Toll-like receptor 3 (TLR3), an endosomal receptor crucial for immune responses upon viral invasion. The TLR3 ectodomain (ECD) is responsible for double-stranded RNA (dsRNA) recognition and ...mutational analysis suggested that TLR3 ECD C-terminal dimerization is essential for dsRNA binding. Moreover, the L412F polymorphism of TLR3 is associated with human diseases. Although the mouse structure of the TLR3-dsRNA complex provides valuable insights, the structural dynamic behavior of the TLR3-dsRNA complex in humans is not completely understood. Hence, in this study, we performed molecular dynamic simulations of human wild-type and mutant TLR3 complexes. Our results suggested that apoTLR3 ECD dimers are unlikely to be stable due to the distance between the monomers are largely varied during simulations. The observed interaction energies and hydrogen bonds in dsRNA-bound TLR3 wild-type and mutant complexes indicate the presence of a weak dimer interface at the TLR3 ECD C-terminal site, which is required for effective dsRNA binding. The L412F mutant exhibited similar dominant motion compared to wild-type. Additionally, we identified the distribution of crucial residues for signal propagation in TLR3-dsRNA complex through the evaluation of residue betweenness centrality (C
). The results of this study extend our understanding of TLR3-dsRNA complex, which may assist in TLR3 therapeutics.
In this study, we utilized processed edible commercial wheat and oat flours to synthesize highly fluorescent carbon dots using green hydrothermal synthesis. The as‐synthesized carbon quantum dots ...(CQDs) were characterized using UV‐vis spectrophotometry, photoluminescence spectrophotometry, high‐resolution transmission electron microscopy, and Fourier transform infrared spectroscopy. The synthesized wheat‐CQDs (W‐CQDs) and oat‐CQDs (O‐CQDs) had monodispersed spherical shapes with average sizes of 3–8 and 5–10 nm, respectively, and exhibited strong fluorescence intensity and excitation‐dependent photoluminescence. The W‐CQDs and O‐CQDs were highly dispersed in aqueous solutions and exhibited bright green and blue fluorescence, respectively, under UV light (λex=380 and 370 nm). Both CQDs contained abundant functional groups, including amino, hydroxyl, and carboxyl groups, which may play a major role in biological applications. The W‐CQDs and O‐CQDs showed good free‐radical scavenging capacity in the 2,2‐diphenylpicrylhydrazyl (DPPH) and H2O2 assays. The anti‐inflammatory activities of W‐CQDs and O‐CQDs were more effective than that of the standard, with EC50 values of 1.8 and 1.3 mg/mL, respectively, in the protein denaturation assay. Additionally, the CQDs exhibited low cytotoxicity toward NIH3T3 fibroblast and human HeLa cervical cancer cells when treated with a 5‐mg/mL concentration. Therefore, green‐synthesized W‐CQDs and O‐CQDs are easily available, less cytotoxic, and applicable to therapeutic and cell nanocarrier purposes.
Wheat and Oat flours extract used for the synthesis of CQDs by sustainable hydrothermal method. The synthesized W‐CQDs and O‐CQDs exhibits potent optical properties. W‐CQDs and O‐CQDs are low toxicity against NIH3T3 cells and HeLa cancer cells. The synthesized CQDs have good anti‐oxidant and anti‐inflammatory activity in in‐vitro assays.
Probiotics in livestock feed supplements are considered a replacement for antibiotics that enhance gastrointestinal immunity. Although bacterial cell wall components have been proposed to be ...associated with probiotic function, little evidence demonstrates that they are responsible for probiotic functions in livestock. The present study demonstrated that lipoteichoic acid (LTA) of
(Lp.LTA) confers anti-inflammatory responses in porcine intestinal epithelial cell line, IPEC-J2. A synthetic analog of viral double-stranded RNA, poly I:C, dose-dependently induced IL-8 production at the mRNA and protein levels in IPEC-J2 cells. Lp.LTA, but not lipoprotein or peptidoglycan from
, exclusively suppressed poly I:C-induced IL-8 production. Compared with LTAs from other probiotic
strains including
,
, and
GG, Lp.LTA had higher potential to suppress poly I:C-induced IL-8 production. Dealanylated or deacylated Lp.LTA did not suppress poly I:C-induced IL-8 production, suggesting that D-alanine and lipid moieties in the Lp.LTA structure were responsible for the inhibition. Furthermore, Lp.LTA attenuated the phosphorylation of ERK and p38 kinase as well as the activation of NF-κB, resulting in decreased IL-8 production. Taken together, these results suggest that Lp.LTA acts as an effector molecule to inhibit viral pathogen-induced inflammatory responses in porcine intestinal epithelial cells.
The history of African indigenous cattle and their adaptation to environmental and human selection pressure is at the root of their remarkable diversity. Characterization of this diversity is an ...essential step towards understanding the genomic basis of productivity and adaptation to survival under African farming systems.
We analyze patterns of African cattle genetic variation by sequencing 48 genomes from five indigenous populations and comparing them to the genomes of 53 commercial taurine breeds. We find the highest genetic diversity among African zebu and sanga cattle. Our search for genomic regions under selection reveals signatures of selection for environmental adaptive traits. In particular, we identify signatures of selection including genes and/or pathways controlling anemia and feeding behavior in the trypanotolerant N'Dama, coat color and horn development in Ankole, and heat tolerance and tick resistance across African cattle especially in zebu breeds.
Our findings unravel at the genome-wide level, the unique adaptive diversity of African cattle while emphasizing the opportunities for sustainable improvement of livestock productivity on the continent.
Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The ...Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
Heat shock proteins (HSPs) function as molecular chaperones with critical roles in chicken embryogenesis, immune response to infectious diseases, and response to various environmental stresses. ...However, little is known on HSP genes in chicken. In this study, to understand the roles of chicken HSPs, we performed genome-wide identification, expression, and functional analyses of the HSP family genes in chicken.
A total of 76 HSP genes were identified in the chicken genome, which were further classified into eight distinct groups (I-VIII) based on phylogenetic tree analysis. The gene-structure analysis revealed that the members of each clade had the same or similar exon-intron structures. Chromosome mapping suggested that HSP genes were widely dispersed across the chicken genome, except in chromosomes 16, 18, 22, 25, 26, and 28-32, which lacked chicken HSP genes. On the other hand, the interactions among chicken HSPs were limited, indicating that the remaining functions of HSPs could be investigated in chicken. Moreover, KEGG pathway analysis showed that the HSP gene family was involved in the regulation of heat stress, apoptotic, intracellular signaling, and immune response pathways. Finally, RNA sequencing data revealed that, of the 76 chicken HSP genes, 46 were differentially expressed at 21 different growth stages in chicken embryos, and 72 were differentially expressed on post-infection day 3 in two indigenous Ri chicken lines infected with highly pathogenic avian influenza.
This study provides significant insights into the potential functions of HSPs in chicken, including the regulation of apoptosis, heat stress, chaperone activity, intracellular signaling, and immune response to infectious diseases.
Exosomes are membrane vesicles containing proteins, lipids, DNA, mRNA, and micro RNA (miRNA). Exosomal miRNA from donor cells can regulate the gene expression of recipient cells. Here, Ri chickens ...were divided into resistant (Mx/A; BF2/B21) and susceptible (Mx/G; BF2/B13) trait by genotyping of Mx and BF2 genes. Then, Ri chickens were infected with H5N1, a highly pathogenic avian influenza virus (HPAIV). Exosomes were purified from blood serum of resistant chickens for small RNA sequencing. Sequencing data were analysed using FastQCv0.11.7, Cutadapt 1.16, miRBase v21, non-coding RNA database, RNAcentral 10.0, and miRDeep2. Differentially expressed miRNAs were determined using statistical methods, including fold-change, exactTest using edgeR, and hierarchical clustering. Target genes were predicted using miRDB. Gene ontology analysis was performed using gProfiler. Twenty miRNAs showed significantly different expression patterns between resistant control and infected chickens. Nine miRNAs were up-regulated and 11 miRNAs were down-regulated in the infected chickens compared with that in the control chickens. In target gene analysis, various immune-related genes, such as cytokines, chemokines, and signalling molecules, were detected. In particular, mitogen-activated protein kinase (MAPK) pathway molecules were highly controlled by differentially expressed miRNAs. The result of qRT-PCR for miRNAs was identical with sequencing data and miRNA expression level was higher in resistant than susceptible chickens. This study will help to better understand the host immune response, particularly exosomal miRNA expression against HPAIV H5N1 and could help to determine biomarkers for disease resistance.
Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via ...tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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•Thalamic astrocytes synthesize GABA via DAO and Aldh1a1 to mediate tonic inhibition•Tonic GABA improves linearity and temporal fidelity of synaptically evoked TC firing•Astrocytic tonic GABA improves tactile discrimination performance
Kwak et al. report that astrocytes synthesize GABA using DAO and Aldh1a1 and release GABA through the Best1 channel to mediate tonic GABA in the thalamus. Astrocytic tonic GABA fine-tunes the dynamic range and precision of stimulation to response of TC firing, thus enhancing the performance of sensory discrimination of mice.
Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for exogenous IL-1. However, its functional role in chicken immunity is poorly understood. Herein, chicken IL-1R2 (chIL-1R2) was identified ...and functionally characterized in vivo and in vitro. The chIL-1R2 coding sequence includes 1,236 nucleotides encoding 412 amino acids, is highly conserved, and has a close relationship with its mammalian counterpart. Its extracellular region has three Ig-like domains but no TIR domain for intracellular signaling. Using ELISA, the recombinant chIL-1R2 protein was demonstrated to specifically bind to the chicken IL-1β. ChIL-1R2 mRNA expression was shown to be higher in the spleen, lung, kidney, small intestine, and liver. The expression of chIL-1R2 and chIL-1R1 was significantly upregulated in DF-1 cells treated with poly (I:C), but significantly downregulated in the presence of NF-κB, JNK, and MEK inhibitors, indicating that the NF-κB, JNK, and MEK signaling pathways are required for the transcriptional regulation of chIL-1R1 and chIL-1R2 expression. It is worth noting that while the p30 MAPK pathway was required for chIL-1R1 expression, it was not required for chIL-1R2 expression. Furthermore, chIL-1R2 expression increased as early as day 1, and then significantly decreased until day 3, while chIL-1R1 was dramatically upregulated in four organs of chickens infected with the highly pathogenic avian influenza virus (HPAIV). These findings indicate that chIL-1R1 and chIL-1R2 may play a crucial in innate and adaptive immune responses toward HPAIV infection. In summary the present study showed that chIL-1R2 binds to chIL-1β antibody. ChIL-1R2 expression can be induced by a viral infection, and may be regulated through NF-κB/JNK/MEK-mediated signaling pathways.
Caveolin 1 (Cav-1) is a plasma membrane-associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein ...receptor-related protein 6 (LRP6) were reported to be important for the regulation of Wnt-β-catenin (β-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt-β-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results show that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt-mTORC1 signaling and aerobic glycolysis in prostate cancer.
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