We study the active dynamics of self-propelled asymmetrical colloidal particles (Janus particles) fueled by an AC electric field. Both the speed and direction of the self-propulsion, and the strength ...of the attractive interaction between particles can be controlled by tuning the frequency of the applied electric field and the ion concentration of the solution. The strong attractive force at high ion concentration gives rise to chain formation of the Janus particles, which can be explained by the quadrupolar charge distribution on the particles. Chain formation is observed irrespective of the direction of the self-propulsion of the particles. When both the position and the orientation of the heads of the chains are fixed, they exhibit beating behavior reminiscent of eukaryotic flagella. The beating frequency of the chains of Janus particles depends on the applied voltage and thus on the self-propulsive force. The scaling relation between the beating frequency and the self-propulsive force deviates from theoretical predictions made previously on active filaments. However, this discrepancy is resolved by assuming that the attractive interaction between the particles is mediated by the quadrupolar distribution of the induced charges, which gives indirect but convincing evidence on the mechanisms of the Janus particles. This signifies that the dependence between the propulsion mechanism and the interaction mechanism, which had been dismissed previously, can modify the dispersion relations of beating behaviors. In addition, hydrodynamic interaction within the chain, and its effect on propulsion speed, are discussed. These provide new insights into active filaments, such as optimal flagellar design for biological functions.
We study self-propulsion of a half-metal coated colloidal particle under laser irradiation. The motion is caused by self-thermophoresis: i.e., absorption of a laser at the metal-coated side of the ...particle creates local temperature gradient which in turn drives the particle by thermophoresis. To clarify the mechanism, temperature distribution and a thermal slip flow field around a microscale Janus particle are measured for the first time. With measured temperature drop across the particle, the speed of self-propulsion is corroborated with the prediction based on accessible parameters. As an application for driving a micromachine, a microrotor is demonstrated.
α-Synuclein (α-Syn), a pathological hallmark of Parkinson's disease (PD), has been recognized to induce the production of interleukin-1β in a process that depends, at least in vitro, on nod-like ...receptor protein 3 (NLRP3) inflammasome in monocytes. However, the role of NLRP3 inflammasome activation in the onset of PD has not yet been fully established.
In this study, we showed that NLRP3 inflammasomes were activated in the serum of PD patients and the midbrain of PD model mice. We further clarified that α-syn activated the NLRP3 inflammasome through microglial endocytosis and subsequent lysosomal cathepsin B release. Deficiency of caspase-1, an important component of NLRP3 inflammasome, significantly inhibited α-syn-induced microglia activation and interleukin-1β production, which in turn alleviated the reduction of mesencephalic dopaminergic neurons treated by microglia medium. Specifically, we demonstrated for the first time that Nlrp3 is a target gene of microRNA-7 (miR-7). Transfection of miR-7 inhibited microglial NLRP3 inflammasome activation whereas anti-miR-7 aggravated inflammasome activation in vitro. Notably, stereotactical injection of miR-7 mimics into mouse striatum attenuated dopaminergic neuron degeneration accompanied by the amelioration of microglial activation in MPTP-induced PD model mice.
Our study provides a direct link between miR-7 and NLRP3 inflammasome-mediated neuroinflammation in the pathogenesis of PD. These findings will give us an insight into the potential of miR-7 and NLRP3 inflammasome in terms of opening up novel therapeutic avenues for PD.
Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects ...and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.
We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.
This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.
Abstract
The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically ...targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well‐known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA‐approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide‐induced systemic inflammation and Parkinson's disease‐like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3‐driven diseases and migth expand its clinical use considerably.
Synopsis
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Mefloquine is a highly selective and potent NLRP3 inhibitor. Mefloquine directly binds to the NACHT and LRR domains of NLRP3, impairs inflammasome assembly and reduces NLRP3‐dependent systemic inflammation and neural injury in mice.
By screening a panel of FDA‐approved drugs, mefloquine is identified as a potent and specific NLRP3 inhibitor.
Mefloquine directly binds to NLRP3 and inhibits inflammasome activation.
Mefloquine suppresses LPS‐induced NLRP3‐driven systemic inflammation and neural injury in mice.
The nonequilibrium distribution of colloids in a polymer solution under a temperature gradient is studied experimentally. A slight increase of local temperature by a focused laser drives the colloids ...towards the hot region, resulting in the trapping of the colloids irrespective of their own thermophoretic properties. An amplification of the trapped colloid density with the polymer concentration is measured, and is quantitatively explained by hydrodynamic theory. The origin of the attraction is a migration of colloids driven by a nonuniform polymer distribution sustained by the polymer's thermophoresis. These results show how to control the thermophoretic properties of colloids.
Engineering microbes to produce terpenes from renewable feedstock is a promising alternative to traditional production approaches. Generally, terpenes are not readily secreted by microbial cells, and ...their distribution within cells is usually obscure and often a restricting factor for the overproduction of terpenes due to the storage limitation. Here, we determined that squalene overproduced in the cytoplasm of Saccharomyces cerevisiae was distributed in a form similar to oil droplets. Interestingly, these suspected oil droplets were confirmed to be inflated peroxisomes that were swollen along with the production of squalene, indicating that peroxisomes in S. cerevisiae are dynamic depots for the storage of squalene. In view of this, harnessing peroxisomes as subcellular compartments for squalene synthesis was performed, achieving a 138-fold improvement in squalene titer (1312.82 mg/L) relative to the parent strain, suggesting that the peroxisome of S. cerevisiae is an efficient subcellular factory for the synthesis of terpenes. By dual modulation of cytoplasmic and peroxisomal engineering, the squalene titer was further improved to 1698.02 mg/L. After optimizing a two-stage fed-batch fermentation method, the squalene titer reached 11.00 g/L, the highest ever reported. This provides new insight into the synthesis and storage of squalene in peroxisomes and reveals the potential of harnessing peroxisomes to overproduce terpenes in S. cerevisiae through dual cytoplasmic-peroxisomal engineering.
•Yeast peroxisome is a dynamic storage depot for squalene.•Yeast peroxisome is an efficient subcellular factory for squalene synthesis.•Dual cytoplasmic and peroxisomal engineering is favorable to high yield of squalene.
In this study, we design a wetting-programable method to create a surface channel for droplets. Superhydrophilic channels can be designed and erased reversibly by selectively masking the wetting and ...prewetting process on superhydrophobic silicone surfaces with microgroove and nanoporous structures fabricated using a micromachining technique. We found that droplets in this flow channel present a complex wetting behavior. The surface that undergoes infiltration by wetting and prewetting transitions from being a superhydrophobic surface to becoming a superhydrophilic surface. To understand the dynamics of droplet exploration, we measured the spreading distance of the droplet’s leading edge and the spontaneous capillary flow (SCF). The final spreading length of the droplet’s leading edge was also recorded. We found that increasing the prewetting volume enhances the final spreading distance of the droplet’s leading edge and the average SCF speed. Prewetting minimizes the apparent contact angle and pinning, promoting superhydrophilicity and increasing the droplet mobility. To further enhance our control over liquid transport, we incorporated vertical vibration as an active approach to regulate the programmed transport of droplets. We observed a substantial extension in the final spreading distance of the droplet’s leading edge. This extension was attributed to the effective overcoming of the pinning phenomena caused by the application of vertical vibration. With the above-mentioned methods, we achieve guided motion and multi-droplet sequence mixing of droplets with the designed channel shapes. Our results suggest how the wetting behavior dynamics of a multi-level structural surface are affected by prewetting liquid and vertical vibration. This provides insight into the wetting mechanism on porous superhydrophobic/superhydrophilic material.
The vertebrate mucosal barrier comprises physical and immune elements, as well as bioactive molecules, that protect organisms from pathogens. Vitamin D is a vital nutrient for animals and is involved ...in immune responses against invading pathogens. However, the effect of vitamin D on the mucosal barrier system of fish, particularly in the skin, remains unclear. Here, we elucidated the effect of vitamin D supplementation (15.2, 364.3, 782.5, 1167.9, 1573.8, and 1980.1 IU/kg) on the mucosal barrier system in the skin of grass carp (
) challenged with
. Dietary vitamin D supplementation (1) alleviated
-induced skin lesions and inhibited oxidative damage by reducing levels of reactive oxygen species, malondialdehyde, and protein carbonyl; (2) improved the activities and transcription levels of antioxidant-related parameters and nuclear factor erythroid 2-related factor 2 signaling; (3) attenuated cell apoptosis by decreasing the mRNA and protein levels of apoptosis factors involved death receptor and mitochondrial pathway processes related to p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signaling; (4) improved tight junction protein expression by inhibiting myosin light-chain kinase signaling; and (5) enhanced immune barrier function by promoting antibacterial compound and immunoglobulin production, downregulating pro-inflammatory cytokine expression, and upregulating anti-inflammatory cytokines expression, which was correlated with nuclear factor kappa B and the target of rapamycin signaling pathways. Vitamin D intervention for mucosal barrier via multiple signaling correlated with vitamin D receptor a. Overall, these results indicate that vitamin D supplementation enhanced the skin mucosal barrier system against pathogen infection, improving the physical and immune barriers in fish. This finding highlights the viability of vitamin D in supporting sustainable aquaculture.
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