Abstract
Background
As a member of the Janus kinase (JAK) family, which includes JAK1, JAK2 and JAK3, tyrosine kinase 2 (TYK2) plays an important role in signal transduction and immune system ...regulation. Moreover, it is also involved in the development of many types of inflammatory and autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE). TYK2 is an attractive therapeutic target, and selective inhibition of TYK2 over other JAK family members is critical for the development of TYK2 small molecule inhibitors. However, targeting the catalytic region of the TYK2 ATP-binding site is a major challenge due to the high structural homology between the catalytic regions of the JAK family proteins.
Results
In this study, we developed a novel small molecule inhibitor (QL-1200186) by targeting the pseudokinase regulatory domain (Janus homology 2, JH2) of the TYK2 protein. The binding sites of QL-1200186 were predicted and screened by molecular docking. The inhibitory effects on IFNα, IL-12 and IL-23 signaling were tested in cell lines, human peripheral blood cells and human whole blood. The pharmacokinetic (PK) and pharmacodynamic properties of QL-1200186 were verified in mice. QL-1200186 showed high affinity for TYK2 JH2 and had no apparent selectivity for the TYK2 and JAK homologous kinase domains; these effects were demonstrated using biochemical binding, signaling pathway transduction (JAK1/2/3) and off-target effect assays. More importantly, we revealed that QL-1200186 was functionally comparable and selectivity superior to two clinical-stage TYK2 inhibitors (BMS-986165 and NDI-034858) in vitro. In the PK studies, QL-1200186 exhibited excellent exposure, high bioavailability and low clearance rates in mice. Oral administration of QL-1200186 dose-dependently inhibited interferon-γ (IFNγ) production after interleukin-12 (IL-12) challenge and significantly ameliorated skin lesions in psoriatic mice.
Conclusion
These findings suggest that QL-1200186 is a highly selective and potent inhibitor of TYK2. QL-1200186 could be an appealing clinical drug candidate for the treatment of psoriasis and other autoimmune diseases.
In the present study, a loop-mediated isothermal amplification (LAMP) assay was developed and validated for the detection of
Paragonimus westermani
adults, metacercariae, and eggs in human and animal ...samples. The LAMP amplification can be finished in 45 min under isothermal condition at 60°C by employing a set of four species-specific primer mixtures and the results can be checked by naked-eye visualization. No amplification products were detected with deoxyribunucleic acid (DNA) of related trematode species including
Fasciola hepatica
,
Fasciola gigantica
,
Clonorchis sinensis
,
Opisthorchis viverrini
,
Schistosoma mansoni
, and
Schistosoma japonicum
. The method was further validated by examining
P. westermani
DNA in intermediate hosts including freshwater crabs and crayfish, as well as in sputum and pleural fluid samples from patients of paragonimiasis. These results indicated that the LAMP assay was highly specific, sensitive, and rapid, and it was approximately 100 times more sensitive than conventional specific PCR. The LAMP assay established in this study provides a rapid and sensitive tool for the detection of
P. westermani
DNA in freshwater crabs, crayfish, sputum, and pleural fluid samples, which has important implications for effective control of human paragonimiasis.
In this study, a combined chemical precipitation and moving bed biofilm system was used to treat municipal wastewater. The moving bed biofilm reactor (MBBR) has been tested for nitrogen removal ...through simultaneous nitrification and denitrification (SND). The SND could be successfully established at DO of about 2
mg/l, and about 89.9% of total nitrogen (TN) removal efficiency through SND had been achieved in the system. Iron(II) sulphate heptahydrate solution was dosed onto the top of MBBR at varying ratios of total phosphorus to iron(II). The performance of the system with respect to BOD, COD, TN removal was not significantly affected by chemical dosing. The phosphorus removal efficiency increased with increasing dose. To meet EC requirements, the most favourable chemical dosing ratio was 1:1.3 (weight ratio P:Fe). The combination of highly efficient nitrogen removal, obtainable in a MBBR and effective phosphorus removal by chemical precipitation with iron(II) should be an ideal option for the total nutrient removal from municipal wastewater.
The evolution of microstructure and mechanical properties of Zr0.5Be alloy were investigated by varying the annealing temperature. X-ray diffraction results show that the examined Zr alloy is ...composed of α phase and Be2Zr compound after annealing at temperatures between 600 and 850°C. The optical and transmission electron microscopy results reveal that the recrystallization volume fraction of the α phase gradually increases with increase in annealing temperature. The mechanical properties of the alloy were also investigated by varying the annealing temperature. It was observed that both the tensile strength and micro-hardness of Zr0.5Be alloy gradually decrease with increase in annealing temperature, while the elongation-to-failure increases at higher annealing temperatures. The decrease in dislocation density, the increase in recrystallization volume fraction of the α phase, and distribution of compounds were largely responsible for the decreased tensile strength and micro-hardness and improved ductility of the examined alloys. This work provides a better understanding of the mechanical properties of Zr alloys and helps pave the path for their further development.
Summary
Toll‐like receptor 9 (TLR9) expression is increased in periodontally diseased tissues compared with healthy sites indicating a possible role of TLR9 and its ligand, bacterial DNA (bDNA), in ...periodontal disease pathology. Here, we determine the immunostimulatory effects of periodontal bDNA in human monocytic cells (THP‐1). THP‐1 cells were stimulated with DNA of two putative periodontal pathogens: Porphyromonas gingivalis and Tannerella forsythia. The role of TLR9 in periodontal bDNA‐initiated cytokine production was determined either by blocking TLR9 signaling in THP‐1 cells with chloroquine or by measuring IL‐8 production and nuclear factor‐κB (NF‐κB) activation in HEK293 cells stably transfected with human TLR9. Cytokine production (IL‐1β, IL‐6, and TNF‐α) was increased significantly in bDNA‐stimulated cells compared with controls. Chloroquine treatment of THP‐1 cells decreased cytokine production, suggesting that TLR9‐mediated signaling pathways are operant in the recognition of DNA from periodontal pathogens. Compared with native HEK293 cells, TLR9‐transfected cells demonstrated significantly increased IL‐8 production (P < 0.001) and NF‐κB activation in response to bDNA, further confirming the role of TLR9 in periodontal bDNA recognition. The results of PCR arrays demonstrated upregulation of proinflammatory cytokine and NF‐κB genes in response to periodontal bDNA in THP‐1 cells, suggesting that cytokine induction is through NF‐κB activation. Hence, immune responses triggered by periodontal bacterial nucleic acids may contribute to periodontal disease pathology by inducing proinflammatory cytokine production through the TLR9 signaling pathway.
The design of the Spectrometer Ring at the HIAF Wu, B.; Yang, J.C.; Xia, J.W. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2018, Letnik:
881
Journal Article
Recenzirano
The Spectrometer Ring (SRing) is an essential part of the High Intensity heavy-ion Accelerator Facility project (HIAF) in China. It is designed as a multi-functional experimental storage ring, which ...will be able to operate in three ion optical operation modes. The SRing will be used as a time-of-flight mass spectrometer for short-lived, especially neutron-rich nuclei. It will also be used to collect and cool Rare Isotope Beams (RIBs) or highly-charged stable ion beams for nuclear and atomic physics experiments. The design magnetic rigidity is in the range 1.5 to 15 Tm. The beam cooling system consists of stochastic cooling and electron cooling devices. With a help of an electron cooler, stored ions will be decelerated to a minimum energy of 30 MeV/u by RF cavities. The extraction system of the SRing will allow cooled ion beams to be extracted to an external target for further ion manipulations or reaction experiments. The general ion optics design and technical requirements of SRing subsystems are presented and discussed in this paper.
Living organisms produce a myriad of molecules to protect themselves from fungal pathogens. This review focuses on antifungal proteins from plants and mushrooms, many of which are components of the ...human diet or have medicinal value. Plant antifungal proteins can be classified into different groups comprising chitinases and chitinase-like proteins, chitin-binding proteins, cyclophilin-like proteins, defensins and defensin-like proteins, deoxyribonucleases, embryo-abundant protein-like proteins, glucanases, lectins, lipid transfer proteins, peroxidases, protease inhibitors, ribonucleases, ribosome-inactivating proteins, storage 2S albumins, and thaumatin-like proteins. Some of the aforementioned antifungal proteins also exhibit mitogenic activity towards spleen cells, nitric oxide inducing activity toward macrophages, antiproliferative activity toward tumor cells, antibacterial activity, and inhibitory activity toward HIV-1 reverse transcriptase. In contrast to the large diversity of plant antifungal proteins, only a small number of mushroom antifungal proteins have been reported. Mushroom antifungal proteins are distinct from their plant counterparts in N-terminal sequence. Nevertheless, some of the mushroom antifungal proteins have been shown to inhibit HIV-1 reverse transcriptase activity and tumor cell proliferation.
Summary
There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on ...questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle‐to‐collagen ratio and alpha‐smooth muscle actin expression and an increase in transforming growth factor‐beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.
Background: Childhood obesity has become a nutritional problem in China since the 1990s. Aims: A family based behavioural treatment was developed and tested, to see if its use was feasible in China ...and to evaluate its impact on obese schoolchildren. Methods: In a single school in Beijing, 33 obese children were randomly assigned to a treatment group and 35 to a control group. The treatment group participated in a family based behavioural treatment programme for two years. Height and weight were measured every six months for all participants. Blood pressure, cholesterol, and triglyceride levels were measured at baseline and after two years of programme implementation. Results: Body mass index (BMI, kg/m2) was significantly reduced in the treatment group (from 26.6 (1.7) to 24.0 (0.9), 95% CI 2.06 to 3.18) but not in the control group (from 26.1 (1.5) to 26.0 (1.6)). Total cholesterol decreased 5.5% and triglycerides 9.7% in the treatment group. There was a significant correlation between change in BMI and change in triglycerides. There were no significant changes in plasma lipids in the controls. Blood pressure values also decreased significantly in the treatment, but not the control group. Conclusions: A family based behavioural intervention was feasible to use in treating obesity in schoolchildren in Beijing, China. After two years of implementation, it successfully decreased the degree of obesity, reduced levels of blood pressure, and decreased serum lipids in treatment; there were no significant changes among control children.
PDF
