Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D ...(1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72 h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48-72 h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-γ, while inducing IL-4 and IL-10, would be beneficial.
Most combination therapies are developed based on targets of existing drugs, which only represent a small portion of the human proteome. We introduce a network controllability-based method, OptiCon, ...for de novo identification of synergistic regulators as candidates for combination therapy. These regulators jointly exert maximal control over deregulated genes but minimal control over unperturbed genes in a disease. Using data from three cancer types, we show that 68% of predicted regulators are either known drug targets or have a critical role in cancer development. Predicted regulators are depleted for known proteins associated with side effects. Predicted synergy is supported by disease-specific and clinically relevant synthetic lethal interactions and experimental validation. A significant portion of genes regulated by synergistic regulators participate in dense interactions between co-regulated subnetworks and contribute to therapy resistance. OptiCon represents a general framework for systemic and de novo identification of synergistic regulators underlying a cellular state transition.
Exploration of effective ways to integrate various functional species into hydrogen‐bonded organic frameworks (HOFs) is critically important for their applications but highly challenging. In this ...study, according to the “bottle‐around‐ship” strategy, core–shell heterostructure of upconversion nanoparticles (UCNPs) and HOFs was fabricated for the first time via a ligand‐grafting stepwise method. The UCNPs “core” can effectively upconvert near‐infrared (NIR) irradiation (980 nm) into visible light (540 nm and 653 nm), which further excites the perylenediimide‐based HOF “shell” through resonance energy transfer. In this way, the nanocomposite inherits the high porosity, excellent photothermal and photodynamic efficiency, NIR photoresponse from two parent materials, achieving intriguing NIR‐responsive bacterial inhibition toward Escherichia coli. This study may shed light on the design of functional HOF‐based composite materials, not only enriching the HOF library but also broadening the horizon of their potential applications.
In this study, core–shell heterostructures of upconversion nanoparticles (UCNPs) and hydrogen‐bonded organic frameworks (HOFs) were fabricated via a stepwise ligand‐grafting method. The UCNP “core” can effectively upconvert near‐infrared (NIR) irradiation into visible ranges, which can further excite the HOF “shell” to achieve near‐infrared‐responsive photothermal and photodynamic bacterial inhibition.
Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in the huntingtin (HTT) gene. When the number of CAG repeats exceeds 36, the translated expanded ...polyglutamine-containing HTT protein (mutant HTT mHTT) interferes with the normal functions of many cellular proteins and subsequently jeopardizes important cellular machineries in major types of brain cells, including neurons, astrocytes, and microglia. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which comprises NLRP3, ASC, and caspase-1, is involved in the activation of IL-1β and IL-18 and has been implicated in various biological functions. Although the existence of the NLRP3 inflammasome in the brain has been documented, the roles of the NLRP3 inflammasome in HD remain largely uncharacterized. MCC950 is a highly selective and potent small-molecule inhibitor of NLRP3 that has been used for the treatment of several diseases such as Alzheimer's disease. However, whether MCC950 is also beneficial in HD remains unknown. Therefore, we hypothesized that MCC950 exerts beneficial effects in a transgenic mouse model of HD.
To evaluate the effects of MCC950 in HD, we used the R6/2 (B6CBA-TgHDexon162Gpb/1J) transgenic mouse model of HD, which expresses exon 1 of the human HTT gene carrying 120 ± 5 CAG repeats. Male transgenic R6/2 mice were treated daily with MCC950 (10 mg/kg of body weight; oral administration) or water for 5 weeks from the age of 7 weeks. We examined neuronal density, neuroinflammation, and mHTT aggregation in the striatum of R6/2 mice vs. their wild-type littermates. We also evaluated the motor function, body weight, and lifespan of R6/2 mice.
Systematic administration of MCC950 to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, as assessed based on increased neuronal density and upregulation of the NeuN and PSD-95 proteins. Most importantly, oral administration of MCC950 increased neuronal survival, reduced neuroinflammation, extended lifespan, and improved motor dysfunction in R6/2 mice.
Collectively, our findings indicate that MCC950 exerts beneficial effects in a transgenic mouse model of HD and has therapeutic potential for treatment of this devastating neurodegenerative disease.
Complex systems in condensed phases involve a multidimensional energy landscape, and knowledge of transitional structures and separation of time scales for atomic movements is critical to ...understanding their dynamical behavior. Here, we report, using four-dimensional (4D) femtosecond electron diffraction, the visualization of transitional structures from the initial monoclinic to the final tetragonal phase in crystalline vanadium dioxide; the change was initiated by a near-infrared excitation. By revealing the spatiotemporal behavior from all observed Bragg diffractions in 3D, the femtosecond primary vanadium-vanadium bond dilation, the displacements of atoms in picoseconds, and the sound wave shear motion on hundreds of picoseconds were resolved, elucidating the nature of the structural pathways and the nonconcerted mechanism of the transformation.
A series of pyrrolo2,1-aisoquinoline and coumarin-fused pentacyclic derivatives were synthesized via base-mediated divergent annulation of 4-chloro-3-formylcoumarin and tetrahydroisoquinoline as a ...key step. This method was then extended to the preparation of isolamellarins A and B (isolamellarin G trimethyl ether). When exposed to UV light, the pyrrolo2,1-aisoquinoline- and coumarin-fused pentacycles B were found to undergo aerobic oxidation to give the corresponding hydroxypyrrolones.
Total electron content (TEC) is an important parameter that describes the features of the ionosphere. The International GNSS Service (IGS) has been providing IGS Global TEC maps using analysis ...algorithms. However, collecting the completed data is difficult because of the lack of ground receivers, and the processing to obtain the completed IGS TEC maps is time‐consuming. The fast development of deep learning brings an effective way to solve these problems. Among the various deep learning methods, the generative adversarial network (GAN) exhibits great potential in recovering missing data. In this paper, we fill the missing data of the global IGS TEC maps using pix2pixhd, which is a novel deep learning method based on GAN. Differing from the traditional GAN, pix2pixhd has two generators and three discriminators. The network enhances the ability of our model to complete images with large‐scale missing areas. The result demonstrates that our model generates the ionospheric peak structures at low latitudes well, while behaving badly (the average correlation coefficient: 0.6857) around the edge of the ionospheric peak region. Comparing different scales of the missing data areas, our model has the best performance with 0%–15% missing data. With the large scale of missing data areas (30%–45% and >45%), the performance is still satisfactory. In addition, the completion effect of our model is slightly affected by geomagnetic and solar activity. Our work demonstrates a new possibility for the application of deep learning to a broader field of geosciences, particularly for problems of missing observational data.
Key Points
We make a model to complete International GNSS Service total electron content maps using pix2pixhd based on generative adversarial network
The completion effect of our model with the large scale of missing data areas is still satisfactory
Our model generates the ionospheric peak structures well while it behaves slightly badly around the edge of ionospheric peak region
To prevent miners’ unsafe behavior, analytic network process was used to construct the indicator system of influence factors and the indicator weights were calculated. Based on the indicator system, ...intervention strategies for miners’ unsafe behavior were designed. The system dynamics model of miners’ unsafe behavior was established based on individual, environment, group and management and simulated by Vensim software, then the effects of different intervention strategies on the level of unsafe behavior were discussed. The results show that the primary indicators in order of weight are safety management, personal factors, leadership climate, group climate, work environment, nature of work; secondary indicators with greater weight are safety regulation, safety education and training, safety culture; the reduction of level in miners’ unsafe behavior is accelerated by the intervention strategies, and there is optimal intervention strategy in each intervention aspect; the optimal intervention strategy provides n
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