Plant immune receptors detect both microbe-derived and endogenous signals to activate defences. XA21, a rice immune receptor, confers strong race-specific resistance to a subset of Xanthomonas oryzae pv. oryzae (Xoo) strains by recognising the microbial sulphated peptide RaxX. However, the molecular basis for the notably robust XA21-mediated immune response has remained unclear. Here, we report that the small secreted peptide OsRALF26, previously identified as an Oryza-specific ligand for FERONIA-like receptor 1 (OsFLR1), is also directly perceived by XA21. Recognition of OsRALF26 by XA21 triggers a pronounced reactive oxygen species (ROS) burst, pathogenesis-related (PR) gene induction, and enhanced resistance to Xoo. Notably, silencing OsRALF26 leads to a spatially biased reduction in XA21-mediated resistance, particularly in distal tissues. These findings identify OsRALF26 as a host-derived ligand of XA21 that is required for full activation of XA21-mediated immunity in distal tissues, consistent with a role for OsRALF26 in spatial propagation of XA21-dependent defence. By integrating microbe-derived and endogenous signals, XA21 exemplifies a versatile immune strategy in rice. This dual recognition may have arisen through the introgression of XA21, which unintentionally conferred OsRALF26 responsiveness-thereby reinforcing immune robustness in rice varieties.

The impact of physiological stress conditions on Kaposi's sarcoma-associated herpesvirus (KSHV) infection remains poorly understood. One such stressor, hypoxia, is regulated by the transcription factor HIF-1α. We recently reported that hypoxia, or HIF-1α expression alone, can promote lytic infection in cells that typically support latent infection under normoxia. Here, we show that hypoxia-induced lytic infection is reversible, leading to an abortive lytic cycle if the hypoxic condition ceases. Additionally, we found that HIF-1α induces lytic de novo infection only if expressed within the first 24 h post-infection (hpi). We show that HIF-1α can bind to viral promoters and induce lytic genes only during this early window of infection, before the KSHV genome undergoes heterochromatinization and establishes latency. In contrast, regardless of the timing of HIF-1α expression during KSHV infection, the induction of HIF-1α host target genes remains unaffected. These results indicate that the heterochromatinized KSHV DNA becomes resistant to HIF-1α-mediated activation after latency is established. These findings may explain why, despite the expression of HIF-1α in Kaposi's sarcoma tumors, KSHV remains in latency, because HIF-1α cannot induce lytic genes once the viral DNA is heterochromatinized. Importantly, we also demonstrate that inhibition of the epigenetic repressor PRC2, which associates with lytic promoters after 24 hpi, restores HIF-1α's ability to bind viral promoters and induce lytic gene expression post-latency. Collectively, our results indicate that not only the presence of HIF-1α, but also the timing and duration of its expression during KSHV infection, are critical determinants of its ability to drive lytic infection.IMPORTANCEThe current view is that the default pathway of KSHV infection is the establishment of latency, however, how this is altered under physiological stress conditions remains largely unknown. We previously showed that hypoxia, or the expression of its transcription factor HIF-1α alone, promotes the establishment of lytic rather than latent KSHV infection. In this study, we show that the duration of hypoxia, as well as the timing and duration of HIF-1α expression, are crucial determinants in facilitating lytic de novo KSHV infection. Notably, we found that PRC2-mediated heterochromatin inhibits the HIF-1α-mediated upregulation of lytic genes as chromatinization of the KSHV genome progresses during infection. Our findings offer a deeper understanding of how epigenetic regulation intersects with host stress responses to influence viral pathogenesis.

Liquid-liquid phase separation of OsvWA36 fine-tunes brassinosteroid signaling and leaf angle in rice.

Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

The Atriplex halimus dehydrin AhDHN1 enhances growth, seed size, and yield under salt and drought stress in Arabidopsis.

(+)-Catechin from Prunus padus disrupts detoxification pathways and provides field-level control of the bird cherry-oat aphid, Rhopalosiphum padi.

Chronic inflammatory skin diseases such as psoriasis and hidradenitis suppurativa are driven by cytokines, including IL-17A and TNF. Although biologics targeting these cytokines have transformed therapy, the transcriptional contributions of individual skin-resident cell types remain unclear, and dermal fibroblasts have been largely overlooked compared with keratinocytes. To address this, we compared the transcriptional responses of primary human dermal fibroblasts and keratinocytes following invitro stimulation with IL-17A, TNF, or both, using bulk RNA sequencing and Western blotting. Dermal fibroblasts mounted a stronger and broader proinflammatory response than keratinocytes. This was particularly evident in response to TNF and combined TNF/IL-17A stimulation, with enrichment for immune signalling and chemotaxis pathways and robust induction of chemokine genes, including CCL20, CXCL8, and IL6. Keratinocytes primarily upregulated genes associated with epithelial differentiation, barrier function, and protein regulation, including IL36G, S100A7A, and DEFB4A. The heightened fibroblast responsiveness correlated with increased TNF sensitivity and substantially higher TNFR2 (TNFRSF1B) expression and signalling compared with keratinocytes, suggesting a fibroblast-specific mechanism amplifying inflammatory responses. These findings challenge the keratinocyte-centric view of skin inflammation and identify dermal fibroblasts as active contributors and potential therapeutic targets in TNF- and Th17-driven skin diseases.

Drought stress is a major limiting factor for canola production in arid and semi-arid regions, particularly during seed germination, seedling and flowering stages. In this study, we evaluated drought responses of doubled haploid (DH) lines derived from interspecific hybrids of B. napus × B. rapa and their parental cultivars under simulated (PEG-6000) and soil-based drought conditions. Drought stress significantly reduced germination, growth, and physiological performance in all genotypes; however, DH lines consistently exhibited superior tolerance. Under PEG-induced osmotic stress, DH lines maintained higher germination rates, root elongation, and relative water content compared with parental genotypes. During seedling and flowering stages drought, DH lines showed lower accumulation of hydrogen peroxide and malondialdehyde, alongside markedly higher antioxidant enzyme activities (CAT and POD) and improved photosynthetic efficiency (Fv/Fm). Gene expression analysis revealed strong induction of drought-responsive genes, including WRKY28, MYB, LTP, WSP, metallothionein, and protein kinase family genes, particularly in DH lines at prolonged stress exposure. Multivariate analyses (PCA and correlation) confirmed a close association between enhanced antioxidant capacity, transcriptional activation, and drought tolerance traits. Overall, our results demonstrate that homozygous doubled haploid lines derived from distant hybridization between B. napus and B. rapa exhibit enhanced drought tolerance at both early and reproductive stages. These genotypes represent valuable genetic resources for breeding drought-tolerance canola cultivars.

HEXIM1/P-TEFb complex controls RNA polymerase II pause release and immediate early gene induction following neuronal depolarization.

Understanding how human pancreatic α and β cell electrical activities mature is critical for building fully functional stem cell-derived (SC-) pancreatic organoids for research and therapeutics. We implanted tissue-like, stretchable electronics during organogenesis of human pancreatic organoids, enabling months-long, single cell-resolved electrophysiology. Longitudinal single-cell tracking suggested that improved hormone responsiveness reflects increasing activity of SC-α and -β cells with low and high basal firing, linked to induction of energy and hormone metabolism genes. Daily metabolic entrainment showed that circadian hormone secretion rhythms reflect daily oscillation of SC-α and -β electrical characteristics, tied to induction of cell-cell communication and exocytic gene networks, revealing circadian coordination of cell-level, stimulus-coupled responses. Lastly, we showed that electrical stimulation, via implanted actuators, enhances SC-α and -β glucose responsiveness. Our results establish a bioelectronic framework to trace and modulate functional organoid maturation.

Introduction Global warming poses significant challenges to agriculture through increased extreme weather events, such as the water deficit, affecting the establishment and yield of crops like cacao and all its value chain. Understanding the complex drought response mechanisms in cacao through integrated methodologies is crucial for developing strategies to enhance crop resilience to this stress. Methods Here, we evaluated the response to a 52 days-long water deficit stress of three commercial cacao hybrid clones: EET8, ICS60 and TSH565 combining growth and physiological parameters with transcriptomic profiles. Results TSH565 and EET8 clones exhibited the highest drought-stress tolerance through different strategies, being able to cope with stress and to better recovery after rewatering. TSH565 showed stomatal limitation but maintained unimpaired photosynthesis under drought. This clone also displayed water use efficiency and relative water content levels comparable to the watered control group, and its total dry weight exceeded that of EET8 and ICS60 under stress. Transcriptomic profiling of TSH565 indicated upregulation of genes encoding aquaporins, PSII proteins, proteins of the antioxidant system and several enzymes participating in the synthesis of osmo-protective secondary metabolites, seemingly contributing to its tolerance. In contrast, EET8 experienced both stomatal limitation and impaired photosynthetic machinery upon the same stress. Its higher stomatal conductance led to a concomitant increased water loss with a significant decrease in leaf water potential. Transcriptomic profiling revealed the activation of numerous biological processes and metabolic pathways, including key hub transcription factors probably responsible for inducing several downstream effector genes, ultimately driving to its stress tolerance. The induction of genes related to acclimation to low water potential and photoprotection was vital for the survival of this clone. Discussion Despite these differences, ABA metabolism and signaling pathways played a significant role in the drought stress tolerance of both clones. Osmoprotection, osmotic adjustment, and antioxidant response appear to be part of the core strategy of T. cacao ’s tolerance to water deficit stress. This research provides valuable insights into the distinct molecular mechanisms underlying drought-stress tolerance in cacao plants. Specifically, it identifies stress-tolerance candidate genes of breeding value, as well as for T. cacao germplasm characterization, conservation and selection.

Streptomyces species are widely distributed in soils and plant tissues and are valued for their ecological safety and diverse biological functions. Here, we describe a multifunctional endophytic actinomycete, Streptomyces griseorubens MEPSL1, isolated from sweetpotato. This strain exhibits multiple growth-promoting traits and significantly increases γ-tocopherol accumulation in sweetpotato leaves, accompanied by the induction of key biosynthetic genes. Our findings highlight the role of endophytic actinomycetes in improving both crop performance and nutritional quality and point to their potential use in sustainable biofortification strategies.

Autopsy-derived brain tissue analysis is crucial for understanding neurobiology, but post-mortem handling can introduce artifacts. We studied adult human brain transcriptomic signatures from tissue immediately extracted from brains (< 0 hours) and compared to autopsy brain tissue with short (~6 hours) and long (~36 hours) post-mortem intervals(PMIs). Significant deviations in gene signatures were observed in both short and long PMIs compared toimmediately extracted tissue, which we defined as Brain Artifact Genes (BAGs). By subjecting brain samples to processing variables that are unavoidable in autopsy programs (post-mortem time and temperature), we characterizeda set of artifact-responsive genes and mapped this signatureonto matchedsingle-nucleus RNA-seq data,revealing that it was predominantly glutamatergic neurons that exhibited the earliest induction of artifact genes followed by oligodendrocytes later.Using deep learning, we distilled this broader processing-response program into a predictive signature, called Time and Temperature Response genes Underlying Transcriptional Heterogeneity (TTRUTH) and provide an Open Science tool for assigning TTRUTH scores to brain RNA-seq data. Together, this work will help better standardize datasets, enable additional sample stratification, and enhance data interpretation.

Abstract Background: PD-1 immune checkpoint inhibitors (ICIs) have reshaped cancer treatment paradigms. While PD-1 ICIs displays monotherapy efficacy in some tumor types, others, such as breast cancer (BC), require a synergistic combination of ICIs and chemotherapy for clinical benefit. Beyond cytotoxicity, chemotherapy synergize with ICIs via chemoimmunomodulation (CIM), which comprise the immunomodulatory signals elicited by chemotherapy. While many studies have examined molecular features influencing chemoresistance, few have focused on the molecular features that influence CIM, despite the overlap between CIM and the hallmarks of response to PD-1 ICIs. This paucity may be driven by inadequate means for phenotypically delineating CIM and presents a challenge to selection of the most synergistic agents for PD-1 ICIs for a given patient. Methods: We leveraged transcriptomic data from 20 pre-/post-treatment specimens obtained from BC patients (N = 2 reps/sample) treated with neoadjuvant chemotherapy, including anthracycline, cyclophosphamide, taxanes, and platinating agent, to identify CIM induction profiles. CIM induction was assessed using Δ log2(TPM+1) values for 377 genes obtained from gene sets and literature related to autophagy, lysosomes, cellular stress, and immune function. We developed a novel iterative k-means-based unsupervised clustering approach to identify discrete CIM induction states using CIM gene induction values. Overrepresentation analysis was used to identify transcriptomic programs induced in each CIM induction states. Differential gene expression (DEG) analysis and inferential statistics were used on matched pre-treatment specimens to evaluate baseline differences between states. The abundances of immune cell types were deconvoluted using CIBERSORT. Results: Our iterative unsupervised approached identified two discrete states: one with high (H-CIM; N = 10) and one with low CIM (L-CIM; N = 10) induction. Only one replicate from patients was separately clustered. Stability, robusticity, and the binary nature of the clusters were confirmed using standard cluster evaluation metrics. There were no significant differences in clinical characteristics or treatments between states. The H-CIM state had induction of antigen presentation, upregulation of T-cell populations, and phagocytosis transcriptomic programs while the L-CIM group was primarily characterized by the induction of MYC-governed reactive oxygen species (ROS) detoxification and proteostasis programs (FDR-adjusted P (adjP) &amp;lt; 0.05). Baseline DEG analysis identified upregulated immunosuppressive features such as S100A9 (Fold Change (FC) = 8.9; adjP = 0.04) and HP (FC = 21.2; adjP = 0.008) in the L-CIM group which was supported by a significantly higher baseline amount of M2 macrophages (P &amp;lt; 0.001). Proteostasis safeguards SEC61G (FC = 3.3; adjP = 0.04) and SEC31B (FC =2.6; adjP = 0.002) were also upregulated in the L-CIM state suggesting a predisposition for protection against cellular stress. Interestingly, there was no significant difference in baseline MYC expression between the L-CIM and H-CIM group (P = 0.34). Conclusion: Our unsupervised approach enabled classification of distinct CIM induction states using paired pre- and post-treatment transcriptomic analysis, allowing interrogation of CIM in a manner not captured via traditional chemoresistance studies alone. We uncover underappreciated molecular programs, like proteostasis and ROS detoxification, that may underlie blunted CIM induction in BC. Future work will focus on characterizing baseline molecular features that prompt drug-specific CIM induction states, with the goal of informing and guiding the personalization of chemoimmunotherapy in breast cancer. Citation Format: M. O. Gbadamosi, I. Lopes de Lima, K. H. Streeks, E. Molchan, M. S. Makarem, K. L. Coleman. Identification and characterization of distinct chemoimmunomodulatory states in breast cancer via unsupervised transcriptomic analysis of pre- and post-treatment specimens [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-30.

The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.

Differentiated cells can return to a progenitor-like state in response to injury via the evolutionarily conserved cellular program called paligenosis. Paligenosis proceeds by three stages: 1) autophagy/autodegradation of differentiated cell architecture, 2) metaplasia/progenitor gene induction, 3) TOR complex 1 (TORC1)-dependent cell cycle re-entry. Using multiple injury and reverse-lineage-tracing approaches in the Drosophila gut, we show that mature polyploid enterocytes dedifferentiate into diploid progenitors in response to epithelial injury. Several key findings suggest a role for paligenosis. Shortly after injury, enterocytes dramatically increased autophagic flux (stage 1); additionally, pharmacological and genetic inhibition of autophagy blocked progenitor recruitment. Rapamycin also blocked recruitment, indicating that TORC1 is required (stage 3). Finally, RNAi knockdown of ifrd1, an evolutionarily conserved protein required for paligenosis, blocked progenitor recruitment. Thus, replenishment of diploid progenitors from differentiated polyploid cells may occur by paligenosis. The Drosophila gut may offer a versatile system for dissecting the mechanisms of this evolutionarily conserved pathway.

Mitsugumin 53 Protects Against Smoke Inhalation Lung Injury via Suppressing the Proinflammatory Response in a Rat Model.

Sulfur is an essential macronutrient for plants, playing a central role in diverse metabolic processes. Under sulfur-deficient conditions, plants undergo extensive transcriptional reprogramming, which includes the induction of numerous genes encoding proteins of largely unknown function. Among these, two protein families have been studied more intensively: SDI (Sulfur Deficiency Induced) and LSU (Response to Low Sulfur). This review summarizes current experimental evidence on their involvement in sulfur assimilation, stress responses, and overall plant adaptation to sulfur scarcity. Special emphasis is placed on the LSU family, where recent evidence suggests that the function of these proteins extends beyond sulfur starvation responses, pointing to broader roles in plant growth, development, and resilience to diverse stresses.

CD4 T cell memory is essential for long-lasting protective immunity to repeat infections. Unlike naïve T cells, memory cells possess rapid recall ability to quickly produce effector molecules in response to antigen re-exposure. This ability was shown to be associated with epigenetic gene poising. Here, we examine how the activation-inducible transcription factors, AP□1 and NF□κB, regulate rapid recall gene expression. We found that AP-1 is required for their induction and that the enhanced induction of rapid recall genes in memory cells is associated with memory-specific binding of AP□1. Memory-specific AP□1 binding, in turn, is enabled by enhanced chromatin accessibility and reduced DNA methylation at regulatory elements. As the AP-1 DNA-binding motif itself does not contain methylatable CpGs, methylation likely affects the binding of AP-1 co-factors, such as ETS proteins, or accessibility of the region in general. Finally, both common and memory-specific AP□1/NF□κB binding sites show strong overlap with autoimmune and inflammatory disease risk variants, highlighting the clinical relevance of memory T cell epigenetic regulation.

The interactions between co-cultivated plant cultivars are increasingly recognized as influencing their susceptibility to pathogens in mixtures. However, the underlying mechanisms remain largely unexplored. Using a model of durum wheat cultivar mixtures where susceptibility to Septoria foliar disease is increased, we combined aerial and root phenotyping with transcriptional analyses and untargeted metabolomics to elucidate the potential signaling cascade driving this modulation of susceptibility. We observed contrasting root architectures between cultivars in mixture. Molecular analysis showed a delayed induction of defense-related genes and metabolites following pathogen inoculation in plants grown in mixture compared to pure stand. The findings suggest that root architecture potentially triggers a competitive response that could delay the induction of defense responses following pathogen inoculation. Altogether, these results point to a possible interplay between root architecture, resource competition, plant metabolism, and defense modulation in shaping plant-pathogen interactions within varietal mixtures.