Besides the well‐documented ophthalmic manifestations, thyroid‐associated ophthalmopathy (TAO) is believed to be related to emotional and psychological abnormalities. Given the previous neuroimaging ...evidence, we hypothesized that TAO patients would have altered neurovascular coupling associated with clinical‐psychiatric disturbances. This study was to investigate neurovascular coupling changes in TAO by combining resting‐state functional magnetic resonance imaging (rs‐fMRI) and arterial spin labeling (ASL) techniques. Amplitude of low‐frequency fluctuation (ALFF) was calculated from rs‐fMRI, and cerebral blood flow (CBF) was computed from ASL in 37 TAO patients and 21 healthy controls (HCs). Global neurovascular coupling was assessed by across‐voxel CBF‐ALFF correlation, and regional neurovascular coupling was evaluated by CBF/ALFF ratio. Auxiliary analyses were performed using fractional ALFF (fALFF) and regional homogeneity (ReHo) as rs‐fMRI measures. Compared with HCs, TAO patients showed significantly reduced global CBF‐ALFF coupling. Moreover, TAO patients exhibited decreased CBF/ALFF ratio in the left lingual gyrus (LG)/fusiform gyrus (FFG), and increased CBF/ALFF ratio in the bilateral precuneus (PCu). In TAOs, CBF/ALFF ratio in the left LG/FFG was positively correlated with visual acuity, while CBF/ALFF ratio in the bilateral PCu was negatively correlated with Montreal Cognitive Assessment score. The auxiliary analyses showed trends of reduced global neurovascular coupling (i.e., CBF‐fALFF correlation and CBF‐ReHo correlation), as well as significant altered regional neurovascular coupling (i.e., CBF/fALFF ratio and CBF/ReHo ratio) in several brain regions. These findings indicated that TAO patients had altered neurovascular coupling in the visual and higher‐order cognitive cortices. The neurovascular decoupling might be a possible neuropathological mechanism of TAO.
The neuropeptide orexin is involved in motor circuit function. However, its modulation on neuronal activities of motor structures, integrating orexin's diverse downstream molecular cascades, remains ...elusive. By combining whole‐cell patch‐clamp recordings and neuropharmacological methods, we revealed that both non‐selective cationic conductance (NSCC) and endocannabinoids (eCBs) are recruited by orexin signalling on reticulospinal neurones in the caudal pontine reticular nucleus (PnC). The orexin–NSCC cascade provides a depolarizing force that proportionally enhances the firing‐responsive gain of these neurones. Meanwhile, the orexin–eCB cascade selectively attenuates excitatory synaptic strength in these neurones by activating presynaptic cannabinoid receptor type 1. This cascade restrains the firing response of the PnC reticulospinal neurones to excitatory inputs. Intriguingly, non‐linear or linear interactions between orexin postsynaptic excitation and presynaptic inhibition can influence the firing responses of PnC reticulospinal neurones in different directions. When presynaptic inhibition is in the lead, non‐linear interactions can prominently downregulate or even gate the firing response. Conversely, linear interactions occur to promote the firing response, and these linear interactions can be considered a proportional reduction in the contribution of depolarization to firing by presynaptic inhibition. Through the dynamic employment of these interactions, adaptive modulation may be achieved by orexin to restrain or even gate the firing output of the PnC to weak/irrelevant input signals and facilitate those to salient signals.
Key points
This study investigated the effects of orexin on the firing activity of PnC reticulospinal neurones, a key element of central motor control.
We found that orexin recruited both the non‐selective cationic conductances (NSCCs) and endocannabinoid (eCB)–cannabinoid receptor type 1 (CB1R) system to pontine reticular nucleus (PnC) reticulospinal neurones. The orexin–NSCC cascade exerts a postsynaptic excitation that enhances the firing response, whereas the orexin–eCB–CB1R cascade selectively attenuates excitatory synaptic strength that restrains the firing response.
The postsynaptic and presynaptic actions of orexins occur in an overlapping time window and interact to dynamically modulate firings in PnC reticulospinal neurones.
Non‐linear interactions occur when presynaptic inhibition of orexin is in the lead, and these interactions can prominently downregulate or even gate firing responses in PnC reticulospinal neurones.
Linear interactions occur when postsynaptic excitation of orexin is in the lead, and these interactions can promote the firing response. These linear interactions can be considered a proportional reduction of the contribution of depolarization to firing by presynaptic inhibition.
figure legend In the reticulospinal neurones of the caudal pontine reticular nucleus (PnC), orexin signalling activates the postsynaptic non‐selective cationic conductance and induces an inward current. In addition, orexin also recruits the endocannabinoid–cannabinoid receptor system and this action selectively inhibits the glutamatergic neurotransmission, but not GABAergic neurotransmission, to these neurones. Orexin's postsynaptic excitation and presynaptic inhibition oppositely modulate the firing responsiveness of PnC reticulospinal neurones. Intriguingly, orexin's two actions occur at overlapping time windows and their interactions lead to dynamic firing responses of PnC reticulospinal neurones to excitatory inputs, including weakly changed, increased, decreased and completely suppressed. Through the dynamic employment of these interactions, adaptive modulation may be achieved by orexin through restraint or may even gate the firing output of the PnC to weak/irrelevant input signals and facilitate those to salient signals.
•There was a three-fold increase from the previous decade in published studies evaluating Tai Chi on various health outcomes.•Most studies were conducted in China, followed by the United States and ...South Korea.•Study participants were mostly adults and older adults, who were healthy or had one or more chronic diseases.•The majority of studies reported at least one outcome in favour of Tai Chi.•Adverse events were reported in only 7 % of studies.
The objective of this bibliometric review was to identify the volume, breadth, and characteristics of clinical studies evaluating Tai Chi published between January 2010 and January 2020. Five English and four Chinese language databases were searched. Following independent screening, 1018 eligible publications representing 987 studies were identified, which was a three-fold increase from the previous decade. Most common were randomized controlled trials (548/987, 55.5 %), followed by systematic reviews (157/987, 15.9 %), non-randomized controlled clinical studies (152/987, 15.4 %), case series (127/987, 12.9 %) and case reports (3/987, 0.3 %) that were conducted in China (730/987, 74.0 %), followed by the United States of America (123/987, 12.5 %) and South Korea (20/987, 2.0 %). Study participants were mostly in the adult (55.2 %) and/or older adult (72.0 %) age groups. The top ten diseases/conditions were hypertension, chronic obstructive pulmonary disease, diabetes, knee osteoarthritis, heart failure, depression, osteoporosis/osteopenia, breast cancer, coronary heart disease and insomnia. A quarter of the studies enrolled healthy participants to evaluate the effects of Tai Chi on health promotion/preservation, balance/falls, and physiological/biomechanical outcomes. Yang style Tai Chi was the most popular, followed by Chen and Sun style. Tai Chi was mostly commonly delivered face-to-face by a Tai Chi instructor in group settings for 60 min, three times a week, for 12 weeks. Most studies (93.8 %) reported at least one outcome in favor of Tai Chi. Adverse events were underreported (7.2 %). Over half fell short of expected intervention reporting standards, signalling the need for Tai Chi extensions to existing guidelines.
High coulombic efficiency and dendrite suppression in carbonate electrolytes remain challenges to the development of high-energy lithium ion batteries containing lithium metal anodes. Here we ...demonstrate an ultrathin (≤100 nm) lithium-ion ionomer membrane consisting of lithium-exchanged sulfonated polyether ether ketone embedded with polyhedral oligosilsesquioxane as a coating layer on copper or lithium for achieving efficient and stable lithium plating-stripping cycles in a carbonate-based electrolyte. Operando analyses and theoretical simulation reveal the remarkable ability of the ionomer coating to enable electric field homogenization over a considerably large lithium-plating surface. The membrane coating, serving as an artificial solid-electrolyte interphase filter in minimizing parasitic reactions at the electrolyte-electrode interface, enables dendrite-free lithium plating on copper with outstanding coulombic efficiencies at room and elevated (50 °C) temperatures. The membrane coated copper demonstrates itself as a promising current collector for manufacturing high-quality pre-plated lithium thin-film anode.
Optical second harmonic generation (SHG) is known as a sensitive probe to the crystalline symmetry of few-layer transition metal dichalcogenides (TMDs). Layer-number dependent and polarization ...resolved SHG have been observed for the special case of Bernal stacked few-layer TMDs, but it remains largely unexplored for structures deviated from this ideal stacking order. Here we report on the SHG from homo- and heterostructural TMD bilayers formed by artificial stacking with an arbitrary stacking angle. The SHG from the twisted bilayers is a coherent superposition of the SH fields from the individual layers, with a phase difference depending on the stacking angle. Such an interference effect is insensitive to the constituent layered materials and thus applicable to hetero-stacked bilayers. A proof-of-concept demonstration of using the SHG to probe the domain boundary and crystal polarity of mirror twins formed in chemically grown TMDs is also presented. We show here that the SHG is an efficient, sensitive, and nondestructive characterization for the stacking orientation, crystal polarity, and domain boundary of van der Waals heterostructures made of noncentrosymmetric layered materials.
Key message
Transformation of
MruGSTU39
in
M
.
ruthenica
and alfalfa enhanced growth and survival of transgenic plants by up-regulating GST and glutathione peroxidase activity to detoxify ROS under ...drought stress.
Glutathione S-transferases (GSTs) are ubiquitous supergene family which play crucial roles in detoxification of reactive oxygen species (ROS). Despite studies on GSTs, few studies have focused on them in perennial, wild plant species with high tolerance to environmental stress. Here, we identified 66
MruGST
genes from the genome of
Medicago ruthenica
, a perennial legume species native to temperate grasslands with high tolerance to environmental stress. These genes were divided into eight classes based on their conserved domains, phylogenetic tree and gene structure, with the tau class being the most numerous. Duplication analysis revealed that
GST
family in
M
.
ruthenica
was expanded by segmental and tandem duplication. Several drought-responsive
MruGSTs
were identified by transcriptomic analyses. Of them, expression of
MruGSTU39
was up-regulated much more in a tolerant accession by drought stress. Transformation of
MruGSTU39
in
M
.
ruthenica
and alfalfa (
Medicago sativa
) enhanced growth and survival of transgenic seedlings than their wild-type counterparts under drought. We demonstrated that MruGSTU39 can detoxify ROS to reduce its damage to membrane by up-regulating activities of GST and glutathione peroxidase. Our findings provide full-scale knowledge on
GST
family in the wild legume
M
.
ruthenica
with high tolerance to drought, and highlight improvement tolerance of legume forages to drought using genomic information of
M
.
ruthenica
.
Abstract
Background
Doublecortin-like kinase 1 (DCLK1) has been recognized as a marker of cancer stem cell in several malignancies. Thrombin is crucial in asthma severity as it can promote IL-8/CXCL8 ...production in lung epithelial cells, which is a potent chemoattractant for neutrophils. However, the pathologic role of DCLK1 in asthma and its involvement in thrombin-stimulated IL-8/CXCL8 expression remain unknown.
Methods
IL-8/CXCL8, thrombin, and DCLK1 expression were observed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. A549 and BEAS-2B cells were either pretreated with inhibitors or small interfering RNAs (siRNAs) before being treated with thrombin. IL-8/CXCL8 expression and the molecules involved in signaling pathway were performed using ELISA, luciferase activity assay, Western blot, or ChIP assay.
Results
IL-8/CXCL8, thrombin, and DCLK1 were overexpressed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. Our in vitro study found that DCLK siRNA or LRKK2-IN-1 (DCLK1 inhibitor) attenuated IL-8/CXCL8 release after thrombin induction in A549 and BEAS-2B cells. Thrombin activated DCLK1, RhoA, and YAP in a time-dependent manner, in which DCLK1 siRNA inhibited RhoA and YAP activation. YAP was dephosphorylated on the Ser127 site after thrombin stimulation, resulting in YAP translocation to the nucleus from the cytosol. DCLK1, RhoA and YAP activation following thrombin stimulation were inhibited by U0126 (ERK inhibitor). Moreover, DCLK1 and YAP siRNA inhibited κB-luciferase activity. Thrombin stimulated the recruitment of YAP and p65 to the NF-κB site of the IL-8/CXCL8 promoter and was inhibited by DCLK1 siRNA.
Conclusions
Thrombin activates the DCLK1/RhoA signaling pathway, which promotes YAP activation and translocation to the nucleus from the cytosol, resulting in YAP/p65 formation, and binding to the NF-κB site, which enhances IL-8/CXCL8 expression. DCLK1 might be essential in thrombin-stimulated IL-8/CXCL8 expression in asthmatic lungs and indicates a potential therapeutic strategy for severe asthma treatment.
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in ...cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
Display omitted
•Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect
Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies.
Background and Aims
Hepatic ischemia‐reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function ...after hepatic I/R injury are limited. Six‐transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R‐induced liver damage remains largely unclear.
Approach and Results
In the present study, we found that Steap3 expression was significantly up‐regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3‐KO) mice, hepatocyte‐specific Steap3 transgenic (Steap3‐HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3‐KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3‐HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor‐β–activated kinase 1 (TAK1) activation and downstream c‐Jun N‐terminal kinase (JNK) and p38 signaling during hepatic I/R injury.
Conclusions
Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1‐dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.
To understand the functions of transcription factor OsNAC5 in response to abiotic stress, we generated transgenic rice plants with knockdown OsNAC5 by RNA-interfered (RNAi) and overexpressing OsNAC5, ...and investigated the effects of cold, drought and salt stress on wild-type (WT), RNAi and overexpression rice lines. Our results demonstrated that RNAi lines became less tolerant to these stresses than WT plants, while overexpression of OsNAC5 in Arabidopsis and rice enhanced tolerance to these stresses. The mechanisms underlying the changes in tolerance of the transgenic rice plants to abiotic stresses were explored by measuring free proline (Pro) and soluble sugar contents in WT and transgenic plants. Accumulation of Pro and soluble sugars was positively correlated with OsNAC5 expression levels. The less accumulation of Pro in RNAi lines may be accounted for by inhibition of Pro synthesis and transport at transcriptional levels. In addition, knockdown and overexpression of OsNAC5 enhanced and reduced accumulation of malondialdehyde and H2O2, suggesting that knockdown of OsNAC5 renders RNAi plants more susceptible to oxidative damage. The RNAi lines displayed higher Na+/K+ ratio due to greater accumulation of Na+ ions than WT under salt stress conditions, and expression of genes encoding tonoplast Na+/H+ antiporter was lower in RNAi lines than in WT under both control and salt-stressed conditions. Seed germination of RNAi and overexpression plants was more and less inhibited by salt and mannitol than that of WT, respectively. Seed germination of overexpression and RNAi plants was more and less sensitive than that of WT to ABA. These findings highlight the important role of OsNAC5 played in the tolerance of rice plants to abiotic stress by regulating downstream targets associated with accumulation of compatible solutes, Na+ ions, H2O2 and malondialdehyde.
PDF
