Search Results (168)

This study investigates the mechanism of cell death associated with discharge plasma treatment from the perspective of electrical energy injection, using equivalent circuit network analysis to represent cells, buffer solutions, and well plates as electrical components. Our analysis demonstrated that the observed cell death cannot be adequately explained by a One-Step Model, which assumes that cell death occurs when the total injected electrical energy simply reaches a specific threshold. Accordingly, we proposed a Two-Step Model that explicitly incorporates biological tolerance to external stimuli. In this model, a stimulus accumulates only when the instantaneous power exceeds a primary threshold, and cell death is induced only when this accumulated stimulus surpasses a secondary threshold of energy. The proposed Two-Step Model successfully reproduced the experimental cell death data. These findings suggest that plasma-induced cell death is not a simple physical destruction process governed solely by cumulative energy, but instead reflects a biologically regulated response characterized by a specific power-dependent tolerance. Consequently, this Two-Step Model could provide a theoretical foundation for future optimization of delivery conditions for macromolecules such as messenger RNA (mRNA). Full article

The central role of YB-1 in messenger ribonucleoprotein particle (mRNP) metabolism and stress-granule biology highlights the importance of defining the determinants of its self-assembly. YB-1 fibrillogenesis has been attributed primarily to the cold shock domain (CSD). Here, we show that the YB-1 fragment spanning residues 1–129 (AP–CSD) form amyloid fibrils under near-physiological ionic strength (0.12–0.15 M KCl). Fibrillization proceeds without a pronounced exponential growth phase and increases approximately linearly over 45–50 h. Far-UV circular dichroism (CD) and attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) indicate no substantial change in overall secondary-structure content during aggregation. In parallel, ¹H nuclear magnetic resonance (NMR) spectroscopy reveals the depletion of soluble species, and oriented fiber X-ray diffraction displays the hallmark cross-β reflections at approximately 4.7 Å and 10 Å. The prolonged formation time implies an activation barrier that is unlikely to require global refolding. Instead, it may reflect early association events such as dimerization or other local rearrangements required for primary nucleation, followed by consolidation into stable intermolecular contacts. Aggregation that preserves a largely native-like fold while establishing cross-β order may reduce recognition by cellular quality-control systems that preferentially target globally unfolded or strongly destabilized states. This provides a plausible framework for how YB-1 derived assemblies could persist under stress and during age-associated proteostasis decline. Full article

The gut microbiota, acting as a critical extrinsic endocrine organ, is profoundly involved in the pathological evolution and therapeutic response of hormone-dependent malignancies. This review elucidates the core mechanisms governing the microbiota, endocrine, and immune triple-axis. Multi-omic and biochemical evidence demonstrates that microbial metabolic networks, comprising the estrobolome, androbolome, and progestobolome/corticobolome, rely on enzymatic systems such as β-glucuronidases (GUS) and steroid-17,20-desmolases to execute hormone deconjugation and structural modification, thereby modulating systemic steroid exposure. Concurrently, microbe-derived metabolites, such as secondary bile acids and purine derivatives, act as inter-kingdom messengers. These metabolites remodel the tumor immune microenvironment by antagonizing hormone receptors and activating specific signaling axes, such as the Inosine-A2AR pathway. By modulating localized immune cells like effector T cells and myeloid cells, they play a pivotal role in tumor immune evasion. Furthermore, pharmacomicrobiomics reveals a bidirectional regulation between anti-tumor agents and the gut microbiota, where endocrine and immunotherapeutic drugs can induce microbial dysbiosis, while specific gut taxa contribute to primary or acquired resistance by enzymatically inactivating drugs (e.g., reductive inactivation of Enzalutamide) or providing hormonal precursors through bypass pathways. Facing translational challenges, such as real-world microbiome complexity and the colonization resistance of indigenous flora, we propose treating the human body as a unified host–microbe holobiont system. Future research should leverage gnotobiotic models and genetic causal inference to establish functional causality. These efforts will facilitate the development of precision tools, including ubiquitin–proteasome system (UPS) modulators, microbial enzyme inhibitors, and engineered live biotherapeutics. Collectively, these systems biology strategies offer a robust framework for overcoming therapeutic resistance in hormone-dependent malignancies. Full article

Low temperature and drought are among the most pervasive abiotic stresses limiting crop productivity worldwide, and their frequent co-occurrence or alternation imposes compounded constraints on agricultural sustainability. Increasing evidence supports cross-tolerance, whereby exposure to one stress enhances resistance to another, as an emergent property of shared signaling networks and integrative regulatory layers. In this review, we summarize recent advances in understanding cold–drought cross-talk, from early stress perception and secondary messengers to hormonal coordination via abscisic acid, transcriptional reprogramming centered on dehydration responsive element binding protein/C repeat binding factor (DREB/CBF) modules, and longer-term regulatory memory mediated by chromatin remodeling and biomolecular condensates. Importantly, we further discuss how these mechanistic insights can be translated into precision breeding strategies, including genome editing, allele mining, and backcross-assisted introgression, to accelerate the development of crop varieties with stable multi-stress tolerance. Finally, we highlight future directions for integrating multi-omics, high-throughput phenotyping, and data-driven approaches to enable efficient molecular design breeding for complex stress environments. Full article

Melatonin (MEL), also known as N-acetyl-5-methoxytryptamine, has been reported in plants as a secondary messenger involved in regulating abiotic stress responses. MEL treatment, either preharvest or postharvest, regulates several physiological and biochemical processes during fruit growth and ripening in horticultural products. These include reproductive development, tissue and quality maintenance, delayed senescence, and responses to abiotic stress. Due to its natural origin, low toxicity, and multifunctional regulatory capacity, MEL has recently attracted attention as a promising ‘green preservative’ for sustainable postharvest management. Additionally, MEL coordinates through cross-talk with other plant hormones, such as abscisic acid, ethylene, polyamines, jasmonic acid, γ-aminobutyric acid, salicylic acid, and nitric oxide, to regulate postharvest ripening and senescence. Furthermore, MEL enhances antioxidant systems and improves membrane integrity, thereby alleviating chilling injury and enhancing fruit firmness and colour. Notably, recent evidence highlights the innovative regulatory mechanisms of MEL involving redox homeostasis, hormone signalling reprogramming, and transcriptional modulation of stress-responsive pathways. MEL could therefore be considered an emerging, eco-friendly tool for prolonging the shelf-life of fruit and vegetables and maintaining their quality. This review summarises the mechanisms by which MEL contributes to plant stress resistance by regulating the biosynthesis and metabolism of stress tolerance and improving fruit quality. Full article

This article explores the multifaceted role of micro-ribonucleic acids (RNAs) (miRNAs) as critical posttranscriptional regulators in renal physiology and disease, with a focus on their emerging significance in glomerulopathies. miRNAs, small endogenous noncoding RNAs, modulate gene expression by promoting messenger RNA degradation or inhibiting translation, thereby orchestrating essential cellular processes such as proliferation, differentiation, apoptosis, and stress responses. Recent advances have revealed that aberrant miRNA expression profiles are intricately linked to the pathogenesis and progression of various renal diseases, including acute kidney injury, chronic kidney disease, alloimmune injury in solid organ transplantation and glomerulonephritis. This review summarizes the pathogenic and protective roles of miRNAs in major glomerulopathies, discusses their potential as diagnostic and prognostic biomarkers, and outlines future directions for their integration into personalized therapeutic strategies. At the moment, it is not fully established whether some of these mechanisms are the primary pathogenic driver or a secondary response. Combining miRNAs with other molecular markers may further enhance diagnostic and predictive accuracy, facilitating clinical translation, while selective targeting of specific miRNAs at different stages of disease progression could offer promising therapeutic opportunities. Full article

Activation of cGAS, a receptor recognizing cytosolic DNA, in macrophages might be associated with rabies (an RNA virus) through mitochondrial damage. A similar mortality rate was observed between cGAS-deficient (cGAS-/-) and wild-type (WT) mice post-CVS-11 strain injection. However, 2 out of 12 cGAS-/- mice (but not WT) survived for 15 days post-injection. At 7 days post-infection, less severe brain inflammation in cGAS-/- mice was demonstrated by the viral abundance in the hippocampus, the expression of proinflammatory genes (TNF-α and IL-1β), and the Evans blue dye assay (blood–brain barrier defect) with the presence of higher anti-inflammatory genes (TGF-β and arginase-1). Fecal Proteobacteria was more prominent in the infected WT mice, while serum cytokines (TNF-α and IL-1β) were similar in both mouse strains. There were less prominent responses against the rabies virus in cGAS-/- macrophages than in WT cells, as indicated by supernatant IL-6 and the gene expression of TLR-3, RIG-1, MDA-5, and iNOS. On the other hand, mitochondrial injury and cGAS activation were more prominent in WT macrophages over cGAS-/- cells, as indicated by cGAS expression, supernatant cGAMP (a secondary messenger of cGAS), and mitochondrial oxidative stress (MitoSox) together with a decrease in mitochondrial DNA and maximal respiration (extracellular flux analysis). In conclusion, (i) rabies-damaged mitochondria led to cGAS activation that was less severe in cGAS-/- than in WT, (ii) rabies-induced dysbiosis was demonstrated, and (iii) cGAS manipulation and gut–brain axis-associated inflammation warrants further investigation. Full article

Determining whether black hole jets are dominated by leptonic or baryonic matter remains an open question in high-energy astrophysics. We propose that extreme mass ratio binary (EMRB) black holes, where an intermediate mass secondary black hole (a “miniquasar”) periodically interacts with the accretion flow of a supermassive black hole (SMBH), offer a natural laboratory to probe jet composition. In an EMRB, the miniquasar jet is launched episodically after each disk-crossing event, triggered by the onset of super-Eddington accretion. The resulting emissions exhibit temporal evolution as the jet interacts with the SMBH accretion disk. Depending on whether the jet is leptonic or hadronic in composition, the radiative signatures differ substantially. Notably, a baryonic jet produces a more pronounced gamma-ray output than a purely leptonic jet. By modeling the evolution of the multifrequency characteristic features, it is suggested that the gamma-ray-to-UV emissions may serve as a diagnostic tool capable of distinguishing between leptonic and baryonic scenarios. The resulting electromagnetic signals, when combined with multi-messenger observations, offer a powerful means to constrain the physical nature of relativistic jets from black holes. Full article

The detection of gamma-ray burst GRB 221009A has attracted significant attention due to its record brightness and first-ever detection of multi-TeV $\mathit{\gamma }$-rays from a GRB. Located at redshift $z=0.151$, this event is relatively nearby by GRB standards yet remains cosmologically distant, making the survival of multi-TeV photons surprising. The Large High Altitude Air Shower Observatory detected photons with energies up to ∼13 TeV during the early afterglow phase, challenging standard EBL models. We investigate whether several theoretical frameworks can explain this anomalous emission: reduced EBL opacity due to cosmic voids along the line of sight, novel emission mechanisms within the GRB environment, secondary $\mathit{\gamma }$-ray production through cosmic-ray cascades, and new physics scenarios involving Lorentz invariance violation or axion-like particles. Our analysis reveals areas of consensus regarding the exceptional nature of this event, while highlighting ongoing theoretical tensions about the dominant physical processes. We discuss the limitations of current models and identify specific observational signatures that future multi-wavelength and multi-messenger observations could provide to discriminate between competing explanations. The continued study of similar events with next-generation facilities will be crucial for resolving these theoretical challenges and advancing our understanding of extreme particle acceleration processes in astrophysical environments. Full article

Although cyclic adenosine monophosphate (cAMP) is not a major secondary messenger in the visual transduction cascade in vertebrates, it may modulate photoreceptor functions. The effects of cAMP have been extensively studied in rods; however, its role in cones remains less understood. The aim of this study was to investigate the effects of increased levels of cAMP on the photoresponses of isolated blue- and green-sensitive cones in adult zebrafish (Danio rerio). To examine the effects of elevated cAMP on individual cone spectral types, photoreceptor currents were recorded using a suction pipette method. The adenylate cyclase activator forskolin was used to increase intracellular cAMP levels. Sensitivity and photoresponse parameters were compared before and after forskolin application. An increase in cAMP levels has similar effects on photoresponses of blue- and green-sensitive cones. Forskolin application to both types of cones resulted in a slight increase in sensitivity, with significant slowing of the phototransduction cascade shutdown processes and a marked increase in the integration time of photoresponses. These findings suggest that intracellular cAMP levels, which fluctuate in the retina during the diurnal cycle, can modulate cone function. The observed effects of cAMP are consistent with its action on one of its main putative targets, opsin kinases. Full article

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation–contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad—translating a propagating action potential (AP) into a myocardial contraction. Ca²⁺, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation–contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality. Full article

Piezo1 is a mechanosensitive non-selective cation channel. Genetic alterations of the channel result in a hematologic phenotype named Hereditary Xerocytosis. With Yoda1 and, more recently, Yoda2, compounds to increase the activity of Piezo1 have become available. However, their concrete effect depends on the nano environment of the channel and hence on the cell type. Here we compare the potency of Yoda1 and Yoda2 in red blood cells (RBCs). We investigate the effect of the compounds on direct channel activity using automated patch clamp, as well as the secondary effects of channel activation on signalling molecules and cellular response. In terms of signalling, we investigate the temporal response of the second messenger Ca²⁺, and in terms of cellular response, the activity of the Gárdos channel. The opening of the Gárdos channel leads to a hyperpolarisation of the RBCs, which is measured by the Macey–Bennekou–Egée (MBE) method. Although the interpretation of the data is not straightforward, we discuss the results in a physiological context and provide recommendations for the use of Yoda1 and Yoda2 to investigate RBCs. Full article

Galactic cosmic rays (GCRs), composed of protons and atomic nuclei, are accelerated in sources such as supernova remnants and pulsar wind nebulae, reaching energies up to the PeV range. As they propagate through the interstellar medium, their interactions with dense regions like molecular clouds produce secondary particles, including gamma-rays and neutrinos. In this study, we use the Geant4 Monte Carlo toolkit to simulate secondary particle production from GCR interactions within the Perseus molecular cloud, a nearby star-forming region. Our model incorporates realistic cloud composition, a wide range of incidence angles, and both hadronic and electromagnetic processes across a broad energy spectrum. The results highlight molecular clouds as significant sites of multi-messenger emissions and contribute to understanding the propagation of GCRs and the origin of diffuse gamma-ray and neutrino backgrounds in the Galaxy. Full article

Male infertility is an under-recognized global health burden. Accumulating evidence position the intestinal microbiota as a pivotal regulator of testicular function, underpinning the emerging gut microbiota–testis axis. This narrative review introduces the conceptual term “androbactome”, referring to gut microorganisms and microbial genes that are hypothesized to influence androgen biosynthesis, spermatogenesis, and broader reproductive endocrinology. The documented worldwide decline in sperm concentration heightens the urgency of clarifying microbe-mediated influences on male reproductive capacity. The synthesis of preclinical and clinical findings reveals four principal pathways by which dysbiosis compromises fertility: systemic inflammation, oxidative stress, endocrine disruption, and epigenetic alteration. Lipopolysaccharide-driven cytokinaemia, reactive oxygen species generation, hypothalamic–pituitary–gonadal axis suppression, and aberrant germ cell methylation collectively impair sperm quality and hormonal balance. Short-chain fatty acids, secondary bile acids, and indole derivatives emerge as pivotal messengers within this crosstalk. Therapeutic approaches targeting the androbactome, namely dietary optimization, probiotic or prebiotic supplementation, and fecal microbiota transplantation, have demonstrated encouraging improvements in sperm parameters and testosterone levels, yet the causal inference is constrained by predominantly cross-sectional designs and limited long-term safety data. Recognizing the androbactome as a modifiable determinant of male fertility may open new avenues for personalized diagnosis, risk stratification, and adjunctive therapy in regard to idiopathic infertility. The integration of multi-omics platforms to characterize microbial and metabolomic signatures promises to enrich diagnostic algorithms and guide precision interventions, but rigorously controlled longitudinal and interventional studies are required to secure a translational impact. Full article

The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2′3′-cGAMP. Binding of 2′3′-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2′3′-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2′3′-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2′3′-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2′3′-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2′3′-cGAMP-induced migratory responses. Full article