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Experimental otitis media with effusion: an immune-complex-mediated response.

The possibility that immune complexes cause otitis media with effusion (OME) has been previously proposed. In order to test this hypothesis we developed an animal model in which immune complexes were injected into the middle ears of chinchillas and the animals killed at various time intervals thereafter. Moderate inflammatory changes were seen in animals killed four hours postinjection, whereas intense inflammation was observed in those killed at 24 hours. Inflammatory changes observed included capillary dilatation with increased capillary permeability, migration of polymorphonuclear leukocytes into the sub-mucosa, hemorrhage, and damage to and actual disruption of the subepithelial basement membrane. These changes are consistent with a complement-mediated acute inflammatory reaction. Although no definite conclusion can be made concerning the etiologic role of immune complex in OME, our findings show that immune complexes can cause acute inflammatory changes in the middle ear of the experimental animal.

Animals↗
PubMed2026

BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.

Extrachromosomal circular DNA (ecDNA) is frequently generated within the nucleus, contributing to genome dynamics and heterogeneity, thereby promoting cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here, using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes as key drivers of ecDNA production. Following DNA segmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively mediates ecDNA production by joining the free ends of the DNA fragments. Furthermore, ecDNA from patient tumors harbors junction sites with a LIG4 signature. Notably, disruption of either LIG4 or the BRCA1-A complex in cancer cells impairs ecDNA-mediated adaptation, hindering the development of resistance to both chemotherapy and targeted therapies. Together, our study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers therapeutic targets to block ecDNA-mediated adaptation for cancer treatment.

Humans↗
PubMed1978

Stacking interactions between aromatic amino acids and adenine ring of ATP in zinc mediated ternary complexes.

Spectrophotometric studies have provided evidence for zinc-mediated ternary complexes between ATP and aromatic amino acids. The hypochromicity observed in the 260 nm band of ATP increased in the order phenylalanine less than tyrosine less than tryptophan. Adding alanine did not produce any change of the ATP spectrum. The association constant was four fold higher for the ATP-Zinc-Tryptophan complex than for that of the ATP-Zinc-Alanine. The increased stability of the former complex was ascribed to the stacking interaction between indole and adenine rings. The maximum concentration of the ATP-Zinc-Tryptophan complex occurred at about pH 8.0. For these ternary complexes several possible stacked structures involving or not involving N(7) of adenine are discussed.

Adenine↗
PubMed2026

Mechanisms of Transcriptional Regulation by Salicylic Acid Receptors.

Salicylic acid (SA) is a key phytohormone that activates plant defense responses 1-3. In Arabidopsis, NPR1 (also known as NIM1) and NPR3/NPR4 have been identified as dual SA receptors responsible for perceiving SA 4-6. However, the mechanisms of how SA binding to the NPR proteins leads to induction of defense gene expression remain unclear. Here, we elucidate how SA triggers transcriptional activation via NPR1 and relieves transcriptional repression mediated by NPR3/NPR4. We identified Mediator Complex Subunit 15A (MED15A) as a bridge between NPR1 and the Mediator complex governing transcription. SA induces direct interaction of NPR1 with MED15A. Structural and functional analysis showed that the binding of NPR1 to MED15A is essential for NPR1-mediated transcriptional activation. Meanwhile, SA relieves transcriptional repression mediated by NPR3/NPR4. NIM1-interacting 1 (NIMIN1) interacts with NPR3/NPR4 and the Topless (TPL) co-repressor, connecting them to Polycomb Repressive Complex 2 (PRC2) to mediate H3K27 trimethylation of SA-responsive genes. SA inhibits the interactions between NPR3/NPR4 and NIMIN1, reduces H3K27 trimethylation levels and increases histone acetylation of the target genes to release NPR3/NPR4-mediated repression. Our study offers a comprehensive view of SA-mediated defense gene activation. These findings lay a foundation for designing more effective SA analogs as agrochemicals and for engineering crop resistance by manipulating SA perception and signaling.

Journal Article↗
PubMed1975

[Pathophysiological implications of antigen-antibody complexes (author's transl)].

Seventy years after the description of the Arthus phenomenon, the concept of immune complex mediated pathology is widely recognized in clinical pathophysiology. The availability of methods for the detection of soluble immune complexes opens new paths for clinical investigation in this field. This is demonstrated for systemic lupus erythematosus, viral hepatitis B and herpes zoster disease. New experimental approaches deal with the question of tissue localization of immune complex mediated diseases, e.g. through affinity of antigens for certain tissue structures.

Animals↗
PubMed2026

Mediator at the Helm: Coordinating transcription and biomolecular condensates in hematopoiesis.

Hematopoiesis relies on precisely coordinated transcriptional programs that balance stem cell self-renewal, lineage commitment, and terminal differentiation. Central to this regulation is the Mediator complex, a large multi-subunit transcriptional co-regulator that integrates signals from transcription factors and chromatin regulators to control RNA polymerase Ⅱ (Pol Ⅱ) activity. The dynamic and modular composition of Mediator enables context-dependent transcriptional outputs, while individual subunits can exert specialized regulatory functions during hematopoietic lineage specification, thereby contributing to cell-fate-specific transcriptional outputs. Recent advances further reveal that transcriptional regulation is shaped by the spatial organization of regulatory machinery with biomolecular condensates formed through liquid-liquid phase separation (LLPS), particularly at super-enhancers. In this emerging framework, Mediator functions not only as a transcriptional integrator but also as a key coordinator of transcriptional machinery within condensates at cell-fate-related gene loci. In this chapter, we summarize how distinct Mediator subunits confer specific modes of transcriptional regulation and discuss how the interplay between Mediator and phase-separated condensates shapes transcriptional control during hematopoiesis. We highlight how specific subunits, including MED1 and MED26, participate in distinct regulatory modes in erythropoiesis, spanning super-enhancer-driven transcriptional activation, progenitor expansion, and condensate-associated mechanisms that influence Pol Ⅱ pausing and global transcription repression during terminal differentiation. Together, these findings support a model in which Mediator integrates transcriptional regulation with nuclear organization through condensate-mediated mechanisms, providing a conceptual framework for understanding hematopoietic cell fate decisions and transcriptional dysregulation in hematological diseases.

Hematopoiesis↗
PubMed2025

Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism.

BACKGROUND: Seven female individuals with multiple congenital anomalies, developmental delay and/or intellectual disability have been found to have a genetic variant of uncertain significance in the mediator complex subunit 12 gene (MED12 c.3412C>T, p.Arg1138Trp). The functional consequence of this genetic variant in disease is undetermined, and insight into disease mechanism is required. METHODS: We identified a de novo MED12 p.Arg1138Trp variant in a female patient and compared disease phenotypes with six female individuals identified in the literature. To investigate affected biological pathways, we derived two induced pluripotent stem cell (iPSC) lines from the patient: one expressing wildtype MED12 and the other expressing the MED12 p.Arg1138Trp variant. We performed neural disease modelling, transcriptomics and protein analysis, comparing healthy and variant cells. RESULTS: When comparing the two cell lines, we identified altered gene expression in neural cells expressing the variant, including genes regulating RNA polymerase II activity, transcription, pre-mRNA processing, and neural development. We also noted a decrease in MED12L expression. Pathway analysis indicated temporal delays in axon development, forebrain differentiation, and neural cell specification with significant upregulation of pre-ribosome complex gene pathways. CONCLUSION: In a human neural model, expression of MED12 p.Arg1138Trp altered neural cell development and dysregulated the pre-ribosome complex providing functional evidence of disease aetiology and mechanism in MED12-related disorders.

Humans↗
PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗
PubMed2026

Mapping convergent regulators of melanoma drug resistance by PerturbFate.

High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.

Humans↗
PubMed1979

Detection of immune complexes by a new assay, the polyethylene glycol precipitation-complement consumption test (PEG-CC).

A new assay for the detection of circulating immune complexes, the polyethylene glycol precipitation-complement consumption assay (PEG-CC), is described. The test is both simple and sensitive, and exhibits a high degree of specificity. Immune complexes are first isolated from serum by precipitation in 2.5% polyethylene glycol (PEG) and concentrated. They are then assayed functionally by measuring their ability to fix complement using a sensitive kinetic assay for total haemolytic complement. The test can detect aggregated IgG in serum at concentrations around 6.0 micrograms/ml (about 2.0 micrograms absolute. Using DNA-anti-DNA and ovalbumin-anti-ovalbumin immune complexes prepared in vitro, antigen concentrations less than 0.5 micrograms/ml can be detected. Interference by endogenous complement, polyanions and other factors in test sera has been virtually eliminted by the design of the assay. The increased specificity of the PEG-CC test for immune complexes, should prove useful in the diagnosis and monitoring of immune complex-mediated diseases.

Animals↗
PubMed1978

Merocyanine 540 as a fluorescent probe of membranes: staining of electrically excitable cells.

With the exception of certain blood cells considered in the accompanying paper (Valinsky, Easton and Reich, 1978), merocyanine 540 (MC 540), a fluorescent membrane probe, selectively strains the membranes of a wide variety of electrically excitable cells, but not those of nonexcitable cells. This reaction is Ca2+-dependent when staining is performed in buffered iso-osmotic sucrose, Ca2+-independent when staining proceeds at high ionic strength, inhibited by La3+ and sodium Suramin, enhanced by controlled, low level photosensitization of cell-associated dye and essentially irreversible. These characteristics of the staining reaction depend upon the maintenance of both cell viability and a normal unperturbed membrane structure. Although the mechanisms involved in the staining specificity remain unknown, observation of MC 540 partitioning between benzene and water in model reactions indicates that dye transport into hydrophobic solvents is accompanied by the formation of stoichiometric complexes with cations and phospholipids. These results may suggest the existence of specific, possibly phospholipid-rich membrane domains that mediate complex formation with MC 540 in excitable cells; comparable domains either would not exist, or would be inaccessible at the external surfaces of nonexcitable cells.

Benzoxazoles↗
PubMed2026

Phosphatase-mediated mitigation of rare earth element toxicity to Pseudomonas putida.

Anthropogenic activities are driving an increasing flux of rare earth elements (REE) into environmental compartments, raising concerns about their biological impact, particularly on microorganisms that sustain ecosystem functioning. Here, we provide a systematic assessment of the toxicity of all 16 REE toward Pseudomonas putida KT2440, a soil bacterium that can use these metals as enzyme cofactors. Dose-response growth inhibition assays revealed high sensitivity to light REE. Toxicity correlated strongly with ionic radius, with IC50 values ranging from 0.3 µM for lanthanum to 10 µM for scandium. Serial propagation of P. putida under gradually increasing REE stress yielded resistant populations, from which two stably resistant strains were isolated. Genome resequencing showed that both strains carried a single mutation in uxpB, encoding an alkaline phosphatase. Gene deletion and overexpression experiments, together with phosphatase activity measurements, confirmed the involvement of uxpB in REE resistance. Our findings reveal a previously unrecognized mechanism of tolerance to REE, suggesting that mutations enhancing phosphatase activity promote phosphate release from organic phosphorus compounds, thereby reducing REE bioavailability through phosphate-mediated complexation and/or immobilization.

Alkaline phosphatase↗
PubMed1979

Electron spin resonance study of the role of NO . catalase in the activation of guanylate cyclase by NaN3 and NH2OH. Modulation of enzyme responses by heme proteins and their nitrosyl derivatives.

The role of NO . catalase in the activation of partially purified soluble guanylate cyclase of rat liver by NaN3 and NH2OH was examined by electron spin resonance (ESR) spectroscopy. Equilibration of bovine liver catalase with NO resulted in formation of a paramagnetic species exhibiting a three-line ESR spectrum similar to that of NO . catalase. This paramagnetic complex produced concentration-dependent stimulation of preparations of partially purified guanylate cyclase that were devoid of detectable endogenous heme content. The stimulation of partially purified guanylate cyclase by NO . catalase was similar to that obtained with NO . hemoglobin and with NO . cytochrome P-420 prepared by reaction of hepatic microsomes of phenobarbital-treated rats with NO. By contrast, these same enzyme preparations did not respond to NO or catalase alone. Addition of hematin or hemoglobin plus a reducing agent to purified guanylate cyclase restored enzyme responsiveness to NO and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but not to NaN3 or NH2OH. Responses to the latter agents were restored by catalase and potentiated by a H2O2-generating system. Formation of the NO . catalase complex was evident by ESR spectroscopy in test solutions containing NaN3 or nh2oh, catalase, and a glucose-glucose oxidase, H2O2-generating system. The presence of NO . catalase correlated well with the ability of test solutions to activate purified guanylate cyclase. These results provide evidence for catalase-dependent NO generation from NaN3 and NH2OH under conditions leading to guanylate cyclase activation. Preformed NO . hemoglobin or NO . cytochrome P-420 also activated heme-deficient partially purified guanylate cyclase. The ability of several preformed NO . heme protein complexes, but not NO, to stimulate heme-deficient guanylate cyclase supports the concept that formation of the paramagnetic nitrosyl . heme complex, mediated by either enzymatic or nonenzymatic reactions, is a common and essential step in the process by which NO or NO-forming compounds activate guanylate cyclase. In the absence of the NO ligand, both hemoglobin and catalase suppress the stimulatory effects of the corresponding NO . heme proteins on guanylate cyclase. Release of each heme protein from the NO . heme protein complex occurs more rapidly under aerobic compared to anaerobic conditions. However, hemoglobin is approximately 2000 times more effective as an inhibitor of NO . hemoglobin stimulation of guanylate cyclase than is catalase as an inhibitor of NO . catalase action. This finding may explain the more pronounced decline in the rate of cGMP generation in air in the presence of NO . hemoglobin compared to NO . catalase. The results imply that guanylate cyclase responses to activators that can form NO are determined by both the stimulatory activity of the endogenous heme acceptors of NO and the relative inhibitory effects of the unliganded heme proteins present.

Anaerobiosis↗
PubMed2026

rRNA expansion segments mediate ribosome dimerization as a conserved stress response.

Inhibition of messenger RNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3' end of aminoacyl-transfer RNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Here, we used electron tomography and topology analysis to define the effects of puromycin on the translation machinery in situ. We show that puromycin-treated neuronal cells exhibit an accumulation of eIF5A-bound ribosomes in a translationally inactive "idle" state, and thereby defining a broader role of eIF5A in ribosome homeostasis. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translational hibernating and protecting idle ribosomes. We further show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including endoplasmic reticulum stress and amino acid depletion. Collectively, our findings illuminate distinct states of mammalian ribosome hibernation and dimerization, providing new insights into the relationship of cellular stress and the dynamic regulation of ribosomal activity.

Ribosomes↗
PubMed2026

Model-driven analysis reveals oxidative stress adaptation enabling efficient energy utilization in a Crabtree-negative Saccharomyces cerevisiae.

Although abolishing the Crabtree effect in Saccharomyces cerevisiae through a pyruvate dehydrogenase bypass eliminates carbon loss through ethanol overflow metabolism, it compromises growth rates. While the Crabtree effect has been a valuable natural adaptation, it is energetically inferior to respiration and is generally undesirable in cell factories engineered to produce assimilatory compounds. Restoring growth efficiency in Crabtree-negative strains remains a central challenge. Through adaptive laboratory evolution of the engineered strain (sZJD23) and subsequent reverse engineering, a variant (sZJD28) with markedly improved growth was identified. This improvement is driven primarily by a mutation in MED2 (encoding a Mediator complex subunit) and, to a lesser extent, a mutation in GPD1 (encoding glycerol-3-phosphate dehydrogenase). By integrating quantitative proteomics with enzyme-constrained genome-scale modelling, we demonstrate that these mutations jointly enable a more efficient mode of oxidative stress adaptation and energy utilization. The GPD1 mutation suppresses a protein-costly, suboptimal NAD⁺-recycling strategy reliant on glycerol synthesis, while the MED2 mutation reshapes the oxidative stress response towards peroxisomal detoxification. Collectively, these adjustments optimize metabolic flux distribution and reduce protein costs in energy metabolism, thereby increasing ATP availability. Our findings reveal how coordinated mutations in regulatory and metabolic genes restore growth fitness in engineered Crabtree-negative yeast.

Saccharomyces cerevisiae↗
PubMed2025

Compensatory evolution to DNA replication stress is robust to nutrient availability.

Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.

DNA Replication↗
PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗
PubMed1978

The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations.

Vasculitis is a clinicopathologic process characterized by inflammation and necrosis of blood vessels. Certain disorders have vasculitis as the predominant and most obvious manifestation, whereas others have various degrees of vasculitis in association with other primary disorders. Within the entire spectrum of vasculitis virtually any size or type of blood vessel in any organ system can be involved. Most of the vasculitides can be associated directly or indirectly with immunopathogenic mechanisms. In this regard, immune complex mediation is being increasingly recognized as the underlying mechanism in several of the vasculitides. With clinical, pathologic, and immunologic criteria, certain vasculitic disorders can be clearly recognized and categorized as distinct entities, whereas in others there is an overlap of different diseases within a broader category. In recent years, several of the more serious vasculitides, such as Wegener's granulomatosis and the systemic necrotizing vasculitides of the polyarteritis nodosa group, which formerly had extremely poor prognoses, have been shown to be extraordinarily responsive to chronic low-dose cytotoxic therapy, particularly cyclophosphamide.

Adult↗