Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly ...evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis.
We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon.
Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.
Developing novel approaches to reverse the drug resistance of tumor-repopulating cells （TRCs） or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we ...show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparficles （T-MPs） containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tu- mor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications.
Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that ...chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca
release via the lysosomal Ca
channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca
activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.
In this paper, a single‐layer substrate‐integrated waveguide (SIW) filtering antenna with three independently controllable radiation nulls is presented. The antenna consists of a single‐layer SIW ...loaded with two radiation gaps, four metallization columns, and folded‐type slots etched on the chip. The back‐cavity double slots are responsible for extending the bandwidth and realizing the radiation function. Three radiation nulls are generated by analyzing the current distribution of the radiation chip, radiation gap, and folded slots. By adjusting the radiation gap distance, the length of the radiation gap, and the folded slot, three broadside radiation nulls are independently controlled without influence on each other. Therefore, flexible out‐of‐band suppression characteristic is obtained. For demonstration, a prototype is fabricated and tested. The measurements match the simulation results better. The filtering antenna operates at 3.70 GHz with a bandwidth of 5.68% (3.59–3.80 GHz), achieving an average realized gain of 5.10 dBi in a flat passband. The out‐of‐band rejection level exceeds 20 dB.
Three radiation nulls are independently controlled by adjusting the radiation gap position, the length of the radiation gap, and the folded slot separately. The single‐layer SIW filtering antenna satisfies the design requirements of integration and miniaturization, while providing filtering performance.
•Single & two-phase anaerobic co-digestion of FVW & FW was compared at various OLRs.•Ethanol-type fermentation controlled the digestion as OLR<2.0g(VS)L−1d−1.•Propionic acid accumulation caused the ...unstable digestion as OLR>2.0g(VS)L−1d−1.•Single-phase digestion presented higher CH4 production as OLR was in low levels.•Two-phase digestion presented more stable and higher buffering to high OLR.
The co-digestion of fruit & vegetable waste (FVW) and food waste (FW) was performed at various organic loading ratios (OLRs) in single-phase and two-phase system, respectively. The results showed that the ethanol-type fermentation dominated in both digestion processes when OLR was at low levels (<2.0g(VS)L−1d−1). The propionic acid was rapidly accumulated as OLR was increased to higher levels (>2.0g(VS)L−1d−1), which could cause unstable anaerobic digestion. Single-phase digestion was better than two-phase digestion in term of 4.1% increase in CH4 production at lower OLRs (<2.0g(VS)L−1d−1). However, at higher level of OLR (⩾2.0g(VS)L−1d−1), two-phase digestion achieved higher CH4 production of 0.351–0.455L(gVS)−1d−1, which were 7.0–15.8% more than that of single-phase. Additionally, two-phase digestion presented more stable operation, and higher OLR treatment capacity. Furthermore, comparison of these two systems with bioenergy recovery revealed that two-phase system overall presented higher bioenergy yield than single-phase.
Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls ...macrophage-mediated inflammatory responses. IFN-γ/LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y
in macrophages. The UDPG/P2Y
signaling pathway not only upregulates the expression of STAT1 via activating RARβ but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases.
Given the severe threats affecting waterbirds and the limited resources, it is crucial to identify priority wetlands to optimize conservation efforts for waterbirds. This study aims to prioritize ...wetlands in Wuhan City based on the diversity, rarity, and conservation costs of waterbirds. Firstly, 17 focal waterbird species were selected as conservation targets based on the data availability and species rarity. The MaxEnt model was used to simulate the potential spatial distributions of the focal waterbirds, and corresponding weights were assigned based on their conservation status. Secondly, the Human Footprint Index (HFI) was employed to represent conservation costs. Finally, the Zonation 5 spatial prioritization software was used to identify cost-effective priority wetlands for waterbird conservation. The results show: (1) The species distribution model indicated that the distance to the wetland, land cover, and distance to the road were the primary environmental variables influencing the potential spatial distribution of focal waterbirds. (2) The top 10 %, top 20 %, and top 30 % priority wetlands identified by Zonation 5 had average coverage rates of 15.2 %, 28.0 %, and 39.6 % for focal waterbirds, respectively. (3) We identified major wetland conservation gaps in Wuhan, primarily including Caohu Lake, Luhu Lake, Futo Lake, and parts of Liangzi Lake. (4) Additionally, we recommend enhancing waterbird management in existing wetland protected areas, such as the Hougong Wetland Park and Donghu Wetland Park, to improve the effectiveness of waterbird conservation efforts. Our research provides scientific evidence to support the conservation of wetlands in Wuhan and the promotion of waterbird diversity. It also emphasizes the importance of finding a balance between conservation effectiveness and cost.
Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces ...tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors.
The dynamics of microbial communities during anaerobic digestion at different states of acclimation and inhibitions is key to diagnosing ailments of this process. Previous studies focused primarily ...on concentrations thresholds for inhibition and adaptation. This study investigated the dynamics of methane (CH4) producing communities subjected to ammonia and salinity stresses during batch anaerobic digestion, of dairy wastewater, in both acclimated and unacclimated conditions. Experimental data was fitted into the ‘Modified Gompertz Model’ and resulting lag phase values related to stress conditions. R2-values ranged between 0.95 and 1.00 suggesting a nearly perfect fit of the model to the observed CH4 production. Irrespective of acclimation conditions, digesters under ammonia stresses produced less CH4 compared to those subjected to salinity stresses. Salinity-acclimated digesters performed similar to salinity-free digesters below 12 g L−1 salinity level. Petrimonas and Clostridium XI were the most dominant (50–61%) bacterial genera in salinity-acclimated digesters, whereas Petrimonas, Clostridium XI, Alkaliflexus, Sedimentibacter, and Clostridium III were the most abundant (69–82%) bacterial genera in salinity-unacclimated digesters. In ammonia-acclimated digesters, Petrimonas, Clostridium XI, and Alkaliflexus were the most dominant (55–68%) genera. Petrimonas, Clostridium XI, Alkaliflexus, Sedimentibacter, Clostridium III, Clostridium XIVa, were the most abundant (74–87%) bacterial genera in TAN-unacclimated digesters. Methanosarcina, Methanobrevibacter and Methanobacterium were most abundant archaea in both salinity (71–99%) and ammonia (87–98%) stressed digesters. The principal component analysis demonstrated bacteria clustering in the acclimated and the unacclimated reactors. No such clustering of archaea was evident in either acclimated or unacclimated reactors.
•Ammonia resulted in higher inhibition to CH4 yield than salinity.•The Gompertz model adequately (95–100%) predicted inhibited CH4 yields.•Methanosarcina tolerate higher inhibitior levels than other archaea.•Acclimation improved inhibition tolerance and CH4 yield.
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