Anisotropic composite aerogel with thermal insulation and flame retardancy from cellulose nanofibers, calcium alginate and boric acid.

With the increasing severity of energy shortages and environmental pollution, there is an urgent need for advanced thermal insulation materials with excellent comprehensive performance, including low thermal conductivity, high flame resistance, and strong compressive strength. Herein, an anisotropic composite aerogel based on cellulose nanofibers (CNF), calcium alginate (CA), and boric acid (BA) is fabricated using a directional freeze-drying strategy. The CA and BA, as double cross-linking agents, associated with oriented porous structure provide the resultant aerogel with good mechanical strength. Additionally, self-flame retardant CA and BA act as synergistic flame retardants that endow the aerogel with excellent flame retardance properties such as a limiting oxygen index value of 44.2 %, UL-94 V-0 rating, and low heat release. Furthermore, this composite aerogel exhibits outstanding thermal insulation performance with a low thermal conductivity of approximately 30 mW m-1 K-1. Therefore, the composite aerogel is expected to have a wide potential application in areas such as construction, automotive industry, batteries, petrochemical pipelines, and high-temperature reaction devices.

Environmental Controls on Evapotranspiration and Its Components in a Qinghai Spruce Forest in the Qilian Mountains.

Qinghai spruce forests, found in the Qilian mountains, are a typical type of water conservation forest and play an important role in regulating the regional water balance and quantifying the changes and controlling factors for evapotranspiration (ET) and its components, namely, transpiration (T), evaporation (Es) and canopy interceptions (Ei), of the Qinghai spruce, which may provide rich information for improving water resource management. In this study, we partitioned ET based on the assumption that total ET equals the sum of T, Es and Ei, and then we analyzed the environmental controls on ET, T and Es. The results show that, during the main growing seasons of the Qinghai spruce (from May to September) in the Qilian mountains, the total ET values were 353.7 and 325.1 mm in 2019 and 2020, respectively. The monthly dynamics in the daily variations in T/ET and Es/ET showed that T/ET increased until July and gradually decreased afterwards, while Es/ET showed opposite trends and was mainly controlled by the amount of precipitation. Among all the ET components, T always occupied the largest part, while the contribution of Es to ET was minimal. Meanwhile, Ei must be considered when partitioning ET, as it accounts for a certain percentage (greater than one-third) of the total ET values. Combining Pearson's correlation analysis and the boosted regression trees method, we concluded that net radiation (Rn), soil temperature (Ts) and soil water content (SWC) were the main controlling factors for ET. T was mainly determined by the radiation and soil hydrothermic factors (Rn, photosynthetic active radiation (PAR) and TS30), while Es was mostly controlled by the vapor pressure deficit (VPD), atmospheric precipitation (Pa), throughfall (Pt) and air temperature (Ta). Our study may provide further theoretical support to improve our understanding of the responses of ET and its components to surrounding environments.

[Retracted] LncRNA GAS6 antisense RNA 1 facilitates the tumorigenesis of clear cell renal cell carcinoma by regulating the AMP­activated protein kinase/mTOR signaling pathway.

[This retracts the article DOI: 10.3892/ol.2021.12988.].

Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.

Intracranial infection accompanied sweet's syndrome in a patient with anti-interferon-γ autoantibodies: A case report.

BACKGROUND: Several reports of adult-onset immunodeficiency syndrome have been associated with anti-interferon-gamma (IFN-γ) autoantibodies (AIGAs). However, it is rare to find AIGAs with intracranial infections. CASE SUMMARY: In this case study, we report a case of an AIGAs with intracranial infection and hand rashes considered Sweet's syndrome. The patient presented to our hospital with a persistent cough, a fever that had been going on for 6 mo, and a rash that had been going on for a week. The patient started losing consciousness gradually on the fourth day after admission, with neck stiffness and weakened limb muscles. The upper lobe of the left lung had a high-density mass with no atypia and a few inflammatory cells in the interstitium. Brain magnetic resonance imaging and cerebrospinal fluid suggest intracranial infection. The pathology of the skin damage on the right upper extremity revealed an infectious lesion that was susceptible to Sweet's disease. It has an anti-IFN-γ autoantibody titer of 1:2500. She was given empirical anti-non-tuberculous mycobacterial and antifungal treatments. The patient had no fever, obvious cough, headache, or rash on the hand. She got out of bed and took care of herself following hospitalization and discharge with medicine. CONCLUSION: Adults with severe and recurrent infections of several organs should be considered for AIGAs if no other known risk factors exist. AIGAs are susceptible to subsequent intracranial infections and Sweet's syndrome.

Program of algorithm for pharmacological treatment of major depressive disorder in China: Benefits or not?

Background: This research was designed to investigate Algorithm Guided Treatment (AGT) and clinical traits for the prediction of antidepressant treatment outcomes in Chinese patients with major depressive disorder (MDD). Methods: This study included 581 patients who had reached treatment response and 406 patients remained non-responded observed after three months of treatment. Sociodemographic factors, clinical traits, and psychiatric rating scales for evaluating therapeutic responses between the two groups were compared. Logistic regression analysis was adopted to determine the risk factors of unresponsive to antidepressant (URA) in MDD. Kaplan-Meier survival analysis was utilized to compare the therapeutic response between AGT and treatment as usual (TAU). Results: Compared to the MDD responsive to antidepressant (RA) group, the URA group had significantly lower rates of the following clinical traits: married status, anxious distress, moderate to severe depressive symptoms, and higher rates of comorbidity (p-value < 0.05). Logistic Regression Analysis showed that eight clinical traits from psychiatric rating scales, such as anxious characteristics, were correlated positively with URA, while the other eight symptoms, such as autonomic symptoms, were negatively correlated. Time to symptomatic remission was longer in TAU without statistically significant (p-value = 0.11) by log-rank testing. Conclusions: The factors may affect the therapeutic responses and compliance of patients, increasing the non-response risk for antidepressants. Therapeutic responses might be improved by increasing the clarification and elucidation of different symptom clusters of patients. Benefits on treatment response to AGT were not found in our study, indicating a one-size-fits-all approach may not work.Trial Registration: We registered as a clinical trial at the International Clinical Trials Registry Platform (No. NCT01764867) and obtained ethical approval 2012-42 from SMHC.

Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

A novel risk variant block across introns 36-45 of CACNA1C for schizophrenia: a cohort-wise replication and cerebral region-wide validation study.

OBJECTIVES: Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. METHODS: We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. RESULTS: A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 × 10-4 ≤ P ≤ 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 × 10-3 ≤ P ≤ 0.050), GMVs of subcortical structures (0.016 ≤ P ≤ 0.048), cortical surface areas (0.010 ≤ P ≤ 0.050), and thickness (0.004 ≤ P ≤ 0.050) in multiple brain regions. CONCLUSION: We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia.

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

Estimating canopy stomatal conductance and photosynthesis in apple trees by upscaling parameters from the leaf scale to the canopy scale in Jinzhong Basin on Loess Plateau.

The estimations of stomatal conductance and photosynthesis performed by upscaling the parameters from the leaf scale to the canopy scale are key points in the fields of forest ecohydrology and physiology. The foundation for solving this scientific problem is determining the optimal models for calculating the leaf stomatal conductance (gl) and photosynthetic rate (Pl). In this study, we used the Jarvis model combined with modification factors, including leaf-air temperature (ΔT) and CO2 concentration inside and outside the stomata (ΔC), to estimate gl and the new Ye light-response model to estimate the Pl of apple trees in Jinzhong Basin on Loess Plateau. The results show that the modified Jarvis (JarvisΔT-ΔC) model and the new Ye light-response model could estimate gl and Pl, respectively, with very high accuracy, with R2 values of 0.926 and 0.959 for the former, and 0.987 and 0.983 for the latter in 2019 and 2021, respectively. Then, we estimated the canopy stomatal conductance (gc) and photosynthetic rate (Pc) by first dividing the apple tree canopy into sunlit and shaded leaves and then summing the contribution of sunlit and shaded gl, Pl and leaf area index. Our efforts will be a valid reference for estimating the gc and Pc of other tree or crop species in the future.

Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling.

High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide both in vitro and in vivo evidence that excessive ß-adrenergic stimulation induces ferroptosis in cardiomyocytes, revealing a novel mechanism for catecholamine-induced cardiotoxicity and remodeling. We found that isoproterenol, a synthetic catecholamine, promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to GPX4 inactivation and enhanced lipid peroxidation. Isoproterenol also promoted heme oxygenase 1 (HO-1) expression by downregulating the transcription suppressor BTB and CNC homology 1 (Bach1), leading to increased labile iron accumulation through heme degradation. Moreover, isoproterenol markedly induced the accumulation of free iron and lipid reactive oxygen species (ROS) in the mitochondria, while targeted inhibition of iron overload and ROS accumulation within mitochondria effectively inhibited ferroptosis in cardiomyocytes. Importantly, isoproterenol administration markedly induced ferroptosis in the myocardium in vivo, associated with elevated non-heme iron accumulation driven by HO-1 upregulation. Strikingly, blockade of ferroptosis with ferrostatin-1 or inhibition of HO-1 activity with zinc protoporphyrin (ZnPP) effectively alleviated cardiac necrosis, pathological remodeling, and heart failure induced by isoproterenol administration. Taken together, our results reveal that catecholamine stimulation primarily induces ferroptotic cell death in cardiomyocyte through GPX4 and Bach1-HO-1 dependent signaling pathways. Targeting ferroptosis may represent a novel therapeutic strategy for catecholamine overload-induced myocardial injury and heart failure.

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders.

BACKGROUND: Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. METHOD: A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. RESULTS: Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10-4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson's disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson's disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10-3 and q < 0.05). CONCLUSION: Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.

Association of lesion location with post-stroke depression in China: a systematic review and meta-analysis.

Background: Post-stroke depression (PSD) is a mental health condition that can develop after a stroke, with a higher risk of death and negative outcomes. However, limited research has explored how PSD incidence relates to brain locations in Chinese patients. This study aims to fill this gap by examining the link between PSD occurrence and brain lesion location, as well as the type of stroke experienced by the patient. Methods: We conducted a systematic search in databases to gather post-stroke depression literature published between January 1, 2015 and May 31, 2021. Following this, we performed a meta-analysis using RevMan to analyze the incidence of PSD associated with different brain regions and types of stroke separately. Results: We analyzed seven studies, with a total of 1604 participants. Our findings indicated that the incidence of PSD was higher when the stroke occurred in the left hemisphere compared to the right hemisphere (RevMan: Z = 8.93, P <0.001, OR = 2.69, 95% CI: 2.16-3.34, fixed model); PSD was more common when the stroke affected the cerebral cortex rather than the subcerebral cortex (RevMan: Z = 3.96, P <0.001, OR = 2.00, 95% CI: 1.42-2.81) and when it affected the anterior cortex compared to the posterior cortex (RevMan: Z = 3.85, P <0.001, OR = 1.89, 95% CI: 1.37-2.62). However, we did not find a significant difference in the occurrence of PSD between ischemic and hemorrhagic strokes (RevMan: Z = 0.62, P = 0.53, OR = 0.02, 95% CI: -0.05-0.09). Conclusions: Our findings revealed a higher likelihood of PSD in the left hemisphere, specifically in the cerebral cortex and anterior region.

Impairment of ß-adrenergic regulation and exacerbation of pressure-induced heart failure in mice with mutations in phosphoregulatory sites in the cardiac CaV1.2 calcium channel.

The cardiac calcium channel CaV1.2 conducts L-type calcium currents that initiate excitation-contraction coupling and serves as a crucial mediator of ß-adrenergic regulation of the heart. We evaluated the inotropic response of mice with mutations in C-terminal phosphoregulatory sites under physiological levels of ß-adrenergic stimulation in vivo, and we assessed the impact of combining mutations of C-terminal phosphoregulatory sites with chronic pressure-overload stress. Mice with Ser1700Ala (S1700A), Ser1700Ala/Thr1704Ala (STAA), and Ser1928Ala (S1928A) mutations had impaired baseline regulation of ventricular contractility and exhibited decreased inotropic response to low doses of ß-adrenergic agonist. In contrast, treatment with supraphysiogical doses of agonist revealed substantial inotropic reserve that compensated for these deficits. Hypertrophy and heart failure in response to transverse aortic constriction (TAC) were exacerbated in S1700A, STAA, and S1928A mice whose ß-adrenergic regulation of CaV1.2 channels was blunted. These findings further elucidate the role of phosphorylation of CaV1.2 at regulatory sites in the C-terminal domain for maintaining normal cardiac homeostasis, responding to physiological levels of ß-adrenergic stimulation in the fight-or-flight response, and adapting to pressure-overload stress.

Comparison on the clinical features in patients with or without treatment-resistant depression: A National Survey on Symptomatology of Depression report.

Patients with treatment-resistant depression (TRD) have fewer treatment options and worse prognoses than those without TRD. Although the etiology or pathophysiology of TRD remains unclear, certain clinical variables have been found to be related to its severity and prognosis. Therefore, 1151 patients with recurrent depression were recruited from the National Survey on Symptomatology of Depression (NSSD) and their depressive symptoms were assessed by using the doctor-rating assessment questionnaire. Then, the differences between patients with or without TRD were compared by parametric or nonparametric tests and the risk factors for TRD were explored by logistic regression. The results showed there were differences in clinical variables between patients with and without TRD. Additionally, we found depression with more somatic symptoms had a higher risk for TRD. Further analysis by stepwise logistic regression showed that age, gender, religious belief, drinking habit, the total course of depression, the number of hospitalizations, characteristics of seasonal episode remission, depressed mood, hypersexuality, emotionally incoherent psychotic symptoms, psychomotor agitation, respiratory system symptoms and history of suicide attempts were strongly associated with TRD. So, it is crucial for clinicians to identify these clinical features and adjust treatments timely.

Chronic restraint stress-induced depression-like behavior is mediated by upregulation of melanopsin expression in C57BL/6 mice retina.

BACKGROUND: Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin. METHODS: Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs. RESULTS: The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid. CONCLUSIONS: CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice.

Inhibition of lncRNA NEAT1 induces dysfunction of fibroblast-like synoviocytes in rheumatoid arthritis via miRNA-338-3p-mediated regulation of glutamine metabolism.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease; cellular glutamine metabolism in fibroblast-like synoviocytes (FLSs) of RA was known to be essential for RA pathogenesis and progression. NEAT1, a long non-coding RNA, functions as an oncogene in diverse cancers. The exact roles and molecular mechanisms of NEAT1 in fibroblast-like synoviocytes (FLSs) of RA patients are unknown. METHODS: Expression of NEAT1 and miR-338-3p was measured by qRT-PCR. lncRNA-miRNA and miRNA-mRNA interactions were predicted from starBase and validated by RNA pull-down and luciferase assay. The glutamine metabolism of FLSs was evaluated by glutamine uptake and glutaminase activity. Cell death in FLSs in response to H2O2 was assessed by MTT and Annexin V assays. RESULTS: NEAT1 was significantly upregulated, and miR-338-3p was significantly downregulated in FLSs from RA patients compared to normal FLSs. Silencing of NEAT1 and overexpression of miR-338-3p suppressed glutamine metabolism in FLSs-RA and promoted H2O2-induced apoptosis. Bioinformatics analysis showed that NEAT1 sponges miR-338-3p to form competing endogenous RNA (ceRNAs), which was verified by RNA pull-down assay and luciferase assay FLSs-RA had an increased rate of glutamine metabolism compared to normal FLSs increased compared to normal FLSs. The results confirmed that GLS (Glutaminase), a key enzyme in glutamine metabolism, is a direct target of miR-338-3p in FLSs-RA. miR-338-3p inhibition of glutamine metabolism was verified by rescue experiments verified. Finally, restoration of miR-338-3p in FLSs-RA expressing NEAT1 overcomes NEAT1-promoted glutamine metabolism and resistance to apoptosis. CONCLUSIONS: This study reveals the essential role and molecular targets of NEAT1-regulated glutamine metabolism and FLSs-RA dysfunction in fibroblast-like synoviocytes of RA and indicates that blocking the molecular pathway via non-coding RNAs may be beneficial for RA patients.

Facile high-quantum-yield sulfur-quantum-dot-based photoluminescent probe for nifedipine detection.

Monitoring of dihydropyridine drugs, such as nifedipine (NIF), has attracted considerable attention owing to the side effects arising from the consumption of such drugs. Herein, a highly sensitive and facile fluorescence-sensing platform based on a high-quantum-yield sulfur quantum dot (SQDs) probe for NIF detection is proposed. Based on the principle of the inner filter effect, the rapid detection of NIF with high sensitivity is successfully realized on the basis of the change in the fluorescence signal due to the quenching effect of NIF on SQDs. The results show a good linear relationship between the NIF concentration and fluorescence intensity within the range of 5-150 µmol/L, with a low detection limit of 1.63 µmol/L (S/N = 3). Moreover, because no surface modification or establishment of any coupling between the receptor and the fluorophore is necessary, this approach provides considerable flexibility and simplicity for the construction of a fluorescence sensor and substantially reduces the detection time. A systematic investigation was conducted to verify the applicability of this method for the analysis of pharmaceutical components in NIF tablets. This study not only promotes the design and development of a fluorescence analysis platform for NIF detection, but also facilitates the fabrication of novel SQD-based fluorescence-sensing systems for the molecular detection of drugs. Proposal for a facile nifedipine assay method based on the inner filter effect of nifedipine to high-quantum-yield sulfur quantum dots, and realizing nifedipine detection in tablets and human urine samples.

Sex-different interrelationships of rs945270, cerebral gray matter volumes, and attention deficit hyperactivity disorder: a region-wide study across brain.

Previous genome-wide association studies (GWAS) reported that the allele C of rs945270 of the kinectin 1 gene (KTN1) most significantly increased the gray matter volume (GMV) of the putamen and modestly regulated the risk for attention deficit hyperactivity disorder (ADHD). On the other hand, ADHD is known to be associated with a reduction in subcortical and cortical GMVs. Here, we examined the interrelationships of the GMVs, rs945270 alleles, and ADHD symptom scores in the same cohort of children. With data of rs945270 genotypes, GMVs of 118 brain regions, and ADHD symptom scores of 3372 boys and 3129 girls of the Adolescent Brain Cognition Development project, we employed linear regression analyses to examine the pairwise correlations adjusted for the third of the three traits and other relevant covariates, and examine their mediation effects. We found that the major allele C of rs945270 modestly increased risk for ADHD in males only when controlling for the confounding effects of the GMV of any one of the 118 cerebral regions (0.026 ≤ p ≤ 0.059: Top two: left and right putamen). This allele also significantly increased putamen GMV in males alone (left p = 2.8 × 10-5, and right p = 9.4 × 10-5; α = 2.1 × 10-4) and modestly increased other subcortical and cortical GMVs in both sexes (α < p < 0.05), whether or not adjusted for ADHD symptom scores. Both subcortical and cortical GMVs were significantly or suggestively reduced in ADHD when adjusted for rs945270 alleles, each more significantly in females (3.6 × 10-7 ≤ p < α; Top two: left pallidum and putamen) and males (3.5 × 10-6 ≤ p < α), respectively. Finally, the left and right putamen GMVs reduced 14.0% and 11.7% of the risk effects of allele C on ADHD, and allele C strengthened 4.5% (left) and 12.2% (right) of the protective effects of putamen GMVs on ADHD risk, respectively. We concluded that the rs945270-GMVs-ADHD relationships were sex-different. In males, the major allele C of rs945270 increased risk for ADHD, which was compromised by putamen GMVs; this allele also but only significantly increased putamen GMVs that then significantly protected against ADHD risk. In females, the top two GMVs significantly decreasing ADHD risk were left pallidum and putamen GMVs. Basal ganglia the left putamen in particular play the most critical role in the pathogenesis of ADHD.

Metabolic and Transcriptomic Analyses Reveal the Effects of Ethephon on Taraxacum kok-saghyz Rodin.

The roots of Taraxacum kok-saghyz Rodin (TKS) are well-known and valued for their rubber-producing ability. Therefore, research on the analysis and detection of metabolites from the roots of TKS have been reported in previous studies. However, all of these studies have the shortcoming of focusing on only the rubber of TKS, without profiling the other metabolites in a systematic and comprehensive way. Here, the primary and secondary metabolites from the leaves of TKS were investigated using UPLC-ESI-MS/MS, and a total of 229 metabolites were characterized. Carboxylic acid derivatives, fatty acyls, phenols, and organooxygen compounds were found to be the major metabolites of TKS. The transcriptome data indicated that ribosomal, glycolysis/gluconeogenesis, phenylpropanoid biosynthesis, and linoleic acid metabolism genes were significantly differentially expressed. This study is the first to report the differences in the metabolic and transcriptome profiles of TKS leaves under exogenous ethephon spray, which improves our understanding of the main metabolites and their molecular mechanisms in TKS leaves.