The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively ...active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or ...upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
Our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The intrinsic neural networks of the gastrointestinal tract are derived from dedicated neural crest progenitors that colonize the gut during embryogenesis and give rise to enteric neurons and glia. ...Here, we study how an essential subpopulation of enteric glial cells (EGCs) residing within the intestinal mucosa is integrated into the dynamic microenvironment of the alimentary tract. We find that under normal conditions colonization of the lamina propria by glial cells commences during early postnatal stages but reaches steady-state levels after weaning. By employing genetic lineage tracing, we provide evidence that in adult mice the network of mucosal EGCs is continuously renewed by incoming glial cells originating in the plexi of the gut wall. Finally, we demonstrate that both the initial colonization and homeostasis of glial cells in the intestinal mucosa are regulated by the indigenous gut microbiota.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
HLA-I molecules bind short peptides and present them for recognition by CD8
T cells. The length of HLA-I ligands typically ranges from 8 to 12 aa, but variability is observed across different HLA-I ...alleles. In this study we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples.
The commercial ceramic nanoparticle coated microporous polyolefin separators used in lithium batteries are still vulnerable under external impact, which may cause short circuits and consequently ...severe safety threats, because the protective ceramic nanoparticle coating layers on the separators are intrinsically brittle. Here, a nacre‐inspired coating on the separator to improve the impact tolerance of lithium batteries is reported. Instead of a random structured ceramic nanoparticle layer, ion‐conductive porous multilayers consisting of highly oriented aragonite platelets are coated on the separator. The nacre‐inspired coating can sustain external impact by turning the violent localized stress into lower and more uniform stress due to the platelet sliding. A lithium‐metal pouch cell using the aragonite platelet coated separator exhibits good cycling stability under external shock, which is in sharp contrast to the fast short circuit of a lithium‐metal pouch cell using a commercial ceramic nanoparticle coated separator.
A nacre‐inspired coating is fabricated to improve the impact tolerance of the separator in a lithium battery via efficient energy dissipation. Remarkably, the pouch cell using the nacre‐inspired porous aragonite platelet coated separator performs with much lower instantaneous open‐circuit voltage change and faster voltage recovery than the cell using the commercial ceramic nanoparticle coated separator under external impaction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Multi-attribute group decision making (MAGDM) problems widely exist in our daily life. In such problems, multiple decision makers (DMs) are involved and elicit their evaluations to assess a set of ...possible alternatives. Their complexity usually implies to deal with uncertain contexts and the use of linguistic preference modelling for the elicited assessments has been common. Linguistic distribution assessments (LDAs) applied to MAGDM, involving several linguistic terms associated with their symbolic proportions, have been effective to describe such assessments. However, to ensure a reasonable decision making result, the consistency of LDAs should be investigated and a corresponding MAGDM method proposed. This paper proposes a MAGDM method based on regret theory, not only to take the psychological behaviors of DMs into account, but also to reflect the consistency of assessments. Hence, the additive regret preference relation is firstly defined and then four algorithms are devised to improve the consistency of assessments. On this basis, two weighting determination models are built to calculate the weights of attributes and DMs respectively. Furthermore, alternatives can be ranked according to their overall synthetic values. The proposed MAGDM method is applied to an emergency assistance area selection problem and its result verifies the feasibility and effectiveness of the proposal.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system ...(CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The conversion of photocatalytic methane into methanol in high yield with selectivity remains a huge challenge due to unavoidable overoxidation. Here, the photocatalytic oxidation of CH
4
...into CH
3
OH by O
2
is carried out on Ag-decorated facet-dominated TiO
2
. The {001}-dominated TiO
2
shows a durable CH
3
OH yield of 4.8 mmol g
−1
h
−1
and a selectivity of approximately 80%, which represent much higher values than those reported in recent studies and are better than those obtained for {101}-dominated TiO
2
. Operando Fourier transform infrared spectroscopy, electron spin resonance, and nuclear magnetic resonance techniques are used to comprehensively clarify the underlying mechanism. The straightforward generation of oxygen vacancies on {001} by photoinduced holes plays a key role in avoiding the formation of •CH
3
and •OH, which are the main factors leading to overoxidation and are generally formed on the {101} facet. The generation of oxygen vacancies on {001} results in distinct intermediates and reaction pathways (oxygen vacancy → Ti–O
2
•
→ Ti–OO–Ti and Ti–(OO) → Ti–O
•
pairs), thus achieving high selectivity and yield for CH
4
photooxidation into CH
3
OH.
Abdominal compartment syndrome (ACS) in children is a neglected complication in the pediatric intensive care unit (PICU) because the onset is insidious. ACS develops rapidly, involves the systemic ...organs, has a high mortality, and is a very serious complication in PICU. Timely and effective treatment of children with suspected or confirmed ACS is of significance to prevent the progression of the disease, improve prognosis and reduce mortality. However, most clinicians have limited understanding of the treatment measures for children with ACS and are unable to correctly choose appropriate treatment strategies, which affect the prognosis of children. To make the optimal treatment plan for ACS in children, the extent of elevated intra-abdominal pressure, the degree of organ dysfunction and the underlying diseases should be considered comprehensively. Mechanical ventilation, continuous renal replacement therapy (CRRT), and extracorporeal membrane oxygenation (ECMO) have a bidirectional effect on the occurrence an
The side effects of cisplatin (CDDP), notably nephrotoxicity, greatly limited its use in clinical chemotherapy. HuangQi Injections (HI), a commonly used preparation of the well-known Chinese herbal ...medicine Astragali radix, appeared to be promising treatment for nephrotoxicity without compromising the anti-tumor activity of CDDP. In this study, the urinary metabolomics approach using liquid chromatography time of flight mass spectrometry (LC-TOF/MS) was developed to assess the toxicity-attenuation effects and corresponding mechanisms of HI on CDDP-exposed rats. As a result, successive administration of HI significantly recovered the decline of body weight and downregulated the abnormal increase of serum creatinine and urea. HI partly restored the CDDP-induced alteration of metabolic profiling back into normal condition. Totally 43 toxicity-attenuation potential biomarkers were screened and tentatively identified, which were involved in important metabolic pathways such as amino acid metabolism, TCA cycle, fatty acid metabolism, vitamin B6 metabolism and purine metabolism. The results clearly revealed that HI could alleviate CDDP-induced nephrotoxicity and improve the disturbed metabolic balance induced by repeated CDDP exposure. The present study provided reliable evidence for the protective effect of HI on CDDP-induced toxicity with the multi-target pharmacological characteristics.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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