The transcriptional landscape of control and K+-deprived kidneys was investigated using single nucleus RNA-Seq (snRNA-Seq). At least 5000 nuclei/sample were analyzed. Results: We found female susceptibility to hypokalemia originates from renal K+ loss. Cell type-dependent transcriptome profiling of whole kidneys revealed that all nephron segments undergo transcriptional reprogramming in response to K+ deprivation, with generally more differentially expressed genes (DEGs) in females than males. The proximal tubules (PTs) exhibit major transcriptional reprogramming with 747 DEGs in females compared to 213 DEGs in males. Pathway enrichment analysis of the DEGs in the PT revealed the response to K+ deficiency involves several regulatory mechanisms common to both sexes, such as monocarboxylic acid metabolic pathway and purine-containing compound metabolism. Among all the nephron segments, the connecting tubules (CNTs) exhibit striking sex-dependent changes in response to K+ deprivation with more DEGs in males (100) compared to females (67) despite the less severe hypokalemia in males. Pathway enrichment analysis of the DEGs in the CNT indicated the cytoskeleton and actin organization were mostly reprogrammed in females. In contrast, in male CNT, ion channel regulating pathways exhibited a more active reprogramming. In the CNT, transcript abundance of the Kl gene encoding for Klotho protein, a positive regulator of the K+ exit channel ROMK, was significantly decreased in K+-deprived males only. Similarly, Klotho protein was significantly reduced in response to K+ deprivation, specifically in males but not females. Confocal imaging confirmed decreased ROMK and Klotho in male CNT, consistent with more effcient K+ conservation in males than females. Conclusion: All nephron segments undergo transcriptional reprogramming in response to K+ deprivation, indicating the K+ response is generalized and not restricted to the distal nephron, as previously described. Among all the segments, the CNT exhibits a striking sex-dependent transcriptional reprogramming in response to K+ deficiency. The female susceptibility to hypokalemia results mainly from a less effcient reduction of ROMK-dependent K+ secretion in the CNT, leading to urinary K+ loss. DK054231, DK137331 and CNVA00060589. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rice melatonin deficiency causes premature leaf senescence via DNA methylation regulation

In a study of DNA methylation changes in melatonin-deficient rice mutants, mutant plants showed premature leaf senescence during grain-filling and reduced grain yield. Melatonin deficiency led to transcriptional reprogramming, especially of genes involved in chlorophyll and carbon metabolism, redox regulation, and transcriptional regulation, during dark-induced leaf senescence. Hypomethylation of mCG and mCHG in the melatonin-deficient rice mutants was associated with the expression change of both protein-coding genes and transposable element-related genes. Changes in gene expression and DNA methylation in the melatonin-deficient mutants were compensated by exogenous application of melatonin. A decreased S-adenosyl-L-methionine level may have contributed to the DNA methylation variations in rice mutants of melatonin deficiency under dark conditions.

Characterization of Endothelial to Mesenchymal Transition in Air Pollution Mediated Atherosclerosis: Insights from Trajectory Inference and Functional Analyses in Single cell RNA Sequencing Data

Background: Air pollution is the world’s leading environmental risk factor for atherosclerotic cardiovascular disease (ASCVD). Regressive transcriptional reprogramming and transition of cells to primordial states has been identified as a driver of atherosclerosis. Endothelial cell to mesenchymal cell transition (EndoMT) whereby an endothelial cell transforms to a mesenchymal-like cellular phenotype is one such mechanism. However its relevance to air pollution exposure remains uncharacterized. Methods: Male ApoE−/− mice were inhalationally exposed to concentrated particulate matter <2.5μ component (PM2.5) or filtered air (FA, controls) using a Versatile Aerosol Concentration Enrichment System (VACES, 5–6 h/day, 5 d/week for 36 weeks, n = 7/group. PM2.5 concentrations were 70-80 μg/m3 or ~10X ambient levels. Following euthanasia, single-cell RNA-sequencing of aortic cells was performed using the 10-X platform (CA). For all subsequent analyses, aortic cell samples were integrated. Unsupervised clustering (k-NN) and low-dimensional space visualization (UMAP) were performed with a supervised graph method (Minimum Spanning Tree and Principal Curves) to infer and visualize trajectory analysis of novel cell lineages (branching and cell ordering in pseudotime/pseudospace). Functional analyses were carried out by statistical enrichment analysis using Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA) against databases of Gene Ontologies (GO), Biological Pathways, putative regulatory motifs, proteins, or disease annotations to find over-representation of terms and functions. Pseudotime distribution assessed along exposure groups and cell-types lineages were statistically compared using GLM models. Differential Expression Analysis within lineages and between groups were tested by GLM and GAM models and FDR correction, followed by functional analyses. Results: Comparison of the pseudotime lineage with lineage root node at the endothelial cells revealed a similarity between observed endothelial (EC) to vascular smooth muscle (VSMC) cell transition with the differential transition noted with PM2.5 from FA. This overlap suggests a potential exaggeration of EC to VSMC transition in response to PM2.5 exposure. Differential gene expression profiling upon PM2.5-exposure in EC revealed significant changes in GO terms related to cell differentiation, cell migration, and regulation of cell population proliferation. Specific genes with variable patterns of expression (4481) were identified along the EC to VSMC lineage. KEGG pathway analysis along the lineage revealed enriched pathways including PI3K/Akt signaling pathway, MAPK signaling pathway, and Rap1 signaling pathway which are all implicated in the development and progression of atherosclerosis. Conclusion: Single-cell analysis reveals that chronic exposure to PM2.5 results in the exaggeration of EC to VSMC transition consistent with the EndoMT paradigm that may help explain the acceleration of ASCVD in response to air pollution exposure. Additional analysis of cell specific pathways may provide improved understanding of mechanisms progression of atherosclerosis in response to environmental exposures. NIH: 1R35ES031702-01, R01 HL155450, 3R35ES031702-02S1; Burroughs Wellcome Fund: 1060485. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Interactive transcriptome analyses of Northern Wild Rice (Zizania palustris L.) and Bipolaris oryzae show convoluted communications during the early stages of fungal brown spot development.

Fungal diseases, caused mainly by Bipolaris spp., are past and current threats to Northern Wild Rice (NWR) grain production and germplasm preservation in both natural and cultivated settings. Genetic resistance against the pathogen is scarce. Toward expanding our understanding of the global gene communications of NWR and Bipolaris oryzae interaction, we designed an RNA sequencing study encompassing the first 12 h and 48 h of their encounter. NWR activated numerous plant recognition receptors after pathogen infection, followed by active transcriptional reprogramming of signaling mechanisms driven by Ca2+ and its sensors, mitogen-activated protein kinase cascades, activation of an oxidative burst, and phytohormone signaling-bound mechanisms. Several transcription factors associated with plant defense were found to be expressed. Importantly, evidence of diterpenoid phytoalexins, especially phytocassane biosynthesis, among expression of other defense genes was found. In B. oryzae, predicted genes associated with pathogenicity including secreted effectors that could target plant defense mechanisms were expressed. This study uncovered the early molecular communication between the NWR-B. oryzae pathosystem, which could guide selection for allele-specific genes to boost NWR defenses, and overall aid in the development of more efficient selection methods in NWR breeding through the use of the most virulent fungal isolates.

Intestinal carbapenem-resistant Klebsiella pneumoniae undergoes complex transcriptional reprogramming following immune activation

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is a significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract. There, the bacterium is usually present at low density but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood, yet it may be relevant to devise strategies to tackle CR-Kp colonization and infection. Here, we adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, treatment increased the concentration of oxidative species and amino acids in the mouse intestine. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were strongly upregulated, however their deletion did not impair CR-Kp fitness in vivo upon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein, CRP, as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, crp deletion in CR-Kp resulted in strongly impaired gut colonization, although this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance toward bacterial fitness warrants further investigation. Additional analyses utilizing this model may identify key factors to tackle CR-Kp colonization of the intestine.

Redox regulation of gene expression: proteomics reveals multiple previously undescribed redox-sensitive cysteines in transcription complexes and chromatin modifiers.

Redox signalling is crucial for regulating plant development and adaptation to environmental changes. Proteins with redox-sensitive cysteines can sense oxidative stress and modulate their functions. Recent proteomics efforts have comprehensively mapped the proteins targeted by oxidative modifications. The nucleus, the epicentre of transcriptional reprogramming, contains a large number of proteins that control gene expression. Specific redox-sensitive transcription factors have long been recognised as key players in decoding redox signals in the nucleus and thus in regulating transcriptional responses. Consequently, the redox regulation of the nuclear transcription machinery and its cofactors has received less attention. In this review, we screened proteomic datasets for redox-sensitive cysteines on proteins of the core transcription complexes and chromatin modifiers in Arabidopsis thaliana. Our analysis indicates that redox regulation affects every step of gene transcription, from initiation to elongation and termination. We report previously undescribed redox-sensitive subunits in transcription complexes and discuss the emerging challenges in unravelling the landscape of redox-regulated processes involved in nuclear gene transcription.

A fine-scale Arabidopsis chromatin landscape reveals chromatin conformation-associated transcriptional dynamics

Plants, as sessile organisms, deploy transcriptional dynamics for adapting to extreme growth conditions such as cold stress. Emerging evidence suggests that chromatin architecture contributes to transcriptional regulation. However, the relationship between chromatin architectural dynamics and transcriptional reprogramming in response to cold stress remains unclear. Here, we apply a chemical-crosslinking assisted proximity capture (CAP-C) method to elucidate the fine-scale chromatin landscape, revealing chromatin interactions within gene bodies closely associated with RNA polymerase II (Pol II) densities across initiation, pausing, and termination sites. We observe dynamic changes in chromatin interactions alongside Pol II activity alterations during cold stress, suggesting local chromatin dynamics may regulate Pol II activity. Notably, cold stress does not affect large-scale chromatin conformations. We further identify a comprehensive promoter-promoter interaction (PPI) network across the genome, potentially facilitating co-regulation of gene expression in response to cold stress. Our study deepens the understanding of chromatin conformation-associated gene regulation in plant response to cold.

Identification of a novel form of caspase-independent cell death triggered by BH3-mimetics in diffuse large B-cell lymphoma cell lines

BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells. Of note, rather than occurring via necroptosis, CICD induced immediately after mitochondrial permeabilization was associated with transcriptional reprogramming mediated by activation of c-Jun N-terminal Kinase (JNK) signaling and Activator Protein 1 (AP1). Thereby, CICD resulted in the JNK/AP1-mediated upregulation of inflammatory chemokines and increased migration of cytotoxic Natural Killer (NK) cells. Taken together, our study describes a novel mode of CICD triggered by BH3-mimetics that may alter the immune response towards dying cells.

Ischemia-Reperfusion Injury in Kidney Transplantation: Mechanisms and Potential Therapeutic Targets.

Kidney transplantation offers a longer life expectancy and a better quality of life than dialysis to patients with end-stage kidney disease. Ischemia-reperfusion injury (IRI) is thought to be a cornerstone in delayed or reduced graft function and increases the risk of rejection by triggering the immunogenicity of the organ. IRI is an unavoidable event that happens when the blood supply is temporarily reduced and then restored to an organ. IRI is the result of several biological pathways, such as transcriptional reprogramming, apoptosis and necrosis, innate and adaptive immune responses, and endothelial dysfunction. Tubular cells mostly depend on fatty acid (FA) β-oxidation for energy production since more ATP molecules are yielded per substrate molecule than glucose oxidation. Upon ischemia-reperfusion damage, the innate and adaptive immune system activates to achieve tissue clearance and repair. Several cells, cytokines, enzymes, receptors, and ligands are known to take part in these events. The complement cascade might start even before organ procurement in deceased donors. However, additional experimental and clinical data are required to better understand the pathogenic events that take place during this complex process.

Perfluorobutanoic acid triggers metabolic and transcriptional reprogramming in wheat seedlings

The environmental risks of fluorinated alternatives are of great concern with the phasing out of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate. Here, multi-omics (i.e., metabolomics and transcriptomics) coupled with physiological and biochemical analyses were employed to investigate the stress responses of wheat seedings (Triticum aestivum L.) to perfluorobutanoic acid (PFBA), one of the short-chain per- and polyfluoroalkyl substances (PFAS) and PFOA alternatives, at environmentally relevant concentrations (0.1–100 ng/g). After 28 days of soil exposure, PFBA boosted the generation of OH and O2− in wheat seedlings, resulting in lipid peroxidation, protein perturbation and impaired photosynthesis. Non-enzymatic antioxidant defense systems (e.g., glutathione, phenolics, and vitamin C) and enzymatic antioxidant copper/zinc superoxide dismutase were strikingly activated (p < 0.05). PFBA-triggered oxidative stress induced metabolic and transcriptional reprogramming, including carbon and nitrogen metabolisms, lipid metabolisms, immune responses, signal transduction processes, and antioxidant defense-related pathways. Down-regulation of genes related to plant-pathogen interaction suggested suppression of the immune-response, offering a novel understanding on the production of reactive oxygen species in plants under the exposure to PFAS. The identified MAPK signaling pathway illuminated a novel signal transduction mechanism in plant cells in response to PFAS. These findings provide comprehensive understandings on the phytotoxicity of PFBA to wheat seedlings and new insights into the impacts of PFAS on plants.

Naringenin restricts the colonization and growth of Ralstonia solanacearum in tobacco mutant KCB-1.

Bacterial wilt severely jeopardizes plant growth and causes enormous economic loss in the production of many crops, including tobacco (Nicotiana tabacum). Here, we first demonstrated that the roots of bacterial wilt-resistant tobacco mutant KCB-1 can limit the growth and reproduction of Ralstonia solanacearum. Secondly, we demonstrated that KCB-1 specifically induced an upregulation of naringenin content in root metabolites and root secretions. Further experiments showed that naringenin can disrupt the structure of R. solanacearum, inhibit the growth and reproduction of R. solanacearum, and exert a controlling effect on bacterial wilt. Exogenous naringenin application activated the resistance response in tobacco by inducing the burst of reactive oxygen species and salicylic acid deposition, leading to transcriptional reprogramming in tobacco roots. Additionally, both external application of naringenin in CB-1 and overexpression of the Nicotiana tabacum chalcone isomerase (NtCHI) gene, which regulates naringenin biosynthesis, in CB-1 resulted in a higher complexity of their inter-root bacterial communities than in untreated CB-1. Further analysis showed that naringenin could be used as a marker for resistant tobacco. The present study provides a reference for analyzing the resistance mechanism of bacterial wilt-resistant tobacco and controlling tobacco bacterial wilt.