Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain‐computer interface. However, the long‐term functionality of these devices is ...hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO‐B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long‐term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO‐B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long‐term functionality of neural devices.
Main Points
KDS2010, a reversible MAO‐B inhibitor, prevent glial scar formation and astrogliosis around implanted neural device.
KDS2010 allows long‐term recordings of neural signals with implantable devices.
Transcriptome expression reflects genetic response in diverse conditions. In this study, RNA sequencing was utilized to profile multiple tissues such as liver, breast, caecum, and gizzard of Korean ...commercial chicken raised in Korea and Kyrgyzstan. We analyzed ten samples per tissue from each location to identify candidate genes which are involved in the adaptation of Korean commercial chicken to Kyrgyzstan. At false discovery rate (FDR) < 0.05 and fold change (FC) > 2, we found 315, 196, 167 and 198 genes in liver, breast, cecum, and gizzard respectively as differentially expressed between the two locations. GO enrichment analysis showed that these genes were highly enriched for cellular and metabolic processes, catalytic activity, and biological regulations. Similarly, KEGG pathways analysis indicated metabolic, PPAR signaling, FoxO, glycolysis/gluconeogenesis, biosynthesis, MAPK signaling, CAMs, citrate cycles pathways were differentially enriched. Enriched genes like TSKU, VTG1, SGK, CDK2 etc. in these pathways might be involved in acclimation of organisms into diverse climatic conditions. The qRT-PCR result also corroborated the RNA-Seq findings with R
of 0.76, 0.80, 0.81, and 0.93 for liver, breast, caecum, and gizzard respectively. Our findings can improve the understanding of environmental acclimation process in chicken.
Dengue is listed as a neglected tropical disease by the Center for Disease Control and Preservation, as there are insufficient integrated surveillance strategies, no effective treatment, and limited ...licensed vaccines. Consisting of four genetically distinct serotypes, dengue virus (DENV) causes serious life-threatening infections due to its complexity. Antibody-dependent enhancement by pre-existing cross-reactive as well as homotypic antibodies further worsens the clinical symptoms of dengue. Thus, a vaccine conferring simultaneous and durable immunity to each of the four DENV serotypes is essential to restrict its escalation. In deeply affected resource-limited countries, oral vaccination using food-grade organisms is considered to be a beneficial approach in terms of costs, patient comfort, and simple logistics for mass immunization. The current study used a mouse model to explore the immunogenicity of an oral dengue vaccine candidate prepared using whole recombinant yeast cells (WC) and cell-free extracts (CFE) from cells expressing recombinant Escherichia coli heat-labile toxin protein B-subunit (LTB) fused to the consensus dengue envelope domain III (scEDIII). Mice were treated orally with recombinant WC and CFE vaccines in 2-week intervals for 4 weeks and changes in systemic and mucosal immune responses were monitored.
Both WC and CFE dosage applications of LTB-scEDIII stimulated a systemic humoral immune response in the form of dengue-specific serum IgG as well as mucosal immune response in the form of secretory sIgA. Antigen-specific B cell responses in isolated lymphoid cells from the spleen and Peyer's patches further indicated an elevated mucosal immune response. Cellular immune response estimated through lymphocyte proliferation assay indicated higher levels in CFE than WC dosage. Furthermore, sera obtained after both oral administrations successfully neutralized DENV-1, whereas CFE formulation only neutralized DENV-2 serotype, two representative serotypes which cause severe dengue infection. Sera from mice that were fed CFE preparations demonstrated markedly higher neutralizing titers compared to those from WC-fed mice. However, WC feeding elicited strong immune responses, which were similar to the levels induced by CFE feeding after intraperitoneal booster with purified scEDIII antigen.
CFE preparations of LTB-scEDIII produced strong immunogenicity with low processing requirements, signifying that this fusion protein shows promise as a potent oral vaccine candidate against dengue viral infection.
In this study, we synthesized fluorescent europium oxide (Eu2O3) nanosheets (EuNSs) using different approaches such as chemical-based methods and green synthesis, using Dedleya brittonii (DB) extract ...as an effective chelating agent for biological preparation. A modified hydrothermal method was used to synthesize chemical Eu2O3 nanosheets (CH-EuNS) and DB extract-based Eu2O3 nanosheets (DB-EuNS). Field emission scanning electron microscopy and HR-TEM analyses revealed that both EuNS had a sheet-like morphology, with an average thickness of 5–8 nm. The UV–Vis absorbance spectra of CH-EuNS and DB-EuNS showed clear bands at 320 and 325 nm, respectively; the band at approximately 320 nm corresponded to the absorbance of the Eu nanomaterial. The luminescence spectra of CH-EuNS and DB-EuNS showed strong red emission peaks centered at 616 and 612 nm, respectively, which were attributed to (5D0→7F3) and (5D0→7F2), respectively. Pure CH-EuNS and DB-EuNS showed no cytotoxicity against NIH 3 T3 fibroblasts and HeLa cancer cells at a high concentration (2 mg/mL) after 24 hr of exposure. Based on this outcome, unmodified CH-EuNS and DB-EuNS were used to detect ampicillin (AMP) antibiotics. The effectiveness of pure EuNS in detecting the presence of AMP was evaluated in various media, i.e., water, ethanol, and citrate buffer. Depending on the concentration of the different media, CH-EuNS with citrate buffer and ethanol exhibited maximum emission intensity variations of the 5D0 → 7F3 transition in the EuNS and AMP complexes at 618 nm. The luminescence of CH-EuNS and DB-EuNS was quenched in the presence of AMP at different concentrations (50 – 1 µM) in citrate buffer, whereas the luminescence intensity of pure EuNS was significantly higher than that of the EuNS-AMP mixture. The optimal linear concentration range for AMP was assessed under photoluminescence intensities of 0 to 50 µM, and the detection limit was determined to be 5 µM. This study suggests that CH-EuNS and DB-EuNS in a citrate buffer medium could effectively bind with AMP without ligand modification and significantly reduce the emission intensity due to the presence of AMP in the solution. Therefore, unmodified EuNS could be applied to detect AMP in a solution; however, for it to be used to detect AMP in real samples, it had to be optimized using a fluorescent nanomaterial.
Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) ...is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER⁺) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the
gene promoter. We also investigated the migration and invasive ability of nobiletin in ER⁺ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER⁺ breast cancer cells.
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We have synthesized three categories of α,β-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including ...α,β-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC50 human MAO-B 16nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,β-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.
The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid ...receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.
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•Hippocampal astrocytic μ-opioid receptor (MOR) activation drives conditioned place preference (CPP)•Astrocytic MOR activation enhances synaptic plasticity at the Schaffer collateral pathway•Chemogenetic activation of astrocytic Gi-DREADD recapitulates MOR-mediated LTP and CPP
Nam et al. demonstrate that activation of hippocampal astrocytic μ-opioid receptor causes glutamate release, which increases the release probability by neuronal presynaptic mGluR1 activation and potentiates synaptic plasticity at the SC-CA1 pathway. This enhanced synaptic transmission and synaptic plasticity account for the acquisition of memory associated with CPP.
Kinetic models were proposed to describe the production of 2,3-BD by K. oxytoca.The models have well elucidated the fermentative characteristics for 2,3-BD production.The models provide ...information to improve the performance of 2,3-BD production.
There has been a growing interest in the fermentative production of 2,3-butanediol (2,3-BD) because of its wide applications in the chemical, food, pharmaceutical, and fuel industries. In this study, we set up kinetic models to predict the behavior of Klebsiella oxytoca οldhA mutant in the batch fermentation of 2,3-BD. Modified Monod model, Luedeking-Piret model, and carbon mass balance were employed to describe the effects of substrate and end-products on cell growth, 2,3-BD production, and substrate consumption, respectively. All the parameters in the models were estimated by minimizing mean-squared errors between the model predictions and experimental data. The model predictions were in good agreement with the fermentation data. In particular, the models accurately described the inhibitory effects of by-products on the growth of K. oxytoca οldhA mutant as well as the production of 2,3-BD. Although the models cannot describe the complex metabolic phenomena, this paper may provide useful information for design and optimization of 2,3-BD fermentation process.
Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in ...reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC
= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
Objective: This study investigates the expression patterns of toll-like receptors (TLRs) and intracellular mediators in horse muscle cells after exercise, and the relationship between TLRS expression ...in stressed horse muscle cells and immune cell migration toward them.Methods: The expression patterns of the TLRs (TLR2, TLR4, and TLR8) and downstream signaling pathway-related genes (myeloid differentiation primary response 88 MYD88; activating transcription factor 3 ATF3) are examined in horse tissues, and horse peripheral blood mononuclear cells (PBMCs), polymorphonuclear cells (PMNs) and muscles in response to exercise, using the quantitative reverse transcription-polymerase chain reaction (qPCR). Expressions of chemokine receptor genes, i.e., C-X-C motif chemokine receptor 2 (CXCR2) and C-C motif chemokine receptor 5 (CCR5), are studied in PBMCs and PMNs. A horse muscle cell line is developed by transfecting SV-T antigen into fetal muscle cells, followed by examination of muscle-specific genes. Horse muscle cells are treated with stressors, i.e., cortisol, hydrogen peroxide (H2O2), and heat, to mimic stress conditions in vitro, and the expression of TLR4 and TLR8 are examined in stressed muscle cells, in addition to migration activity of PBMCs toward stressed muscle cells.Results: The qPCR revealed that TLR4 message was expressed in cerebrum, cerebellum, thymus, lung, liver, kidney, and muscle, whereas TLR8 expressed in thymus, lung, and kidney, while TLR2 expressed in thymus, lung, and kidney. Expressions of TLRs, i.e., TLR4 and TLR8, and mediators, i.e., MYD88 and ATF3, were upregulated in muscle, PBMCs and PMNs in response to exercise. Expressions of CXCR2 and CCR5 were also upregulated in PBMCs and PMNs after exercise. In the muscle cell line, TLR4 and TLR8 expressions were upregulated when cells were treated with stressors such as cortisol, H2O2, and heat. Migration of PBMCs toward stressed muscle cells was increased by exercise and oxidative stresses, and combinations of these. Treatment with methylsulfonylmethane (MSM), an antioxidant on stressed muscle cells, reduced migration of PBMCs toward stressed muscle cells.Conclusion: In this study, we have successfully cultured horse skeletal muscle cells, isolated horse PBMCs, and established an in vitro system for studying stress-related gene expressions and function. Expression of TLR4, TLR8, CXCR2, and CCR5 in horse muscle cells was higher in response to stressors such as cortisol, H2O2, and heat, or combinations of these. In addition, migration of PBMCs toward muscle cells was increased when muscle cells were under stress, but inhibition of reactive oxygen species by MSM modulated migratory activity of PBMCs to stressed muscle cells. Further study is necessary to investigate the biological function(s) of the TLR gene family in horse muscle cells.
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