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Results for “combinatorial stress”

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PubMed2026

Hormone priming and metabolic engineering of phytohormone crosstalk in rice under combined biotic and abiotic stresses: a multi-omics perspective for climate-resilient crop development.

Rice (Oryza sativa L.) is the caloric backbone for more than half of humanity, yet it remains one of the most vulnerable crops to the simultaneous biotic and abiotic stresses exacerbated by climate change. Phytohormone priming and the complex crosstalk networks governed by transcription factor hubs like WRKY, MYB, and NAC serve as the central adaptive mechanism for stress resilience. This review synthesizes how multi-omics integration, including spatial and single-cell transcriptomics, is resolving the molecular architecture of hormonal priming and epigenetic stress memory. We critically evaluate advanced metabolic engineering and genome-editing strategies such as CRISPR-Cas9, base/prime editing, and synthetic gene circuits that enable precision modifications to decouple stress tolerance from historical yield penalties. Furthermore, we discuss the emerging roles of microbiome-assisted priming via synthetic consortia and the application of artificial intelligence and digital twins (continuously updated computational models of crop physiology) for predictive stress management. By integrating these diverse technological pillars, we propose a systems-level roadmap for developing climate-resilient rice cultivars capable of maintaining yield stability across a volatile combinatorial stress landscape. This synthesis provides a framework for translating mechanistic hormonal insights into field-applicable cultivars to ensure global food security.

CRISPR↗

PubMed2025

Growth-limiting drought increases sensitivity of Asian rice (Oryza sativa) leaves to heat shock through physiological and spatially distinct transcriptomic responses.

Growth-limiting droughts (GLD) impair tissue expansion and delay developmental transitions but are often not considered as stressors, as many physiological traits are only slightly altered relative to well-watered counterparts. Concurrently, cell size, biochemical makeup, and transcriptome profiles vary along the leaf blade in accordance with the partitioning of distinct functions to spatially defined regions of the leaf. This suggests that because different parts of the leaf have underlying differences in their transcriptome profiles, they might respond to GLD in distinctive ways. Moreover, how antagonistic stressors influence physiology and gene expression in different zones of leaves is an open question. In this study, we profiled growth, anatomy, and gas exchange in Asian rice (Oryza sativa) leaves developed in well-watered and GLD conditions, with or without a secondary heat shock. We dissected leaves into seven equal-length segments for transcriptome analysis in these conditions. We hypothesized that GLD would make the leaves more sensitive to heat shock and would disrupt the underlying heterogeneity of the leaf transcriptome. GLD plants were more strongly affected by heat shock with respect to gas exchange and the number and types of genes that were differentially expressed and that these differences varied along the leaf blade. We developed an eFP browser tool with these data to facilitate exploration and hypothesis testing. These findings show that even mild drought treatments are sufficient to impact responses to antagonistic stressors and that substantial within-organ variance exists with respect to stress responses.

Oryza↗

PubMed2026

Context matters: coordinated transcriptional regulation and root plasticity under multinutrient conditions.

Plants often encounter simultaneous imbalances in multiple nutrients, but the regulatory logic coordinating their responses remains poorly understood. We aimed to uncover shared transcriptional programs and regulatory nodes underpinning multinutrient adaptation in Arabidopsis thaliana roots. We analyzed publicly available RNA-seq datasets spanning 15 nutrient and beneficial element conditions using differential expression, co-expression network (WGCNA), and gene regulatory network analysis. Selected transcription factors (TFs) were validated via root phenotyping, suberin staining, and ionomic profiling under two-nutrient stress conditions. We identified a core set of 2050 genes responsive to multiple nutrient treatments, enriched for suberin biosynthesis, and structured into modular co-expression clusters. Eight prioritized candidate TFs (ARR10, GBF3, HHO5, NAC32, NF-YA3, NF-YB2, SARD1, and WRKY33) were shown to modulate root system architecture under specific nutrient combinations. WRKY33 and NF-YB2, in particular, regulated nutrient-responsive suberin deposition and ionomic plasticity. These findings reveal suberin remodeling as a shared downstream process in multinutrient responses and suggest that plasticity is not a fixed trait but a modular, polygenic, and context-dependent outcome. Repurposed TFs with pleiotropic functions coordinate structural and physiological traits, providing regulatory entry points for improving nutrient resilience.

Plant Roots↗

PubMed2025

Mapping transcriptional responses to cellular perturbation dictionaries with RNA fingerprinting.

Single-cell perturbation dictionaries provide systematic measurements of how cells respond to genetic and chemical perturbations, and create the opportunity to assign causal interpretations to observational data. Here, we introduce RNA fingerprinting, a statistical framework that maps transcriptional responses from new experiments onto reference perturbation dictionaries. RNA fingerprinting learns denoised perturbation "fingerprints" from single-cell data, then probabilistically assigns query cells to one or more candidate perturbations while accounting for uncertainty. We benchmark our method across ground-truth datasets, demonstrating accurate assignments at single-cell resolution, scalability to genome-wide screens, and the ability to resolve combinatorial perturbations. We demonstrate its broad utility across diverse biological settings: identifying context-specific regulators of p53 under ribosomal stress, characterizing drug mechanisms of action and dose-dependent off-target effects, and uncovering cytokine-driven B cell heterogeneity during secondary influenza infection in vivo. Together, these results establish RNA fingerprinting as a versatile framework for interpreting single-cell datasets by linking cellular states to the underlying perturbations which generated them.

Journal Article↗

PubMed1992

Emerging strategies for enhancing crop resistance to microbial pathogens.

There are marked differences in the pattern of host gene expression in incompatible plant:microbial pathogen interactions compared with compatible interactions, associated with the elaboration of inducible defenses. Constitutive expression of genes encoding a chitinase or a ribosome-inactivating protein in transgenic plants confers partial protection against fungal attack, and a large repertoire of such antimicrobial genes has been identified for further manipulation. In addition, strategies are emerging for the manipulation of multigenic defenses such as lignin deposition and synthesis of phytoalexin antibiotics by overexpression of genes encoding rate determining steps, modification of transcription factors or other regulatory genes, and engineering production of novel phytoalexins by interspecies transfer of biosynthetic genes. The imminent cloning of disease resistance genes, further molecular dissection of stress signal perception and transduction mechanisms, and identification of genes that affect symptom development will provide attractive new opportunities for enhancing crop protection. Combinatorial integration of these novel strategies into ongoing breeding programs should make an important contribution to effective, durable field resistance.

Amino Acid Sequence↗

PubMed2022

WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy.

Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53-/-] and [HBx,src,p53-/-,RPIA], while ppp2r1bb is downregulated in [tert x p53-/-]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53-/-,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1β expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated β-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1-OSR1-PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1-OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1-OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy.

Animals↗

PubMed2026

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

Humans↗

PubMed2026

A voyage of reprogrammable metabolic bioengineering reshapes plant defense: from editing tools to synthetic systems.

Metabolic bioengineering has emerged as a transformative approach for reshaping plant defense by targeting intrinsic biosynthetic pathways to enhance immunity in modern agriculture. Moving beyond proof-of-concept metabolomics to broad-spectrum programmable pathway engineering addresses gaps in plant rational design and optimizes resilience in response to diverse environmental cues. This review aims to comprehensively highlight the transition of innovative approaches to phenolics, alkaloids, flavonoids, terpenoids, and benzoxazinoids, inferring adaptive reprogramming that mediates the growth-defense balance and functions as molecular sentinels in plants. Furthermore, decoding the volatile metabolome reveals a dynamic signaling interface that influences defense responses and stress-induced plant-microbe interactions, with the shikimate, jasmonate, and salicylate pathways functioning as central hubs for microbial deterrence and priming immune memory. Recent developments in multi-scalar genome-editing strategies, including CRISPR-driven combinatorial edits, enzyme orthogonalization, fluxomics, and spatially resolved multi-omics, reconfigure central and specialized metabolic fluxes toward improved defense function and regulation. Additionally, emerging tools, such as WUSCHEL2 and BABY BOOM transcriptional modules, and artificial engineering strategies integrating deep learning model-driven predictions facilitate rapid development of synthetic genetic circuits and support a predictive engineering of plants. Moreover, Mass spectrometry imaging (MSI) in spatial metabolomics enables to obtain structures and locations of unidentified endogenous metabolites within cells and tissues. Overall, this review emphasizes a diverse array of primary and secondary metabolites, spanning molecular concepts to recent advances in plant immune mechanisms. It also illustrates new frontiers in programmable metabolic engineering that accelerate the understanding of plant-microbe-metabolite cross-talks, offering strategies to improve plant resistance and advance sustainable agricultural solutions.

metabolic bioengineering↗

PubMed1991

A simplified mechanical model of proteins tested on the globin fold.

It has been shown that the distribution of presently known protein loop lengths is consistent with even the simplest available theory of rubber-like elasticity, and with the idea that such loops generate an entropically derived end-to-end tension. It has also been asserted that the molten globule phase, just like the native form, must be mechanically stable, and that a simple demonstration of the potential for mechanical stability would be a powerful test in predictions of new protein folds. This paper amplifies this suggestion by explicit calculation of a familiar but non-trivial test case: sperm-whale myoglobin. The method used is to describe the protein molecule in terms of a highly simplified mechanical model bearing some resemblance to a pre-stressed mechanism. The alpha-helices are treated as rigid rods and the loops are treated as elastic strings. The entropic tensions exerted by the loops are imposed on the mechanism using an approximation proposed earlier. The helices are then held to generate frictionless reaction forces at their mutual points of contact. These contact forces are calculated to null out maximally the effects of the loop tensions, and hence stabilize the molecule. It is shown that the crystallographically determined structure of myoglobin has a significantly higher mechanical stability on this model than does any of a previously published set of combinatorially generated predictions. Amongst the predictions alone, the best is also the one with the highest stability. It is anticipated that this result could be of general importance in sorting or filtering out bad predictions. A further exciting feature of the model is that it offers a natural explanation for the strong conservation of the C2 proline and the invariably long unconserved sequence from the end of the C helix to the start of the E helix in the globins and phycocyanins.

Animals↗

PubMed2022

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Cysteine↗

PubMed2025

Quantitative Profiling of Histone Variants and Posttranslational Modifications by Tandem Mass Spectrometry in Arabidopsis.

Histone dynamics constitute an important layer of gene regulations associated with development and growth in multicellular eukaryotes. They also stand as key determinants of plant responses to environmental changes. Histone dynamics include the exchange of histone variants as well as post-translational modifications of their amino acid residues (such as acetylation and mono/di/trimethylation), commonly referred to as histone marks. Investigating histone dynamics with a focus on combinatorial changes occurring at their residues will greatly help unravel how plants achieve phenotypic plasticity.Mass spectrometry (MS) analysis offers unequaled resolution of the abundance of histone variants and of their marks. Indeed, relative to other techniques such as western blot or genome-wide profiling, this powerful technique allows quantifying the relative abundances of histone forms, as well as revealing coexisting marks on the same histone molecule. Yet, while MS-based histone analysis has proven efficient in several animals and other model organisms, this method stands out as more challenging in plants. One major challenge is the isolation of sufficient amounts of pure, high-quality histones, likely rendered difficult by the presence of the cell wall, for sufficiently deep and resolutive identification of histone species.In this chapter, we describe a straightforward MS-based proteomic method, implemented to characterize histone marks from Arabidopsis thaliana seedling tissues and cell culture suspensions. After acid extraction of histones, in vitro propionylation of free lysine residues, and digestion with trypsin, a treatment at highly basic pH allows obtaining sharp spectral signals of biologically relevant histone peptide forms.The method workflow described here shall be used to measure changes in histone marks between Arabidopsis thaliana genotypes, along developmental time-courses, or upon various stresses and treatments.

Histones↗

PubMedDate not supplied

[The psychopathological text].

Starting from the different epistemological status of looking and hearing in the clinical field, the author stresses the importance of the modalities of approaching the psychopathological text, embodied in its context, and conceived as an intersubjective production rather than an individual phenomenon. The author contends that the psychopathological text can be read in three different ways: 1. Informative. First-hand reading provides cumulative information, conditioned by reader's limitations and imaginary endowment. Likelihood and truth provide its framework, but colliding with each other, being likelihood the first way of organizing perceptual data, whereas truth is to be seeked behind apparent phenomena. 2; Hermeneutical. Reading through interpretation entails deciphering the text according to certain definite rules. The logic of hermeneutics differs from oridinary linear logic in its stemming from joint intersubjective sintactic and semantic recreation. Interpretation provides a joint signification for the discourse, but, because of this very fact, it also makes the codes used to hinge and to create a different universe of signification, and allows for starting the whole process anew. This new universe gives rise to a different link between likelihood and truth, making at least possible, if not necessary, their simultaneous positive values. 3. Maieutical. When the new universes of significations built up by hermeneutical reading are articulated among them, and the system of articulations are set forth, another level is attained, in which meaning is created. Meaning, according to the author's proposal, is generated by the systems of transformations of former universes, both in their synchronic and diachronic processes. Thus, meaning, being open to any possible combinatory of transformations, provides the widest gamut of possibilities to produce sense-and change-in their widest acception.

Psycholinguistics↗