Search Results (578)

Nuclear receptors are involved in multiple biological processes, among which RORγ can regulate the expression of inflammation-related genes and is thus frequently used as a therapeutic target for cancer. Canine mammary cancer is one of the most common tumor diseases in dogs, with a relative incidence rate of 46.71% for CMT in China over the past five years, severely threatening the life and health of dogs. Therefore, the search for novel drugs targeting canine mammary cancer is of great significance. This study aims to investigate how the RORγ inhibitors W6134 and XY018 affect the expression of inflammatory genes through histone modifications in CMT-N7 cells. These results show that W6134 and XY018 can upregulate signaling pathways related to inflammation and apoptosis and influence the expression of associated genes. The close link between RORγ and inflammation-related genes further confirms that RORγ may serve as a therapeutic target for canine cancer. Additionally, ChIP-qPCR was used to detect the enrichment of histone markers such as P300, H3K27ac, H3K4me1, H3K9la, and H3K9bhb at the target loci of CXCL10 and MECOM genes. Collectively, our findings provide molecular evidence for the protective role of RORγ in canine mammary cancer, potentially by regulating inflammatory pathways via histone modifications, offering new insights for improving the cure rate and survival of affected dogs. Full article

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

Multiple metrics for read-level DNA methylation pattern analysis have provided new insights into DNA methylation modifications. However, the performance of these metrics and their relationship with DNA methylation ratios in identifying biologically meaningful regions have remained unclear. Here, we systematically benchmarked five read-level DNA methylation metrics using whole-genome bisulfite sequencing data from 59 individuals across six healthy tissue types and six tumor types. We found that DNA methylation concurrence (MCR) effectively captured tissue-specific features independent of the DNA methylation ratios. Regions that exhibited decreased MCR (MCDRs) in tumors were significantly enriched in promoter and intergenic regions and strongly overlapped with tumor-gained chromatin accessibility sites. The further analysis of histone modifications, including H3K4me3, H3K27ac, and H3K9ac, confirmed that MCDRs marked active gene regulatory elements. Motif enrichment analysis revealed a strong preference for CTCF binding within MCDRs. Additionally, 3D genome analysis supported a model in which MCDRs, independent of DNA methylation ratios, contribute to active gene regulation by facilitating CTCF binding and long-range chromatin interactions. Full article

The rapid evolution of SARS-CoV-2 has underscored the need for a detailed understanding of antibody binding mechanisms to combat immune evasion by emerging variants. In this study, we investigated the interactions between Class I neutralizing antibodies—BD55-1205, BD-604, OMI-42, P5S-1H1, and P5S-2B10—and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein using multiscale modeling, which combined molecular simulations with the ensemble-based mutational scanning of the binding interfaces and binding free energy computations. A central theme emerging from this work is that the unique binding strength and resilience to immune escape of the BD55-1205 antibody are determined by leveraging a broad epitope footprint and distributed hotspot architecture, additionally supported by backbone-mediated specific interactions, which are less sensitive to amino acid substitutions and together enable exceptional tolerance to mutational escape. In contrast, BD-604 and OMI-42 exhibit localized binding modes with strong dependence on side-chain interactions, rendering them particularly vulnerable to escape mutations at K417N, L455M, F456L and A475V. Similarly, P5S-1H1 and P5S-2B10 display intermediate behavior—effective in some contexts but increasingly susceptible to antigenic drift due to narrower epitope coverage and concentrated hotspots. Our computational predictions show strong agreement with experimental deep mutational scanning data, validating the accuracy of the models and reinforcing the value of binding hotspot mapping in predicting antibody vulnerability. This work highlights that neutralization breadth and durability are not solely dictated by epitope location, but also by how binding energy is distributed across the interface. The results provide atomistic insight into mechanisms driving resilience to immune escape for broadly neutralizing antibodies targeting the ACE2 binding interface—which stems from cumulative effects of structural diversity in binding contacts, redundancy in interaction patterns and reduced vulnerability to mutation-prone positions. Full article

The synthesis and structural characterization of three new triple-stranded helical complexes ([Dy₂(L²)₃]2Cl∙15H₂O (C1), [Y₂(L²)₃]3(NO₃)Cl∙14H₂O∙DMSO (C2), and [Eu₂(L⁴)₃]∙12H₂O (C3), where L² and L⁴ are ligands derived from pyridoxal hydrochloride and succinic or adipic acid dihydrazides, respectively, were described. The X-ray data, combined with spectroscopic measurements, indicated that L² and L⁴ act as bis-tridentate ligands, presenting two tridentate chelating cavities O,N,O to obtain the dinuclear complexes C1–C3. Their antiviral profile was predicted via in silico calculations in terms of interaction with the structural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein in the down- and up-states and complexed with the cellular receptor angiotensin-converting enzyme 2 (ACE2). The best affinity energy values (−9.506, −9.348, and −9.170 kJ/mol for C1, C2, and C3, respectively) were obtained for the inorganic complexes docked in the model spike-ACE2, with C1 being suggested as the most promising candidate for a future in vitro validation. The obtained in silico antiviral trend was supported by the prediction of the electronic and physical–chemical properties of the inorganic complexes via the density functional theory (DFT) approach, representing an original and relevant contribution to the bioinorganic and medicinal chemistry fields. Full article

Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the best characterized. A notable feature of class IIa HDACs is the substitution of tyrosine for histidine in the catalytic site, which has occurred over the course of evolution and has a profound effect on the efficiency of catalysis against acetyl-lysine. Another distinctive feature of this family of “pseudoenzymes” is the regulated nucleus–cytoplasm shuttling associated with several non-histone proteins that have been identified as potential substrates, including proteins localized in the cytosol. Within the complexity of class IIa HDACs, several aspects deserve further investigation. In the following, I will discuss some of the recent advances in our knowledge of class IIa HDACs. Full article

In this study, we identify cortical molecular biomarkers potentially associated with learning in mice using artificial intelligence (AI), inclusive of established and novel feature selection combined with supervised learning technologies. We applied multiple machine learning (ML) algorithms, using public domain ML software, to a public domain dataset, in order to support reproducible findings. We developed technologies tasked with predicting whether a given mouse was shocked to learn, based on protein expression levels extracted from their cortices. Results indicate that it is possible to predict whether a mouse has been shocked to learn or not based only on the following cortical molecular biomarkers: brain-derived neurotrophic factor (BDNF), NR2A subunit of N-methyl-D-aspartate receptor, B-cell lymphoma 2 (BCL2), histone H3 acetylation at lysine 18 (H3AcK18), protein kinase R-like endoplasmic reticulum kinase (pERK), and superoxide dismutase 1 (SOD1). These results were obtained with a novel redundancy-aware feature selection method. Five out of six protein expression biomarkers (BDNF, NR2A, H3AcK18, pERK, SOD1) identified have previously been associated with aspects of learning in the literature. Three of the proteins (BDNF, NR2A, and BCL2) have previously been associated with pruning, and one has previously been associated with apoptosis (BCL2), implying a potential connection between learning and both cortical pruning and apoptosis. The results imply that these six protein expression profiles (BDNF, NR2A, BCL2, H3AcK18, pERK, SOD1) are highly predictive of whether or not a mouse has been shocked to learn. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is known to affect multiple organ systems, including the respiratory tract and nervous and ocular systems. This retrospective study aimed to characterize the spatiotemporal distribution of viral antigen and associated pathological changes in the nose, lungs, brain, and eyes of K18-hACE2 mice intranasally infected with SARS-CoV-2. Using histology and immunohistochemistry, tissues were examined at 3, 6, and 7/8 days post-infection (dpi). In addition, lung and brain tissues were analyzed by means of RT-qPCR to determine viral RNA titers. Viral antigen was most pronounced in the nose, brain, and lung at 3, 6, and 7/8 dpi, respectively, whereas viral antigen was detected at 6 and 7/8 dpi in the retina. Quantitative PCR confirmed increasing viral RNA levels in both lung and brain, peaking at 7/8 dpi. Nasal and lung inflammation mirrored viral antigen distribution and localization. In the brain, the predominantly basal viral spread correlated with lymphohistiocytic meningoencephalitis, neuronal vacuolation, and altered neurofilament immunoreactivity. Retinal ganglion cells showed viral antigen expression without associated lesions. Microglial activation was evident in both the optic chiasm and the brain. These findings highlight the K18-hACE2 model’s utility for studying extrapulmonary SARS-CoV-2 pathogenesis. Understanding the temporal and spatial dynamics of viral spread enhances insights into SARS-CoV-2 neurotropism and its clinical manifestations. Full article

We use Co doping to alter the magnetic relaxation dynamics in superparamagnetic nanofluids made of 18 nm average diameter Fe₃O₄ nanoparticles immersed in Isopar M. Ac-susceptibility data recorded at different frequencies and temperatures, χ″vs. T|_f, reveals a major (~100 K) increase in the superspin blocking temperature of the Co_0.2Fe_2.8O₄-based fluid (CFO) compared to its Fe₃O₄ counterpart (FO). We ascribe this behavior to the strengthening of the interparticle magnetic dipole interactions upon Co doping, as demonstrated by the relative χ″-peak temperature variation per frequency decade $\mathsf{\Phi }={\displaystyle \frac{∆\mathrm{T}}{\mathrm{T}·∆\mathrm{l}\mathrm{o}\mathrm{g}\left(\mathrm{f}\right)}}$, which decreases from Φ~0.15 in FO to Φ~0.025 in CFO. In addition, χ″vs. T|_f datasets from the CFO fluid reveal two magnetic events at temperatures T_p1 = 240 K and T_p2 = 275 K, both above the fluid’s freezing point (T_F = 197 K). We demonstrate that the physical rotation of the nanoparticles within the fluid, the Brown mechanism, is entirely responsible for the collective superspin relaxation observed at T_p1, whereas the Néel mechanism, the superspin flip across an energy barrier within the particle, is dominant at T_p2. We confirm this finding through fits of models that describe the temperature dependence of the relaxation time via the two mechanisms: ${\mathsf{\tau }}_{\mathrm{B}}(\mathrm{T})={\displaystyle \frac{3{\mathsf{\eta }}_0{\mathrm{V}}_{\mathrm{H}}}{{\mathrm{k}}_{\mathrm{B}}\mathrm{T}}}\exp \left[{\displaystyle \frac{{\mathrm{E}}^{\prime }}{{\mathrm{k}}_{\mathrm{B}}\left(\mathrm{T}-{{\mathrm{T}}_0}^{\prime }\right)}}\right]$ and ${\mathsf{\tau }}_{\mathrm{N}}\left(\mathrm{T}\right)={\mathsf{\tau }}_0\exp \left[{\displaystyle \frac{{\mathrm{E}}_{\mathrm{B}}}{{\mathrm{k}}_{\mathrm{B}}\left(\mathrm{T}-{\mathrm{T}}_0\right)}}\right]$. The best fits yield ${\mathsf{\gamma }}_0={\displaystyle \frac{3{\mathsf{\eta }}_0{\mathrm{V}}_{\mathrm{H}}}{{\mathrm{k}}_{\mathrm{B}}}}$= 1.5 × 10⁻⁸ s·K, E′/k_B = 7 03 K, and T₀′ = 201 K for the Brown relaxation, and E_B/k_B = 2818 K and T₀ = 143 K for the Néel relaxation. Full article

This paper presents a study on the optimization of 2,4-Dichlorophenoxyacetic (2,4-D) acid removal from synthetic wastewater by batch Fenton-Ozonation. The aim of this study is to evaluate the potential of the catalytic system Fe-L27 coupled to ozonation in the presence and absence of H₂O₂ as an effective and affordable technique for the treatment of organic pollutants in water. Fenton-like catalysts for the removal of 2,4-D in aqueous solutions were elaborated using catalysts synthesized by the wet impregnation method. The ACs and prepared catalysts were characterized by nitrogen adsorption–desorption isotherms at 77 K, TGA, XPS, SEM, and TEM. Their efficiency as Fenton-like catalysts was studied. In a first step, a response surface modeling method was employed in order to find the optimal parameters of the Fenton process, and then the optimal O₃/H₂O₂ ratio was established at laboratory scale. Finally, the investigated advanced oxidation processes were carried out at pilot scale. The results show that Fenton-like catalysts obtained by the direct impregnation method enhance the degradation rate and mineralization of 2,4-D. Full article

Rationally designing and synthesizing chemosensors capable of simultaneously detecting both anions and cations via water content modulation is challenging. In this study, we synthesized and characterized a novel triazine calixarene derivative-based iodide and copper ion-selective fluorescent “turn-off” sensor. This dual-channeled fluorescent probe is able to recognize Cu²⁺ and I⁻ ions simultaneously in aqueous systems. The fluorescent sensor s4 was synthesized by displacement reaction of acridine with 1, 3-bis (dichloro-mono-triazinoxy) benzene in acetonitrile. Mass spectrometry (MS), UV-vis, and fluorescence spectra were acquired to characterize the fluorescence response of s4 to different cations and anions, while infrared (IR) spectroscopy and isothermal titration calorimetry (ITC) were employed to study the underlying selectivity mechanism of s4 to Cu²⁺ and I⁻. In detail, s4 displayed extremely high sensitivity to Cu²⁺ with over 80% fluorescence decrement caused by the paramagnetic nature of Cu²⁺ in the aqueous media. The reversible fluorescence response to Cu²⁺ and the responses to Cu²⁺ in the solution of other potential interferent cations, such as Li⁺, Na⁺, K⁺, Ca²⁺, Cd²⁺, Zn²⁺, Sr²⁺, Ni²⁺, Co²⁺ were also investigated. Probe s4 also exhibited very good fluorescence selectivity to iodide ions under various anion (F⁻, Cl⁻, Br⁻, NO₃⁻, HSO₄⁻, ClO₄⁻, PF₆⁻, AcO⁻, H₂PO₄⁻) interferences. In addition to the fluorescent response to I⁻, s4 showed a highly selective naked-eye-detectable color change from colorless to yellow with the other tested anions. Full article

This report is on Co and Ti substituted M-type barium and strontium hexagonal ferrites that are reported to be single phase multiferroics due to a transition from Neel type ferrimagnetic order to a spiral spin structure that is accompanied by a ferroelectric polarization in an applied magnetic field. The focus here is the nature of magnetoelectric (ME) interactions in the bilayers of ferroelectric PZT and Co and Ti substituted BaM and SrM. The ME coupling in the ferrite-PZT bilayers arise due to the transfer of magnetostriction-induced mechanical deformation in a magnetic field in the ferrite resulting in an induced electric field in PZT. Polycrystalline Co and Ti doped ferrites, Ba (CoTi)_x Fe_12−2xO_19, (BCTx), and Sr (CoTi)_x Fe_12−2xO₁₉ (SCTx) (x = 0–4) were found to be free of impurity phases for all x-values except for SCTx, which had a small amount of α-Fe₂O₃ in the X-ray diffraction patterns for x ≤ 2.0. The magnetostriction for the ferrites increased with applied filed H to a maximum value of around 2 to 6 ppm for H~5 kOe. BCTx/SCTx samples showed ferromagnetic resonance (FMR) for x = 1.5–2.0, and the estimated anisotropy field was on the order of 5 kOe. The magnetization increased with the amount of Co and Ti doping, and it decreased rapidly with x for x > 1.0. Measurements of ME coupling strengths were conducted on the bilayers of BCTx/SCTx platelets bonded to PZT. The bilayer was subjected to an AC and DC magnetic field H, and the magnetoelectric voltage coefficient (MEVC) was measured as a function of H and frequency of the AC field. For BCTx-PZT, the maximum value of MEVC at low frequency was ~5 mV/cm Oe, and a 40-fold increase at electromechanical resonance (EMR). SCTx–PZT composites also showed a similar behavior with the highest MEVC value of ~14 mV/cm Oe at low frequencies and ~200 mV/cm Oe at EMR. All the bilayers showed ME coupling for zero magnetic bias due to the magnetocrystalline anisotropy field in the ferrite that provided a built-in bias field. Full article

GCN5-containing SAGA complex is evolutionarily conserved across yeast, plants, and humans and acts as a general transcription coactivator in the genome-wide regulation of genes. In Plasmodium falciparum, PfGCN5 forms a divergent complex, and the mis-localization of this complex by deleting the PfGCN5 bromodomain (ΔBrd) causes a plethora of growth defects. To directly test the PfGCN5 function, we performed conditional knockdown (KD) of PfGCN5. Whereas PfGCN5 KD phenotypically recapitulated the ΔBrd growth defects, it caused fewer transcriptional alterations compared to ΔBrd. To decipher the mechanism by which PfGCN5 regulates gene expression, we applied a new chromatin landscape analysis tool, CUT&Tag-seq, to map the chromatin localization of PfGCN5 and its deposited histone mark H3K9ac. Compared to ChIP-seq, CUT&Tag-seq identified substantially more H3K9ac peaks in the promoters of its target genes, with the peak intensity positively correlated with the levels of gene expression. CUT&Tag-seq analysis was remarkably more sensitive in mapping chromatin positions of PfGCN5, which colocalized with H3K9ac. The genes enriched with PfGCN5/H3K9ac signals at their promoters are involved in broad biological processes. Notably, PfGCN5′s positions overlapped with sequence motifs recognized by multiple apetela2 (AP2)-domain-containing transcription factors (AP2 TFs), suggesting that they recruited PfGCN5 to these promoters. Additionally, PfGCN5 was also colocalized with AP2-LT, further validating that AP2-LT is an integral component of the PfGCN5 complex. Collectively, these findings establish PfGCN5 as a master gene regulator in controlling general and parasite-specific cellular processes in this low-branching parasitic protist. Full article

Lysine acetyltransferase 8 (KAT8) is a member of the MYST family of histone acetyltransferases. It catalyzes the acetylation of histone H4 at lysine 16 (H4K16ac) and non-histone proteins. Abnormal upregulation or downregulation of KAT8 and its associated H4K16ac have been observed in malignant tumors, suggesting its close association with tumorigenesis and progression. Characterized by structural diversity and multi-target mechanisms, natural agents have been increasingly shown to possess significant antitumor activity. This review focuses on KAT8, summarizing its molecular mechanisms in regulating tumor development by catalyzing substrate protein acetylation, which impacts tumor cell proliferation, cell cycle regulation, apoptosis, DNA damage repair, and autophagy. It also systematically discusses the pharmacological activities and molecular mechanisms of small-molecule agents that target KAT8 to inhibit tumor proliferation, including natural compounds, synthetic drugs, and non-coding RNAs. Full article

Background: The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit notable adipogenic potential, possibly linked to histone 3 acetylation at lysine 9 (H3K9ac); however, the mechanistic role of this modification remains unclear. Methods: To address this gap, we investigated how histone deacetylase inhibitors (HDACis)—valproic acid (VPA, 8 mM) and trichostatin A (TSA, 100 nM)—modulate H3K9ac dynamics, adipogenic gene expression (C/EBPβ and PPARγ-2), and chromatin remodeling during PDLSCs differentiation. Techniques used included quantitative PCR (qPCR), lipid droplet analysis, and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR). Results: TSA-treated cells exhibited increased lipid deposition with smaller lipid droplets compared to VPA-treated cells. Global H3K9ac levels correlated positively with adipogenic progression. VPA induced early upregulation of C/EBPβ and PPARγ-2 (day 7), whereas TSA triggered a delayed but stronger PPARγ-2 expression. ChIP-qPCR analysis revealed significant H3K9ac enrichment at the PPARγ-2 promoter in TSA-treated cells, indicating enhanced chromatin accessibility. Conclusions: These findings demonstrate that H3K9ac-mediated epigenetic remodeling plays a critical role in the adipogenic differentiation of PDLSCs and identifies TSA as a potential tool for modulating this process. Full article