Search Results (9,921)

14-3-3 proteins are highly conserved regulatory molecules in plants. In grapevine (Vitis vinifera L.), 14-3-3 proteins are studied under abiotic stress. However, the role of 14-3-3 proteins in the interaction between grapevine and downy mildew is yet to be studied. In this study, we identified a highly conserved 14-3-3 protein in grapevine and performed a phylogenetic analysis, revealing a close relationship between one of its homologs, 14-3-3ω proteins from Arabidopsis thaliana and Nicotiana benthamiana. We designated this homolog as Vv14-3-3ω. Subcellular localization studies showed that Vv14-3-3ω resides in the plasma membrane and cytoplasm. Expression analysis revealed a strong induction of Vv14-3-3ω at early time points following Plasmopara viticola infection, correlating with enhanced pathogen sporulation in grapevine. Furthermore, transient overexpression of Vv14-3-3ω in N. benthamiana increased susceptibility to the Phytophthora capsici pathogen and suppressed Flg22-induced pattern-triggered immunity (PTI) responses. Overexpression of Vv14-3-3ω in Nb14-3-3-silenced N. benthamiana plants resulted in increased susceptibility to P. capsici, suggesting functional conservation of this isoform. These findings indicate that Vv14-3-3ω functions as a susceptibility factor, facilitating pathogen infection and disease progression in grapevine, and highlight its potential role for improving resistance against downy mildew. Full article

Alopecia areata (AA) is a chronic autoimmune disorder characterized by non-scarring hair loss, with subtypes ranging from patchy alopecia (AAP) to alopecia totalis and universalis (AT/AU). The aim of this research is to investigate molecular features across AA severity by performing an integrated analysis of scalp transcriptomic datasets (GSE148346, GSE68801, GSE45512, GSE111061) and matched serum proteomic data from GSE148346. Differential expression analysis indicated that, relative to normal scalp, non-lesional AA tissue shows early immune activation—including Type 1 (C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CD8a molecule (CD8A), C-C motif chemokine ligand 5 (CCL5)) and Type 2 (CCL13, CCL18) signatures—together with reduced expression of hair-follicle structural genes (keratin 32(KRT32)–35, homeobox C13 (HOXC13)) (FDR < 0.05, |fold change| > 1.5). Lesional AAP and AT/AU scalp showed stronger pro-inflammatory upregulation and greater loss of keratins and keratin-associated proteins (KRT81, KRT83, desmoglein 4 (DSG4), KRTAP12/15) compared with non-lesional scalp (FDR < 0.05, |fold change| > 1.5). Ferroptosis-associated genes (cAMP responsive element binding protein 5 (CREB5), solute carrier family 40 member 1 (SLC40A1), (lipocalin 2) LCN2, SLC7A11) and IRS (inner root sheath) differentiation genes (KRT25, KRT27, KRT28, KRT71–KRT75, KRT81, KRT83, KRT85–86, trichohyalin (TCHH)) were consistently repressed across subtypes, with the strongest reductions in AT/AU lesions versus AAP lesions, suggesting that oxidative-stress pathways and follicular structural integrity may contribute to subtype-specific pathology. Pathway analysis of lesional versus non-lesional scalp highlighted enrichment of IFN-α/γ, cytotoxic, and IL-15 signaling. Serum proteomic profiling, contrasting AA vs. healthy controls, corroborated scalp findings, revealing parallel alterations in immune-related proteins (CXCL9–CXCL10, CD163, interleukin-16 (IL16)) and structural markers (angiopoietin 1 (ANGPT1), decorin (DCN), chitinase-3-like protein 1 (CHI3L1)) across AA subtypes. Together, these data offer an integrated view of immune, oxidative, and structural changes in AA and found ferroptosis-related and IRS genes, along with immune signatures, as potential molecular indicators to support future studies on disease subtypes and therapeutic strategies. Full article

Chlorpyrifos CPF (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate), known also as Chlorpyrifos-ethyl, is one of the most utilized organophosphorus pesticides worldwide. Additionally, CPF could be used as a chemical warfare agent surrogate. Although its acute toxicity is not high, it is responsible for both a large number of intoxications and chronic, delayed neurological effects. In this work, it is reported for the first time the qualitative and quantitative response produced by CPF vapors, using a pocket-held Time-of-Flight Ion Mobility Spectrometer (ToF IMS) with a non-radioactive ionization source and ammonia doping, model LCD-3.2E (Smiths Detection Ltd.), operated near ambient temperature (below 30 °C). Spectra of CPF in positive ion mode included two distinct product ion peaks; thus, identification of CPF vapors by IMS relies on these peaks—the monomer M·NH₄⁺ with reduced ion mobility K₀ = ca. 1.76 cm²V⁻¹s⁻¹ and the dimer M₂·NH₄⁺ with K₀ = ca. 1.47 cm²V⁻¹s⁻¹ (where M may be assignable to CPF molecule)—and positive reactant ions (Pos RIP) have K₀ = ca. 2.25 cm²V⁻¹s⁻¹. Excellent sensitivity, with a limit of detection LOD of 0.72 ppb_v (10.5 μg m⁻³) and a limit of quantification LOQ of 2.41 ppb_v (35.1 μg m⁻³), has been noticed; linear response was up to 100 ppb_v, while saturation occurs over ca. 1000 ppb_v (14.6 mg m⁻³). Our results demonstrate that this method provides a robust tool for both off-site and on-site detecting and quantifying CPF vapors at trace levels, which has strong implications for either industrial hygiene or forensic investigations concerning the pesticide Chlorpyrifos, as well as for monitoring of environmental contamination by organophosphorus pesticides. Full article

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC₅₀ values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Plant-based extracts and elicitors (signaling molecules that activate the fruit’s innate defense responses) have emerged as promising and sustainable alternatives to synthetic chemicals for preserving postharvest fruit quality and extending shelf life. This review provides a comprehensive analysis, uniquely complemented by a bibliometric assessment of the research landscape from 2005 to 2025, to identify key trends and effective solutions. This review systematically examined the efficacy of various natural compounds including essential oils (complex volatile compounds with potent antimicrobial activity such as lemongrass and thyme), phenolic-rich botanical extracts like neem and aloe vera, and plant-derived elicitors such as methyl jasmonate and salicylic acid. Their preservative mechanisms are multifaceted, involving direct antimicrobial activity by disrupting microbial membranes, potent antioxidant effects that scavenge free radicals, and the induction of a fruit’s innate defense systems, enhancing the activity of enzymes like superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). Applications of edible coatings of chitosan or aloe vera gel, nano-emulsions, and pre- or postharvest treatments effectively reduce decay by Botrytis cinerea and Penicillium spp.), delay ripening by suppressing ethylene production, minimize water loss, and alleviate chilling injury. Despite their potential, challenges such as sensory changes, batch-to-batch variability, regulatory hurdles, and scaling production costs limit widespread commercialization. Future prospects hinge on innovative technologies like nano-encapsulation to improve stability and mask flavors, hurdle technology combining treatments synergistically, and optimizing elicitor application protocols. This review demonstrates the potential of continued research and advanced formulation to create plant-based preservatives, that can become integral components of an eco-friendly postharvest management strategy, effectively reducing losses and meeting consumer demands for safe, high-quality fruit. Full article

RNA-targeting techniques have emerged as powerful tools in cancer research and therapeutics, offering precise and programmable control over gene expression at the post-transcriptional level. Once viewed as passive intermediates in the central dogma, RNA molecules are now recognized as dynamic regulators of cellular function, capable of influencing transcription, translation, and epigenetic regulation. Advances in high-throughput sequencing technologies, transcriptomics, and structural RNA biology have uncovered a diverse landscape of coding and non-coding RNAs involved in oncogenesis, drug resistance, and tumor progression. In response, several RNA-targeting strategies have been developed to modulate these transcripts, including antisense oligonucleotides (ASOs), RNA interference (RNAi), CRISPR-Cas13 systems, small molecules, and aptamers. This review provides a comparative analysis of these technologies, highlighting their molecular mechanisms, therapeutic potential, and current limitations. Emphasis is placed on the translational progress of RNA-targeting agents, including recent FDA approvals and ongoing clinical trials for cancer indications. Through a critical comparison of these strategies, this review underscores the growing significance of RNA-targeting technologies as a foundation for next-generation cancer therapeutics and precision oncology. Full article

Titanium and its alloys are the most widely used metallic materials for bone contact implants. However, despite advances in implant technology, these alloys are still susceptible to post-operative clinical complications such as inflammation, which is often joined by infections and biofilm formation. A number of coatings were studied to overcome the drawbacks of these complications, but the controlled release of bioactive molecules over the first few days and the adhesion of the coating to the substrate remain recognized challenges. Carbon dots and the antibacterial potential of chiral carbon dots (CCDs) were recently reported, and their chirality was identified as a major contribution to the bactericidal effect. This study aimed to achieve a stimuli-responsive medium-term controlled release for up to one month. Two types of chiral carbon dots (CCDs) with distinct functional groups were incorporated into a stable and adherent biodegradable polymer coating, i.e., poly(lactic-co-glycolic acid) (PLGA). To enhance the coating adhesion, the titanium alloy surfaces were pre-treated and activated. The wettability, morphology, and surface composition of the coatings were characterized by contact angle, profilometry, SEM, and XPS, respectively. Coating degradation, adhesion, and CCDs release were studied at physiological pH (7.4) and at an acidic pH characteristic of an inflammatory site (pH 3.0) for up to one month. Their biological performances and blood compatibility were assessed as well. Degradation studies conducted over 28 days revealed a slow mass loss of approximately 10%, with maximum release rates for CCDs-OH and CCDs-NH₂ of 67% and 45% at pH 7.4, respectively. At pH 3.0 an inverse trend was observed with 49% and 59% maximum release after 28 days. Furthermore, the coatings did not exhibit any cytotoxic and hemolytic effects. These findings demonstrate the potential of this approach to providing titanium implants with pH-sensitive controlled release of bioactive CCDs lasting up to one month, which could address key challenges in implant-associated complications. Full article

Animal venoms are rich in bioactive molecules with promising biotechnological potential. They comprise both protein and non-protein toxins. Among the protein toxins are enzymes, such as phospholipases A₂, proteases and L-amino acid oxidases (LAAOs). LAAOs exhibit antimicrobial, antiparasitic, antiviral, and anticancer effects, making them potential candidates for biotechnological applications. These activities are linked to their ability to catalyze oxidative reactions that convert L-amino acids into α-keto acids, releasing ammonia and hydrogen peroxide, which contribute to the immune response, pathogen elimination, and oxidative stress. However, in snakes of the Micrurus genus, LAAOs generally represent a small portion of the venom (up to ~7%), which limits their isolation and study. To overcome this, the present study aimed to produce Ml-LAAO, the enzyme from Micrurus lemniscatus, through heterologous expression in mammalian cells. The gene sequence was inferred from its primary structure and synthesized into the pSecTag2B vector for expression in HEK293T cells. After purification using a His Trap-HP column, the presence of recombinant Ml-LAAO (Ml-LAAOrec) was confirmed by Western blot and mass spectrometry, validating its identity. These results support successful recombinant expression of Ml-LAAO and highlight its potential for scalable production and future biotechnological applications. Full article

Next-generation cancer immunotherapy increasingly combines tumor-targeting antibodies or antibody–drug conjugates (ADCs) with immune effector cells to enhance therapeutic precision. However, many existing approaches rely on genetic modification or complex manufacturing, limiting their clinical scalability and rapid deployment. To address this issue, we developed an antibody capture protein (ACP)-based surface engineering platform that enables the rapid, reversible, and non-genetic functionalization of NK cells with therapeutic antibodies or ADCs. This approach uses a DMPE-PEG-lipid conjugate to anchor thiolated protein A (ACP) to the NK cell membrane via hydrophobic insertion, thereby stably and selectively binding to the Fc region of IgG molecules. Using this strategy, we developed ACP-modified NK cells (AC-NKs) that can selectively capture therapeutic antibodies (trastuzumab (TZ), trastuzumab-emtansine (T-DM1), and sacituzumab (SZ)) pre-bound to each target antigen on tumor cells and induce antigen-specific cytotoxic responses. The resulting AC-NKs exhibited enhanced tumor recognition and cytotoxicity against HER2-positive and Trop-2-positive cancer cells in vitro. Compared with conventional combination therapies, AC-NKs enhanced immune activation, as demonstrated by effective delivery of cytotoxic agents, enhanced cancer cell engagement, and upregulation of CD107a expression. Notably, the system supports multiple antigen targeting and tunable antibody loading, enabling adaptation to tumor heterogeneity and resistant phenotypes. This platform might also provide a simple, scalable, and safe method for rapidly developing programmable immune cell therapies without genetic modification. Its versatility supports multi-antigen targeting and broad applicability across NK and T cell therapies, offering a promising path toward personalized, off-the-shelf chemoimmunotherapy. Full article

Plants have evolved a complex, multilayered immune system that integrates molecular recognition, signaling pathways, epigenetic regulation, and small RNA-mediated control. Recent studies have shown that DNA-level regulatory mechanisms, such as RNA-directed DNA methylation (RdDM), histone modifications, and chromatin remodeling, are critical for modulating immune gene expression, allowing for rapid and accurate pathogen-defense responses. The epigenetic landscape not only maintains immunological homeostasis but also promotes stress-responsive transcription via stable chromatin modifications. These changes contribute to immunological priming, a process in which earlier exposure to pathogens or abiotic stress causes a heightened state of preparedness for future encounters. Small RNAs, including siRNAs, miRNAs, and phasiRNAs, are essential for gene silencing before and after transcription, fine-tuning immune responses, and inhibiting negative regulators. These RNA molecules interact closely with chromatin features, influencing histone acetylation/methylation (e.g., H3K4me3, H3K27me3) and guiding DNA methylation patterns. Epigenetically encoded immune memory can be stable across multiple generations, resulting in the transgenerational inheritance of stress resilience. Such memory effects have been observed in rice, tomato, maize, and Arabidopsis. This review summarizes new findings on short RNA biology, chromatin-level immunological control, and epigenetic memory in plant defense. Emerging technologies, such as ATAC-seq (Assay for Transposase-Accessible Chromatin using Sequencing), ChIP-seq (Chromatin Immunoprecipitation followed by Sequencing), bisulfite sequencing, and CRISPR/dCas9-based epigenome editing, are helping researchers comprehend these pathways. These developments hold an opportunity for establishing epigenetic breeding strategies that target the production of non-GMO, stress-resistant crops for sustainable agriculture. Full article

The voltage-gated proton channel (H_v1) selectively transports protons (H⁺) across biological membranes in response to membrane potential changes. H_v1 is assembled as a dimer, and unlike most voltage-gated ion channels, it lacks a traditional central pore domain; instead, the voltage-sensing domain (VSD) of each monomer facilitates proton conduction via a hydrogen-bond network. H_v1 is widely expressed in various human cell types (e.g., immune cells, sperm, etc.) including tumor cells. In tumor cells, the accumulation of acidic intermediates generated by glycolysis under hypoxic conditions or ROS production leads to significant cytosolic acidification. H_v1 can remove protons from the cytosol rapidly, contributing to the adaptation of the cells to the tumor microenvironment, which may have significant consequences in tumor cell survival, proliferation, and progression. Therefore, H_v1 may be very promising not only as a tumor marker but also as a potential therapeutic target in oncology. Molecules that modulate the proton flux through H_v1 can be divided into two broad groups: inhibitors and activators. H_v1 inhibitors can be simple ions, small molecules, lipids, and peptides. In contrast, fewer H_v1 activators are known, including albumin, NH29, quercetin, and arachidonic acid. The mechanism of action of some inhibitors is well described, but not all. H_v1 modulation has profound effects on cellular physiology, especially under stress or pathological conditions, like cancer and inflammation. The therapeutic application of selective H_v1 inhibitors or activators could be a very promising strategy in the treatment of several serious diseases. Full article

Noninvasive liquid biopsy for monitoring circulating tumor cells offers valuable insights for predicting therapeutic responses. We developed TelomeScan^® (OBP-401), based on the detection of telomerase activity as a universal cancer cell marker and an indicator of the presence of viable circulating tumor cells (CTCs) for patients with advanced non-small cell lung cancer (NSCLC). This system evaluated CTC subtypes characterized by programmed death ligand 1 (PD-L1), an immune checkpoint molecule, and vimentin, an epithelial–mesenchymal transition (EMT) marker, using a multi-fluorescent color microscope reader. The prognostic value and therapeutic responses were predicted by dynamically monitoring CTC counts in 79 patients with advanced NSCLC. The sensitivity and specificity values of TelomeScan^® for PD-L1⁽⁺⁾ cells (≥1 cell) were 75% and 100%, respectively, indicating high diagnostic accuracy. PD-L1⁽⁺⁾ and EMT⁽⁺⁾ in CTCs were detected in 75% and 12% of patients, respectively. Detection of PD-L1⁽⁺⁾CTCs and PD-L1⁽⁺⁾EMT⁽⁺⁾ CTCs before treatment was associated with poor prognosis (p < 0.05). Monitoring of reducing and increasing PD-L1⁽⁺⁾ CTC counts in two sequential samples (baseline, cycle 2 treatment) correlated significantly with partial response (p = 0.032) and progressive disease (p = 0.023), respectively. Monitoring PD-L1⁽⁺⁾CTCs by TelomeScan^® will aid in anticipating responses or resistance to frontline treatments, optimizing precision medicine choices in patients with NSCLC. Full article

Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, plays a vital role in regulating immune responses across various infectious and inflammatory conditions. While IL-10 is essential for preventing excessive tissue damage and maintaining immune homeostasis (e.g., respiratory syncytial virus), its elevated levels could result in immunosuppression during viral infections, enabling viruses to evade host defenses (e.g., foot-and-mouth disease virus). This review aims to elucidate the mechanisms through which IL-10 mediates immunosuppression in viral infections and to explore the implications of these mechanisms for therapeutic intervention. The key scientific concepts outlined in this review include the mechanisms of IL-10 production and its varied impacts on the immune response during viral infections. Specifically, we discuss the multifaceted inhibitory effects of IL-10 on innate and adaptive immunity, including its implications for antigen presentation, T cells activation, pro-inflammatory cytokine production, immune cell differentiation, trafficking, apoptosis, and co-inhibitory expression related to T cells exhaustion. Finally, we discuss the therapeutic potential of targeting IL-10, such as monoclonal antibodies and small molecule inhibitors, and their potential to restore effective immune responses. By summarizing current knowledge on IL-10’s role in viral infections, this review offers a thorough insight into its immunosuppressive mechanisms and their therapeutic potential, paving the way for innovative treatment strategies in viral diseases. Full article

Allorecognition, or distinguishing between the self and nonself within the same species, is observed in both animals and plants, particularly in the context of immune reactions and self-incompatibility in sexual reproduction. Polymorphic recognition molecules are known to be responsible for such allorecognition during fertilization. Previous studies have reported that in ascidians and flowering plants, inbreeding avoidance relies on a pair of polymorphic recognition molecules with a receptor-ligand relationship that are encoded at a single locus, the S locus (Self-incompatibility locus), but the process by which such pairs of recognition molecules emerge and evolve to become polymorphic is not known. Here, a population genetics study was carried out as a novel approach for investigating allorecognition. To study the process by which self-recognition emerges, we simulated a situation in which an allorecognizing genotype is generated from a nonallorecognizing genotype through mutation and then analyzed whether the two genotypes could coexist. The conditions under which the numbers of allorecognition alleles could increase over evolutionary time were investigated, and the generational dynamics of nonallorecognizing genotypes were analyzed. Subsequent modeling was carried out to reproduce the allorecognition mechanism in Ciona, and consistency between the simulation results and experimental data was observed. Our approach provides new insight into the evolutionary process of allorecognition. Full article