Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are ...unclear.
We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis.
We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6.
We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by
-infected tissues.
Biodegradable transparent wood was fabricated by introducing epoxy resin E51 modified with the silane coupling agent (KH550) into bleached poplar veneer. The light transmittance of transparent wood ...was modulated by KH550 content. The silane coupling agent KH550 was able to change the compatibility of epoxy resin and wood substrate, thereby affecting the performance of transparent wood. In this study, the effect of KH550 on the properties of transparent wood and its mechanism were investigated. The light transmittance, tensile strength, and elongation at break of transparent wood showed an increasing and then decreasing trend with increased KH550 dosage. When the mass ratio of the coupling agent KH550 to the epoxy resin was 1:20, the transparent wood made by impregnating wood substrate with epoxy resin modified by KH550 had the best performance, with the fast degradation starting temperature of 338 °C, 81.07% light transmittance at λ = 780 nm, 59.92 MPa tensile strength, and 3.47% elongation at break. This work provides a new way for preparing high performance transparent wood.
Macrophages are the primary human host cells of intracellular
(
) infection, where the magnitude of inflammatory reactions is crucial for determining the outcome of infection. Previously, we showed ...that the anti-inflammatory drug sulfasalazine (SASP) significantly reduced the
bactericidal burden and histopathological inflammation in mice. Here, we asked which genes in human inflammatory macrophages are affected upon infection with
and how would potential changes impact the functional state of macrophages. We used a flow cytometry sorting system which can distinguish the dead and alive states of
harbored in human monocyte-derived macrophages (MDM). We found that the expression of cyclooxygenase-2 and microsomal prostaglandin E
synthase (mPGES)-1 increased significantly in tagRFP
MDM which were infected with alive
. After exposure of polarized M1-MDM to
(H37Rv strain)-conditioned medium (MTB-CM) or to the
-derived 19-kD antigen, the production of PGE
and pro-inflammatory cytokines increased 3- to 4-fold. Upon treatment of M1-MDM with SASP, the MTB-CM-induced expression of COX-2 and the release of COX products and cytokines decreased. Elevation of PGE
in M1-MDM upon MTB-CM stimulation and modulation by SASP correlated with the activation of the NF-κB pathway. Together, infection of human macrophages by
strongly induces COX-2 and mPGES-1 expression along with massive PGE
formation which is abrogated by the anti-inflammatory drug SASP.
Tuberculosis (TB) is still the leading killer caused by
infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen ...receptor modulator (SERM), exhibits antimycobacterial activity and inhibits
growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular
growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in
-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB.
Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of
in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.
Background Attentional deficits accompany many psychiatric disorders, underscoring the need for rodent models of attention to screen novel therapeutic agents and characterize the biological basis of ...attention. The five-choice serial reaction time task (5CSRTT) is one such model. Here, we characterized the effects of four standard psychotropic agents on performance in the 5CSRTT. Methods Male Sprague-Dawley rats were trained in the 5CSRTT (5-sec inter-trial interval and .5-sec stimulus duration) until they reliably performed at > 60% accuracy and < 20% omissions. They were then treated systemically with the stimulant methylphenidate (MPH) (.063–2.0 mg/kg), the N -methyl-D-aspartate antagonist dizocilpine (MK-801) (.008–.25 mg/kg), the norepinephrine reuptake inhibitor desipramine (DMI) (.63–10 mg/kg), or the κ-receptor agonist U69,593 (.25–2.0 mg/kg) 30 min before testing. Results Methylphenidate (.5 mg/kg) increased accuracy. Dizocilpine impaired accuracy (.25 mg/kg), increased premature responses (.063–.25 mg/kg), and increased omissions (.25 mg/kg). Desipramine decreased premature responses (5.0 mg/kg) but increased omissions (10 mg/kg), correct response latencies (5.0–10.0 mg/kg), and reward latencies (5.0–10.0 mg/kg). The κ-opioid agonist U69,593 (1.0–2.0 mg/kg) increased omissions and correct response latencies. Conclusions In Sprague-Dawley rats, psychotropic drugs with distinct pharmacological profiles produced distinguishable effects in the 5CSRTT. The effects of these classes of drugs under our testing conditions are qualitatively similar to their effects in humans.
Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are ...biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC50 = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG.
Background:
Clinical observation and experimental studies have indicated that a single exposure to morphine could induce tolerance and dependence. It has become a concern in clinical antinociceptive ...practice. However, the underling mechanism remains unknown. This study was designed to explore the changes of dopamine (DA) neuron activities in the ventral tegmental area (VTA) by employing a spectral analysis followed single morphine treatment.
Results:
Acute morphine treatment significantly increased not only the firing rate and firing population but also the power of slow oscillation of DA neurons in naïve rats. These changes lasted at least for 3 days following the morphine treatment. During this period of time, responses of the DA neurons to subsequent morphine challenge were diminished. We further demonstrated a transient desensitization of opiate receptors as monitored by GTPγS binding to G-proteins. The present study provided first direct evidence for the temporal changes in the VTA DA neuron activities and opiate receptors desensitization.
Conclusion:
Prolonged VTA DA neuron activation and opiate receptors desensitization followed single morphine exposure may underlie the development of dependence and tolerance that may associate with the acute analgesic tolerance and acute addiction of morphine.
The optimal path problem of graph data is a classical problem, but with the continuous development of information technology, the linguistic attributes of path descriptions are becoming more and more ...abundant. The nature of these attributes has uncertainty feature, which makes the choice of optimal path more difficult. Therefore, in order to solve this problem, this paper takes the path of large-scale graph and the uncertainty of linguistic attributes and the inconsistency of evaluation scale described as the research object and uses LWAA and landmark community technology to effectively solve the query problem of approximate optimal path. The efficiency of the algorithm is also verified by experiments.
Using Langevin dynamics simulations, we investigate the dynamics of polymer translocation into a circular nanocontainer through a nanopore under a driving force F. We observe that the translocation ...probability initially increases and then saturates with increasing F, independent of φ, which is the average density of the whole chain in the nanocontainer. The translocation time distribution undergoes a transition from a Gaussian distribution to an asymmetric distribution with increasing φ. Moreover, we find a nonuniversal scaling exponent of the translocation time as chain length, depending on φ and F. These results are interpreted by the conformation of the translocated chain in the nanocontainer and the time of an individual segment passing through the pore during translocation.
Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D1 and ...D2 receptors, with most evidence suggesting a dominant role for the D1 receptor. Since the dopamine D4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D4 receptor in working memory, and suggest innovative, D4-based, treatment of cognitive deficits associated with neuropsychiatric disorders.
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