Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple ...progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.
•We provide an extensive definition of basic properties of basal ganglia microglia•Microglia in the healthy brain exist along a spectrum of functional states•Midbrain microglia differ significantly from their cortical counterparts•Region-specific phenotypes reemerge following microglial ablation and repopulation
De Biase et al. show that microglia in different basal ganglia nuclei exhibit region-specific phenotypes, with distinct anatomical features, lysosome content, membrane properties, and transcriptomes. Local regulatory cues guide establishment and maintenance of this regional specialization.
•A global oil trade core network is analyzed using complex network theory.•The global oil export core network displays a scale-free behaviour.•The current global oil trade network can be divided into ...three trading blocs.•The global oil trade network presents a ‘robust and yet fragile’ characteristic.
The Global oil trade pattern becomes increasingly complex, which has become one of the most important factors affecting every country’s energy strategy and economic development. In this paper, a global oil trade core network is constructed to analyze the overall features, regional characteristics and stability of the oil trade using complex network theory. The results indicate that the global oil export core network displays a scale-free behaviour, in which the trade position of nodes presents obvious heterogeneity and the ‘hub nodes’ play a ‘bridge’ role in the formation process of the trade network. The current global oil trade network can be divided into three trading blocs, including the ‘South America-West Africa-North America’ trading bloc, the ‘Middle East–Asian–Pacific region’ trading bloc, and ‘the former Soviet Union–North Africa–Europe’ trading bloc. Geopolitics and diplomatic relations are the two main reasons for this regional oil trade structure. Moreover, the global oil trade network presents a ‘robust but yet fragile’ characteristic, and the impacts of trade interruption always tend to spread throughout the whole network even if the occurrence of export disruptions is localised.
Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N‐heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with ...concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra‐ortho‐substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC‐catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzyl‐benzothiophene/benzofuran‐3‐carbaldehydes through a 2+4 annulation, decarboxylation, and oxidative aromatization cascade with central‐to‐axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran‐fused biaryls in high enantioselectivities and works well for the synthesis of tetra‐ortho‐substituted biaryls.
The N‐heterocyclic carbene catalyzed enantioselective de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzylbenzothiophene/benzofuran‐3‐carbaldehydes has been developed. This cascade process comprises a 2+4 annulation, decarboxylation, and oxidative aromatization with central‐to‐axial chirality conversion, allowing rapid access to atropoisomeric tri‐ and tetra‐ortho‐substituted biaryls with high enantioselectivities.
This paper studies the competition among oil importers using complex network theory, combined with several alternative measures of competition intensity, to analyze the evolution of the pattern and ...transmission of oil-trading competition. The results indicate that oil trade has formed a global competition pattern and that the role played by the Asian-Pacific region in the evolution of this competition pattern is becoming increasingly prominent. In addition, global competition intensity has continued to rise, and non-OECD countries have become the main driving force for this increase in global competition intensity. The large oil importers are the most significant parts of the global oil-trading competition pattern. They are not only the major participants in the competition for oil resources but also play important roles in the transmission of oil-trading competition. China and the United States especially display the feature of globalization, whose impacts of transmission reach across the whole oil-trading competition network. Finally, a “5C” (changeability, contestability, cooperation, commitment and circumstances) policy framework is put forward to maintain the stability of oil trade and improve the energy security of oil importers in various aspects.
•An oil-trading competition network is constructed using complex network theory.•Oil trade has formed a global competition pattern and its intensity has kept rising.•The status of the Asian-Pacific region in the competition pattern becomes prominent.•Large oil importers play important roles in transmitting the trading competition.•A “5C” policy framework is put forward to cope with the intensive competition.
STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, ...we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity.
The selective oxidation of methane to high value‐added liquid oxygenated compounds under mild conditions is of great significance to promote the efficient utilization of the carbon source, but it ...also faces the dilemma of low activity and over‐oxidation. Here, ZnTi‐layered double hydroxides (LDH)‐A200 photocatalysts with Pd loading are prepared to achieve efficient oxidation of methane, with O2 as an oxidant under ambient condition. The highest generation rate of C1 liquid products (methanol and formaldehyde) reaches 4924.47 µmol g−1 h−1 with a selectivity close to 100% over 0.5Pd‐ZnTi‐LDH‐A200, which is 20 times higher than that of bare ZnTi‐LDH‐A200. The photochemical results show that the modified photocatalysts present much higher generation and separation efficiency of electron‐hole pairs. In situ X–ray photoelectron spectroscopy indicates that Pd nanoparticles are the hole acceptor, which is beneficial to charge separation in the photocatalysis. Furthermore, electron spinresonance spectroscopy and temperature–programmed–desorption analysis prove that Pd loading is helpful to the adsorption of methane and oxygen on the surface of ZnTi‐LDH‐A200, promoting the production of reactive oxygen species and activation of methane. All these factors work together to promote the efficient conversion of CH4 to high value‐added C1 oxygenates.
Pd‐assisted layered double hydroxides facilitate the photocatalytic conversion of CH4 to high value‐added C1 oxygenated compounds with nearly 100% selectivity under ambient conditions using O2 as the oxidant. The loaded Pd not only acts as the adsorption sites of CH4, but also acts as the hole acceptor to active CH4 and promote the separation of photocarriers.
Cannabinoid CB ₂ receptors (CB ₂Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we ...report that CB ₂Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB ₂ mRNA and CB ₂R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB ₂Rs by JWH133 or other CB ₂R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB ₁⁻/⁻ mice are blocked by CB ₂R antagonist and absent in CB ₂⁻/⁻ mice. These data suggest that CB ₂R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.
Significance Although early studies suggested that cannabinoid CB ₂ receptors (CB ₂Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB ₂R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB ₂R genes and receptors are expressed in midbrain DA neurons, and that activation of CB ₂Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings not only challenge the long-held view that brain CB ₂Rs are not expressed in neurons, but also suggest that neuronal CB ₂Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB ₂Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders.
Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism ...of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated the anti-tumor effects of LTL on NSCLC in vitro and in vivo. The results revealed that LTL could inhibit cell proliferation and induce apoptosis in both A549 and H460 cells. In a H460 xenograft tumor model of nude mice, LTL significantly suppressed tumor growth, inhibited cell proliferation, and induced apoptosis. miRNA microarray and quantitative PCR (qPCR) analysis indicated that miR-34a-5p was dramatically upregulated upon LTL treatment in tumor tissues. Furthermore, MDM4 was proved to be a direct target of miR-34a-5p by luciferase reporter gene assay. LTL treatment was associated with increased p53 and p21 protein expressions and decreased MDM4 protein expression in both NSCLC cells and tumor tissues. When miR-34a-5p was inhibited in vitro, the protein expressions of Bcl-2 and MDM4 were recovered, while that of p53, p21, and Bax were attenuated. Moreover, caspase-3 and caspase-9 activation induced by LHL treatment in vitro were also suppressed by miR-34a-5p inhibition. Overall, LTL could inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p via targeting MDM4. These findings provide novel insight into the molecular functions of LTL that suggest its potential as a therapeutic agent for human NSCLC.
Summary
Aims
To investigate the critical role of Tim‐3 in the polarization of microglia in intracerebral hemorrhage (ICH)‐induced secondary brain injury (SBI).
Methods
An in vivo ICH model was ...established by autologous whole blood injection into the right basal ganglia in rats. The primary cultured microglia were treated with oxygen‐hemoglobin (OxyHb) to mimic ICH in vitro. In this experiment, specific siRNA for Tim‐3 and recombinant human TIM‐3 were exploited both in vivo and in vitro.
Results
Tim‐3 was increased in the brain after ICH, which mainly distributed in microglia, but not neurons and astrocytes. However, the blockade of Tim‐3 by siRNA markedly reduced secretion of inflammatory factors, neuronal degeneration, neuronal cell death, and brain edema. Meanwhile, downregulation of Tim‐3 promoted the transformation of microglia phenotype from M1 to M2 after ICH. Furthermore, upregulation of Tim‐3 can increase the interaction between Tim‐3 and Galectin‐9 (Gal‐9) and activate Toll‐like receptor 4 (TLR‐4) pathway after ICH. Increasing the expression of Tim‐3 may be related to the activation of HIF‐1α.
Conclusion
Tim‐3 may be an important link between neuroinflammation and microglia polarization through Tim‐3/Gal‐9 and TLR‐4 signaling pathways which induced SBI after ICH.
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