NLRP3 licenses NLRP11 for inflammasome activation in human macrophages.

Intracellular sensing of stress and danger signals initiates inflammatory innate immune responses by triggering inflammasome assembly, caspase-1 activation and pyroptotic cell death as well as the release of interleukin 1ß (IL-1ß), IL-18 and danger signals. NLRP3 broadly senses infectious patterns and sterile danger signals, resulting in the tightly coordinated and regulated assembly of the NLRP3 inflammasome, but the precise mechanisms are incompletely understood. Here, we identified NLRP11 as an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacted with NLRP3 and ASC, and deletion of NLRP11 specifically prevented NLRP3 inflammasome activation by preventing inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis and cytokine release but did not affect other inflammasomes. Restored expression of NLRP11, but not NLRP11 lacking the PYRIN domain (PYD), restored inflammasome activation. NLRP11 was also necessary for inflammasome responses driven by NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS). Because NLRP11 is not expressed in mice, our observations emphasize the specific complexity of inflammasome regulation in humans.

ADAR1 mutation causes ZBP1-dependent immunopathology.

The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.

Analysis and Regulatory Mechanisms of Platelet-Related Genes in Patients with Ischemic Stroke.

It was found that ischemic stroke (IS) was associated with abnormal platelet activity and thrombosis. However, the potential significance of platelet-related genes (PRGs) in IS still needs to be more thorough. This study extracted IS-related transcriptome datasets from the Gene Expression Omnibus (GEO) database. The target genes were obtained by intersecting the differentially expressed genes (DEGs), the module genes related to IS, and PRGs, where the key genes of IS were screened by two machine learning algorithms. The key genes-based diagnostic model was constructed. Gene set enrichment analysis (GSEA) and the immune microenvironment analyses were analyzed targeting key genes in IS. The co-expression, TF-mRNA, and competitive endogenous RNAs (ceRNA) regulatory networks were constructed to reveal the potential regulation of key genes. Potential drugs targeting key genes were predicted as well. Totals of eight target genes were obtained and were associated with immune-related functions. Four platelet-related key genes were acquired, which were related to immunity and energy metabolism. The abnormal expressions of DOCK8, GIMAP5, ICOS were determined by the quantitative real-time polymerase chain reaction (qRT-PCR), and the significant correlations among these key genes were identified. Notably, hsa-miR-17-3p, hsa-miR-3158-3p, hsa-miR-423-3p, and hsa-miR-193a-8p could regulate all key genes at the same time. In addition, Caffeine, Carboplatin, and Vopratelimab were the targeted drugs of these key genes. This study identified four platelet-related key genes of IS, which might help to deepen the understanding of the role of platelet-related genes in the molecular mechanism of IS.

A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Vitamin D levels and olfactory dysfunction in multiple sclerosis patients.

OBJECTIVE: The objective was to explore the possible relationship between the serum vitamin D level and olfactory impairment in a population of multiple sclerosis (MS) patients in Guizhou, China. METHODS: We included 25 patients with MS and 18 healthy controls (HCs) who were recruited from the Affiliated Hospital of Guizhou Medical University from February 2021 to September 2021. The University of Pennsylvania Smell Identification Test (UPSIT) was used to test the patients' sense of smell, and the level of serum 25-hydroxyethylene polyprotein D was measured. RESULTS: Serum vitamin D levels and UPSIT scores were significantly different between the MS group and the control group (both p < 0.001). Moreover, a significant positive correlation emerged between vitamin D levels and UPSIT scores in MS patients (r = 0.537, p = 0.021). CONCLUSIONS: The serum vitamin D level may be involved in the regulation of olfactory dysfunction in MS patients in Guizhou, China.

Multiple sclerosis is a rare disease in China.Compared with that of healthy controls, the olfactory function of MS patients was severely impaired.Compared with healthy controls, MS patients had low vitamin D levels.A significant positive correlation emerged between vitamin D levels and UPSIT scores in MS patients.The vitamin D levels of MS patients may be associated with olfactory impairment, which may have implications for future mechanistic studies.

Natural resources-environmental technology-ecological footprint nexus: Does natural resources rents diversification make a difference?

Researchers have shown a growing interest in investigating the environmental consequences of energy exploitation and green technologies, particularly in light of the escalating severity of climate change issues in recent times. However, these researches remain incomplete in terms of the various elements and mechanisms of impact. By assessing the novel facet of resource diversification, this study has assessed the direct and indirect effects of this feature on environmental quality. This study used the Moment quantile Regression technique to examine data from 31 OECD nations spanning the time frame of 2009-2019. The findings indicate that resource diversification has an adverse effect on environmental quality, however this effect is not homogeneously observed across all countries. Countries with favorable environmental conditions will encounter a more pronounced influence from the diversification of natural resources extraction. This study further demonstrates that expanding the variety of natural resource exploitation will amplify the negative effects of resource exploitation on environmental quality. Furthermore, the degree of environmental technology exerts a beneficial impact on environmental quality across various degrees of environmental quality. Our findings offer several insightful policies for natural resources management in the context of the ongoing industrial revolution.

The influence of shadow economy, environmental policies and geopolitical risk on renewable energy: A comparison of high- and middle-income countries.

Given the alarming rate of climate change and environmental degradation, major countries are seeking ways to curtail environmental damage and attain sustainability in the future. In the quest for a green economy, countries are motivated to adopt renewable energy that can assist in resource conservation and efficiency. Accordingly, this study examines the diverse effects of the underground economy, environmental policy strictness, geopolitical risk, gross domestic product, carbon emissions, population, and oil prices on renewable energy for 30 high- and middle-income countries from 1990 to 2018. The empirical outcomes based on quantile regression document significant variations across two country groups. For instance, for high-income countries, the shadow economy has a detrimental effect across all quantiles but it is statistically significant at the top quantiles. Nonetheless, the effect of the shadow economy on renewable energy is detrimental and significant statistically across all quantiles for middle-income countries. In the context of environmental policy stringency, the effect is positive across both country groups, though there is heterogeneity in outcomes. Geopolitical risk has a positive influence on the deployment of renewable energy for high-income countries but negatively impacts renewables for middle-income countries. As far as policy suggestions are concerned, the policymakers of both high- and middle-income countries need to take steps to constrain the growth of the shadow economy by adopting effective policy strategies. Policies need to be implemented for middle income-countries to reduce the unfavorable effect of geopolitical uncertainty. The findings of this study contribute to a better and more precise understanding of factors shaping the role of renewables whereby the energy crisis would be mitigated.

Lactobacillus plantarum-derived extracellular vesicles protect against ischemic brain injury via the microRNA-101a-3p/c-Fos/TGF-ß axis.

Currently, the reported source of extracellular vesicles (EVs) for the treatment of ischemic stroke（IS）is limited to mammals. Moreover, these EVs are restricted to clinical translation by the high cost of cell culture. In this respect, Lactobacillus plantarum culture is advantaged by low cost and high yield. However, it is poorly understood whether Lactobacillus plantarum-derived EVs (LEVs) are applicable for the treatment of IS. Here, our results demonstrated that LEVs reduced apoptosis in ischemic neuron both in vivo and in vitro. As revealed by high-throughput sequencing, miR-101a-3p expression was significantly elevated by LEV treatment in OGD/R-induced neurons, as confirmed in the tMCAO mice treated with LEVs. Mechanistically, c-Fos was directly targeted by miR-101a-3p. In addition, c-Fos determined ischemia-induced neuron apoptosis in vivo and in vitro through the TGF-ß1 pathway, miR-101a-3p inhibition aggravated ischemia-induced neuron apoptosis in vitro and in vivo, and miR-101a-3p overexpression produced the opposite results. Hsa-miR-101-3p was downregulated in the plasma of patients with IS but upregulated in the patients with neurological recovery after rt-PA intravenous thrombolysis. In conclusion, Our results demonstrated for the first time that LEVs might inhibit neuron apoptosis via the miR-101a-3p/c-Fos/TGF-ß axis, and has-miR-101-3p is a potential marker of neurological recovery in IS patients.

Critical issues concerning the assessment sets in agreement assessment.

Since Bland and Altman's pioneering work, the assessment set has been an important constituent of agreement assessment. This article explores critical issues concerning the assessment set. First, we point out the fundamental differences between assessment approaches based on point estimation and those based on hypothesis testing related to the assessment set, and further present how the related disciplines choose between the two. Second, we argue that an assessment set with minimum volume should be preferred, as in the comparison of confidence intervals. Finally, we discuss assessment sets for the assessment of multiple methods, and propose two methods for the construction of assessment sets. Numerical examples further establish the applicability of these approaches.

Plasma-promoted reactions of the heterobimetallic anions CuNb- with dinitrogen and subsequent reactions with carbon dioxide: formation of C-N bonds.

The activation and functionalization of dinitrogen with carbon dioxide into useful chemicals containing C-N bonds are significant research projects but highly challenging. Herein, we report that N2 molecules are dissociated by heterobimetallic CuNb- anions assisted by surface plasma radiation, leading to the formation of CuNbN2- anions; the CuNbN2- anions can further react with CO2 to generate products NCO- with one C-N bond and NbO2NCN- with two C-N bonds under thermal collision conditions. For the activation of dinitrogen, the plasma atmosphere is conducive to the dissociation of the NN bond, which renders the coupling reactions of N2 and CO2 molecules easier to proceed. This is the first report of coupling of N2 and CO2 to generate C-N bonds by making good use of the plasma effect to assist in the activation of N2 molecules. This new strategy with the assistance of plasma provides a practicable route to construct C-N bonds by directly using N2 and CO2 at room temperature.

Parametric and nonparametric improvements in Bland and Altman's assessment of agreement method.

The Bland-Altman method, which assesses agreement via an assessment set constructed by the difference of the measurement variables, has received great attention. Other assessment approaches have been proposed following the same difference-based framework. However, the exact assessment set constructed by the difference is achievable only for measurements with certain joint distributions. To provide a more general assessment framework, we propose two approaches. First, when the measurement distribution is known, we propose a parametric approach that constructs the assessment set through a measure of closeness corresponding to the distribution. Second, when the measurement distribution is unknown, we propose a nonparametric approach that constructs the assessment set through quantile regression. Both approaches quantify the degree of agreement with the presence of both systematic and random measurement errors, and enable one to go beyond the difference-based approach. Results of simulation and data analyses are presented to compare the two approaches.

Conversion of carbon dioxide to a novel molecule NCNBO- mediated by NbBN2- anions at room temperature.

The activation of carbon dioxide (CO2) mediated by NbBN2- cluster anions under the conditions of thermal collision has been investigated by time-of-flight mass spectrometry combined with density functional theory calculations. Two CO double bonds in the CO2 molecule are completely broken and two C-N bonds are further generated to form the novel molecule NCNBO-. To the best of our knowledge, this new molecule is synthesized and reported for the first time. In addition, one oxygen atom transfer channel produces another product, NbBN2O-. Both of the Nb and B atoms in NbBN2- donate electrons to reduce CO2, and the carbon atom originating from CO2 serves as an electron reservoir. The reaction of NbB- with N2 was also investigated theoretically, and the formation of NbBN2- from this reaction is thermodynamically and kinetically quite favorable, indicating that NCNBO- might be produced from the coupling of N2 and CO2 mediated by NbB- anions.

The complementarity of income equalization and innovation for more effective emission reduction.

This study examines the effects of income inequality and innovation on environmental quality, conditional on the level of each factor. We apply system generalized method of moments to a panel dataset of 91 countries from 1971 to 2015. The estimation results consistently reveal that although income inequality and innovation significantly contribute to better environmental quality, the effect of one factor largely depends on the evolution of the other. Specifically, the beneficial impact of income equality on environmental quality can only be achieved at a high level of innovation. In the same way, innovation is only an effective tool for a nation to reduce environmental degradation when income is fairly distributed among its citizens. This means that more equitable income distribution and higher innovative capacities are two interrelated prerequisites that must both be in place for a country to actualize their beneficial environmental impacts. Overall, our findings shed new light on the relationship between income inequality, innovation, and environmental quality, and they provide relevant implications for policymakers with regard to tackling the dual tasks of reducing inequality and pollution.

The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease.

INTRODUCTION: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. METHODS: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. RESULTS: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P < .001). DISCUSSION: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.

Alterations of white matter network in patients with left and right non-lesional temporal lobe epilepsy.

OBJECTIVES: The goal of this study was to investigate alterations of white matter (WM) network in patients with left non-lesional temporal lobe epilepsy (nl-TLE) and right nl-TLE to assess the relationship between the white matter network properties and clinical parameters. METHODS: T1 magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were acquired for 45 participants, including 30 nl-TLE patients (13 left, 17 right) and 15 healthy controls. Diffusion tensor tractography was computed to model the WM structural network. The topologic properties of the WM network were obtained by graph theoretical analysis, and the between-group differences in global and nodal properties of the WM network were examined by network-based statistical analysis (NBS). The relationship between WM network properties and clinical parameters was assessed by Pearson's correlation analysis. RESULTS: NBS results indicated that patients with left and right nl-TLE experienced distinct changes of WM nodal and global network properties compared with HCs. Positive correlation coefficients were found in several regions. The structural disruptions of networks in the two nl-TLE groups were observed to be different in distribution and severity. CONCLUSIONS: This study provides evidence for changes of the WM network topological properties and structural connectivity in nl-TLE patients, which provide useful insights for the understanding of disease mechanisms of TLE and improving treatment outcomes for nl-TLE. KEY POINTS: • This study aims to investigate alterations of white matter (WM) network in patients with non-lesional temporal lobe epilepsy (nl-TLE). • Network-based statistical analysis results indicated that patients with left and right nl-TLE experienced distinct changes of WM nodal and global network properties compared with healthy controls. • This study provides useful insights for the understanding of disease mechanisms of TLE and improving treatment outcomes for nl-TLE.

Mixed cerebrovascular disease in an elderly patient with mixed vascular risk factors: a case report.

BACKGROUND: Mixed cerebrovascular disease is a diagnostic entity that presents with hemorrhagic and ischemic stroke clinically and/or subclinically. Here, we report a patient with mixed vascular risk factors, who presented with multiple intracerebral hemorrhages and a simultaneously occurring cerebral infarction with hemorrhagic transformation. CASE PRESENTATION: A 63-year-old male with no history of trauma or prior neurological disease presented with a sudden onset of weakness in his right limbs, followed by an episode of focal seizure without impaired awareness. The patient had a 4-year history of deep vein thrombosis in the lower limbs, and a 2-year history of Raynaud's phenomenon in the hands. He also had a family history of hypertension and thrombophilia. Head computed tomography plain scans showed two high densities in the bilateral parietal lobes and one mixed density in the left frontal lobe. The patient was diagnosed with mixed cerebrovascular disease. In this report, we make a systematic clinical reasoning regarding the etiological diagnosis, and discuss the possible pathogenic mechanisms leading to mixed cerebrovascular disease. We exclude coagulopathy, endocarditis, atrial fibrillation, patent foramen ovale, brain tumor, cerebral venous thrombosis, cerebral vascular malformation, cerebral amyloid angiopathy and vasculitis as causative factors. We identify hypertension, hereditary protein S deficiency, hypercholesteremia and hyperhomocysteinemia as contributing etiologies in this case. CONCLUSION: This case presents complex underlying mechanisms of mixed cerebrovascular disease, in which hypertension and hyperhomocysteinemia are considered to play a central role.

Concordance between the assessment of Aß42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid.

INTRODUCTION: Neuronal-derived exosomal Aß42, T-tau, and P-T181-tau have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, no study has assessed the association of Aß42, T-tau, and P-T181-tau between exosomes and CSF. METHODS: This was a multicenter study with two-stage design. The subjects included 28 AD patients, 25 aMCI patients, and 29 controls in the discovery stage; the results of which were confirmed in the validation stage (73 AD, 71 aMCI, and 72 controls). RESULTS: The exosomal concentrations of Aß42, T-tau, and P-T181-tau in AD group were higher than those in aMCI and control groups (all P < .001). The level of each exosomal biomarker was highly correlated with that in CSF. DISCUSSION: This study verified the agreement between CSF and blood exosomal biomarkers and confirmed that exosomal Aß42, T-tau, and P-T181-tau have the same capacity as those in CSF for the diagnosis of AD and aMCI.

Inhibiting the inflammasome: one domain at a time.

Inflammasomes are protein complexes that promote the maturation and release of pro-inflammatory cytokines and danger signals as well as pyroptosis in response to infections and cellular stress. Inflammasomes consist of a sensor, an adapter, and the effector caspase-1, which interact through homotypic interactions of caspase recruitment domains (CARDs) or PYRIN domains (PYDs). Hence, decoy proteins encoding only a CARD or PYD, COPs and POPs, respectively, are assumed to inhibit inflammasome assembly. Sensors encoding a PYD belong to the families of NOD-like receptors containing a PYD (NLRPs) or AIM2-like receptors (ALRs), which interact with the PYD- and CARD-containing adapter ASC through homotypic PYD interactions. Subsequently, ASC undergoes PYD-dependent oligomerization, which promotes CARD-mediated interactions between ASC and caspase-1, resulting in caspase-1 activation. POPs are suggested to interfere with the interaction between NLRPs/ALRs and ASC to prevent nucleation of ASC and therefore prevent an oligomeric platform for caspase-1 activation. Similarly, COPs are suggested to bind to the CARD of caspase-1 to prevent its recruitment to the oligomeric ASC platform and its activation. Alternatively, the adapter ASC may regulate inflammasome activity by expressing different isoforms, which are either capable or incapable of assembling an oligomeric ASC platform. The molecular mechanism of inflammasome assembly has only recently been elucidated, but the effects of most COPs and POPs on inflammasome assembly have not been investigated. Here, we discuss our model of COP- and POP-mediated inflammasome regulation.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Glycyrrhizin inhibits LPS-induced inflammatory mediator production in endometrial epithelial cells.

Endometriosis is a continuous inflammation of uterine endometrium that usually affects women of reproductive age. Glycyrrhizin, a triterpene isolated from the roots and rhizomes of licorice (Glycyrrhiza glabra), has been known to have anti-inflammatory effect. The purpose of this study was to investigate the anti-inflammatory effect of glycyrrhizin on LPS-stimulated mouse endometrial epithelial cells (MEEC). The levels of TNF-α, IL-1ß, and PGE2 were measured by ELISA. The expression of COX-2, iNOS, TLR4, and NF-ĸB were detected by western blot analysis. The results showed that glycyrrhizin significantly suppressed LPS-induced TNF-α, IL-1ß, NO, and PGE2 production. Also, LPS-induced iNOS and COX-2 expression were attenuated by glycyrrhizin. Furthermore, glycyrrhizin significantly attenuated TLR4 expression and NF-κB activation induced by LPS in MEEC. In conclusion, the present study demonstrated that glycyrrhizin inhibited LPS-induced inflammatory response by inhibiting TLR4 signaling pathway in MEEC. Glycyrrhizin may be used as a potential agent for the treatment of endometriosis.