Plaat1l1 controls feeding induced NAPE biosynthesis and contributes to energy balance regulation in zebrafish.

Dysregulation of energy balance leading to obesity is a significant risk factor for cardiometabolic diseases such as diabetes, non-alcoholic fatty liver disease and atherosclerosis. In rodents and several other vertebrates, feeding has been shown to induce a rapid rise in the intestinal levels of N-acyl-ethanolamines (NAEs) and the chronic consumption of a high fat diet abolishes this rise. Administering NAEs to rodents consuming a high fat diet reduces their adiposity, in part by reducing food intake and enhancing fat oxidation, so that feeding-induced intestinal NAE biosynthesis appears to be critical to appropriate regulation of energy balance. However, the contribution of feeding-induced intestinal NAE biosynthesis to appropriate energy balance remains poorly understood in part because there are multiple enzymes that can contribute to NAE biosynthesis and the specific enzyme(s) that are responsible for feeding-induced intestinal NAE biosynthesis have not been identified. The rate-limiting step in the intestinal biosynthesis of NAEs is formation of their immediate precursors, the N-acyl-phosphatidylethanolamines (NAPEs), by phosphatidylethanolamine N-acyltransferases (NATs). At least six NATs are found in humans and multiple homologs of these NATs are found in most vertebrate species. In recent years, the fecundity and small size of zebrafish (Danio rerio), as well as their similarities in feeding behavior and energy balance regulation with mammals, have led to their use to model key features of cardiometabolic disease. We therefore searched the Danio rerio genome to identify all NAT homologs and found two additional NAT homologs besides the previously reported plaat1, rarres3, and rarres3l, and used CRISPR/cas9 to delete these two NAT homologs (plaat1l1 and plaat1l2). While wild-type fish markedly increased their intestinal NAPE levels in response to a meal after fasting, this response was completely ablated in plaat1l1-/-fish. Furthermore, plaat1l1-/- fish fed a standard flake diet had increased weight gain and glucose intolerance compared to wild-type fish. The results support a critical role for feeding-induced NAPE and NAE biosynthesis in regulating energy balance and suggest that restoring this response in obese animals could potentially be used to treat obesity and cardiometabolic disease.

Enhanced Selective Degradation of Pharmaceutical and Personal Care Products by ß-Cyclodextrin-Decorated ZIF-67 Nanocomposites in Reclaimed Water.

A peroxymonosulfate oxidation system was developed via modification of ß-cyclodextrin (ß-CD) on the surface of Fe2+-doped ZIF-67 (CD/Fe@ZIF-67) as an activator. The 99.7% carbamazepine, 91.3% bisphenol A (BPA), and 95.4% diclofenac (DCF) degradation efficiency were achieved within 10 min, 60, and 1 min, respectively. The hydrophobicity of these three pollutants is positively correlated with their adsorption kinetic constants by CD/Fe@ZIF-67 due to the introduction of ß-CD. Scavenger experiments and electron spin resonance spectra confirmed that carbamazepine was preferentially oxidized by SO4•- [λ(SO4•-)(70.5%) > λ(•OH)(28.2%) > λ(O2•-)(1.3%)], where SO4•- and O2•- played dominant roles in the degradation of BPA [λ(SO4•-)(71.7%) > λ(O2•-)(22.8%) > λ(•OH)(5.5%)], and O2•- was responsible for DCF removal [λ(O2•-) = 93.2%]. Additionally, the particulate catalyst was immobilized in the shell side of a ceramic membrane in a membrane reactor for catalyst recovery. This reactor achieved nearly 100% removal efficiency under optimal conditions: 0.036 wt % catalyst loading, 0.5 mM peroxymonosulfate concentration, 1 L inflow, 10 mg/L initial carbamazepine concentration, and 0.012 L/min hydraulic retention time. In summary, this study elucidates the active role of ß-CD in a polymetallic/peroxymonosulfate system and provides valuable insights into the development of effective oxidation methods for pharmaceutical and personal care products in wastewater.

Efficacy and safety of apheresis therapy in AQP4 antibody-positive NMOSD attack: A propensity score-matched cohort study.

OBJECTIVE: Plasma exchange (PE) and immunoadsorption (IA) are recognized as effective ways to treat attacks in AQP4 antibody-positive NMOSD, but high-quality evidence was lacking. To evaluate the efficacy and safety of PE/IA plus intravenous methylprednisolone (IVMP) in NMOSD attacks using propensity scores to match IVMP as control. METHODS: Patients were from a prospective observational cohort study. Stratification and interval propensity score matching (PSM) were used to reduce selection bias by matching baseline characteristics (gender, age, time to IVMP, EDSS at attack) between PE/IA + IVMP and IVMP group (in a ratio of 1:2). The primary endpoint of efficacy was EDSS change at 6 months. Adverse events and changes in laboratory tests were recorded. RESULTS: Four hundred and eleven attacks of 336 patients were screened for PSM, and 90 attacks (30 PE/IA + IVMP and 60 IVMP) were included in the analysis. There were significant differences in EDSS [6.25 vs. 6.75; IQR (4.50-8.38 vs. 5.00-8.00), p = 0.671] and visual acuity [median logMAR = 0.35 vs. 1.00; IQR (0.30-0.84 vs. 0.95-1.96), p = 0.002] change between two groups at 6 months. PE/IA + IVMP treatment demonstrated predictive capacity for good recovery as indicated by an area under the curve (AUC) of 0.726. Fibrinogen reduction was found during PE/IA + IVMP treatment [n = 15 (50.00%)], but no severe adverse events led to apheresis treatment discontinuation. DISCUSSION: After PSM analysis, IVMP+PE/IA in acute attack of NMOSD achieved better and continuous improvement in neurological function within 6 months compared with IVMP alone. PE/IA treatment showed a good safety profile.

Low energy-consumption oriented membrane fouling control strategy in anaerobic fluidized membrane bioreactor.

Anaerobic fluidized membrane bioreactors (AFMBR) has attracted growing interest as an emerging wastewater treatment technology towards energy recovery from wastewater. AFMBR combines the advantages of anaerobic digestion and membrane bioreactors and shows great potential in overcoming limiting factors such as membrane fouling and low efficiency in treating low-strength wastewater such as domestic sewage. In AFMBR, the fluidized media performs significant role in reducing the membrane fouling, as well as improving the anaerobic microbial activity of AFMBRs. Despite extensive research aimed at mitigating membrane fouling in AFMBR, there has yet to emerge a comprehensive review focusing on strategies for controlling membrane fouling with an emphasis on low energy consumption. Thus, this work overviews the recent progress of AFMBR by summarizing the factors of membrane fouling and energy consumption in AFMBR, and provides targeted in-depth analysis of energy consumption related to membrane fouling control. Additionally, future development directions for AFMBR are also outlooked, and further promotion of AFMBR engineering application is expected. By shedding light on the relationship between energy consumption and membrane fouling control, this review offers a useful information for developing new AFMBR processes with an improved efficiency, low membrane fouling and low energy consumption, and encourages more research efforts and technological advancements in the domain of AFMBR.

Decreased serum tryptophan levels in patients with MOGAD:a cross-sectional survey.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder of central nervous system (CNS). Tryptophan indole catabolites have been reported to associate with the inflammatory diseases of the CNS. However, the roles of tryptophan indole catabolites have been rarely elucidated in MOGAD. METHODS: This cross-sectional study enrolled forty MOGAD patients, twenty patients with other non-inflammatory neurological diseases (OND) and thirty-five healthy participants. Serum and cerebrospinal fluid (CSF) samples of MOGAD and OND subjects during clinical attacks, serum samples of healthy participants were obtained. The concentrations of tryptophan, indoleacetic acid (IAA), indoleacrylic acid (IA) and indole-3-carboxylic acid (I-3-CA) were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The correlations between tryptophan indole catabolites and maintenance immunotherapy, disease duration, overall numbers of attacks, short-term outcome in MOGAD patients were investigated. RESULTS: Levels of serum tryptophan, IAA, IA and CSF tryptophan in MOGAD patients were significantly decreased, while levels of serum I-3-CA and CSF IA were markedly increased compared with OND patients and healthy controls. Levels of serum tryptophan, CSF tryptophan and IA were significantly decreased in MOGAD patients who had received maintenance immunotherapy within 6 months before the attack. In MOGAD patients, serum and CSF tryptophan conversely correlated with disease duration and overall numbers of attacks, and serum IA negatively correlated with disease duration. Furthermore, serum tryptophan in MOGAD patients negatively correlated with the modified Rankin Scale (mRS) scores at 3 months. CONCLUSION: This study manifested decreased serum tryptophan levels and serum tryptophan may be the potential marker to predict the short-term outcome in MOGAD patients.

Lactate dehydrogenase A is implicated in the pathogenesis of B-cell lymphoma through regulation of the FER signaling pathway.

Lactate dehydrogenase A (LDHA) is highly expressed in various tumors. However, the role of LDHA in the pathogenesis of B-cell lymphoma remains unclear. Analysis of data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases revealed an elevated LDHA expression in diffuse large B-cell lymphoma (DLBC) tissues compared with normal tissues. Similarly, our results demonstrated a significant increase in LDHA expression in tumor tissues from the patients with B-cell lymphoma compared with those with lymphadenitis. To further elucidate potential roles of LDHA in B-cell lymphoma pathogenesis, we silenced LDHA in the Raji cells (a B-cell lymphoma cell line) using shRNA techniques. Silencing LDHA led to reduced mitochondrial membrane integrity, adenosine triphosphate (ATP) production, glycolytic activity, cell viability and invasion. Notably, LDHA knockdown substantially suppressed in vivo growth of Raji cells and extended survival in mice bearing lymphoma (Raji cells). Moreover, proteomic analysis identified feline sarcoma-related protein (FER) as a differential protein positively associated with LDHA expression. Treatment with E260, a FER inhibitor, significantly reduced the metabolism, proliferation and invasion of Raji cells. In summary, our findings highlight that LDHA plays multiple roles in B-cell lymphoma pathogenesis via FER pathways, establishing LDHA/FER may as a potential therapeutic target.

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

The landscape of PBMCs in AQP4-IgG seropositive NMOSD and MOGAD, assessed by high dimensional mass cytometry.

OBJECTIVES: Data on peripheral blood mononuclear cells (PBMCs) characteristics of aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are lacking. In this study, we describe the whole PBMCs landscape of the above diseases using cytometry by time-of-flight mass spectrometry (CyTOF). METHODS: The immune cell populations were phenotyped and clustered using CyTOF isolated from 27 AQP4-IgG seropositive NMOSD, 11 MOGAD patients, and 15 healthy individuals. RNA sequencing was employed to identify critical genes. Fluorescence cytometry and qPCR analysis were applied to further validate the algorithm-based results that were obtained. RESULTS: We identified an increased population of CD11b+ mononuclear phagocytes (MNPs) in patients with high expression of CCR2, whose abundance may correlate with brain inflammatory infiltration. Using fluorescence cytometry, we confirmed the CCR2+ monocyte subsets in a second cohort of patients. Moreover, there was a wavering of B, CD4+ T, and NKT cells between AQP4-IgG seropositive NMOSD and MOGAD. CONCLUSIONS: Our findings describe the whole landscape of PBMCs in two similar demyelinated diseases and suggest that, besides MNPs, T, NK and B, cells were all involved in the pathogenesis. The identified cell population may be used as a predictor for monitoring disease development or treatment responses.

Fast needling combined with occupational therapy for hand dysfunction of spastic cerebral palsy : a randomized controlled trial. / å¿«é’ˆç»“åˆä½œä¸šç–—æ³•æ²»ç–—ç—‰æŒ›åž‹è„‘ç˜«æ‚£å„¿æ‰‹åŠŸèƒ½éšœç¢ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To compare the clinical effect of fast needling (without needle retaining), needle retaining acupuncture combined with occupational therapy and simple occupational therapy for hand dysfunction of spastic cerebral palsy in children. METHODS: A total of 75 children with spastic cerebral palsy were randomly divided into an occupational therapy group (25 cases), a fast needling group (25 cases, 1 case dropped out) and a needle retaining group (25 cases, 1 case dropped out). The patients in the occupational therapy group were only treated with occupational therapy for 20 min each time. The patients in the fast needling group were treated with acupuncture (without needle retaining) combined with occupational therapy, and the needle retaining group was treated with acupuncture (needle retaining) combined with occupational therapy, and acupuncture was taken at Hegu (LI 4), Houxi (SI 3), Yuji (LU 10), Waiguan (SJ 5), Jianyu (LI 15) and so on. The needles were retained for 30 min in patients of the needle retaining group. All the above treatments were performed once a day, 5 times a week for 12 weeks. The scores of fine motor function measure (FMFM) and Peabody developmental motor scale 2 (PDMS-2) were observed in patients of the three groups before and after treatment, and the safety of the fast needling group and the needle retaining group was compared. RESULTS: After treatment, the scores of FMFM and PDMS-2 in patients of the three groups were higher than those before treatment (P<0.01), and the scores of FMFM and PDMS-2 in the fast needling group and the needle retaining group were higher than those in the occupational therapy group (P<0.05, P<0.01). The incidence of acupuncture abnormalities in the fast needling group was 0.3% (5/1 440), which was lower than 1.4% (20/1 440) in the needle retaining group (P<0.05). CONCLUSIONS: Acupuncture combined with occupational therapy has better clinical effect than occupational therapy alone in improving hand dysfunction in children with spastic cerebral palsy, and there is no statistical difference in effect between fast needling acupuncture and needle retaining acupuncture, but fast needling has better safety than needle retaining acupuncture.

Tocilizumab treatment in neuromyelitis optica spectrum disorders: Updated meta-analysis of efficacy and safety.

This systematic review and meta-analysis summarize the efficacy and safety of Tocilizumab (TCZ) in treating NMOSD and investigates the factors that affect its efficacy. TCZ is the first monoclonal antibody against the IL-6 receptor for treating NMOSD, and its efficacy and safety vary in different studies. We collected English-language research literature until January 1, 2023, by searching databases such as PubMed, MEDLINE, Embase, Cochrane Library, and clinicaltrials.gov, and identified 9 studies involving 153 patients (139 female and 14 male) that met our inclusion criteria. In these studies, the average ARR ratio and EDSS score reduction values in the TCZ treatment group were -1.34 (95 % CI, -1.60 to -1.09) and -0.81 (95 % CI, -1.04 to -0.58), respectively. Based on the data we have collected, compared to the AQP4-IgG negative NMOSD patients, TCZ demonstrates a more pronounced effectiveness in AQP4-IgG positive NMOSD patients. The study also found that the effectiveness of TCZ in reducing NMOSD patients' ARR ratio was related to gender, race, and TCZ dosage, while the effectiveness of reducing EDSS score was not related to these factors. Among the 153 patients receiving TCZ treatment, 101 (66 %) experienced mild adverse reactions, and one patient experienced a severe adverse reaction (facial cellulitis). The comprehensive data indicate that TCZ treatment can reduce the frequency of NMOSD relapses, improve patients' neurological function, and have good safety. The effectiveness of TCZ in reducing NMOSD patients' ARR ratio is related to multiple factors.

Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2.

Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver-α cell axis. We hypothesized that α cells detect and respond to circulating amino acids levels via a unique amino acid transporter repertoire. We found that Slc7a2ISLC7A2 is the most highly expressed cationic amino acid transporter in α cells with its expression being three-fold greater in α than ß cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that both's role in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated α cell proliferation and islet hormone secretion.

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

CD4+ T-Cell Subsets in Aplastic Anemia, Myelodysplastic Syndrome, and Acute Myelogenous Leukemia Patients: a Comparative Analysis.

BACKGROUND: Systematic and comparative studies on CD4+ T-lymphocytes in aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML) are scarce. This study aimed to investigate the importance of CD4+ T-cells in bone marrow (BM) failure. METHODS: The proportions of Th1, Th2, Th17, and Treg cells in peripheral blood mononuclear cells (PBMCs) were examined by flow cytometry (FCM). The mRNA expression levels of transcription factors were measured using real-time PCR. RESULTS: The proportions of Th1, Th17 cells, and Th1/Th2 in the AA group were higher, whereas Th2 and Tregs were lower compared to controls. The proportions of Th17 and Treg cells accompanied by RORγt, and Foxp3 expression were significantly higher in the MDS group. The proportions of Th1, Th17, and Th1/Th2 were higher, whereas Th2 cells and GATA3 expression were significantly lower in MDS-multilineage dysplasia group, than in control group. The proportions of Th1, Th17, and Th1/Th2 were lower in MDS-excess blasts, and AML groups, than in controls, whereas that of Th2 and Treg cells accompanied by GATA3, and Foxp3 expression were significantly higher. CONCLUSIONS: Imbalance in CD4+ T-cell subsets may play a critical role in the pathogenesis and BM failure in the investigated diseases.

Profile and potential role of novel metabolite biomarkers, especially indoleacrylic acid, in pathogenesis of neuromyelitis optica spectrum disorders.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory and demyelinating disorder that can lead to serious disability and mortality. Humoral fluid biomarkers with specific, convenient, and efficient profiles that could characterize and monitor disease activity or severity are very useful. We aimed to develop a sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS)/MS-based analytical method for novel biomarkers finding in NMOSD patients and verified its function tentatively. Methods: Serum samples were collected from 47 NMOSD patients, 18 patients with other neurological disorders (ONDs), and 35 healthy controls (HC). Cerebrospinal fluid (CSF) samples were collected from 18 NMOSD and 17 OND patients. Three aromatic amino acids (phenylalanine, tyrosine, and tryptophan) and nine important metabolites that included phenylacetylglutamine (PAGln), indoleacrylic acid (IA), 3-indole acetic acid (IAA), 5-hydroxyindoleacetic acid (HIAA), hippuric acid (HA), I-3-carboxylic acid (I-3-CA), kynurenine (KYN), kynurenic acid (KYNA), and quinine (QUIN) were analyzed by using the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method. The profile of IA was further analyzed, and its function was verified in an astrocyte injury model stimulated by NMO-IgG, which represents important events in NMOSD pathogenesis. Results: In the serum, tyrosine and some of the tryptophan metabolites IA and I-3-CA decreased, and HIAA increased significantly in NMOSD patients. The CSF levels of phenylalanine and tyrosine showed a significant increase exactly during the relapse stage, and IA in the CSF was also increased markedly during the relapse and remission phases. All conversion ratios had similar profiles with their level fluctuations. In addition, the serum IA levels negatively correlated with glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels in the serum of NMOSD patients were measured by using ultra-sensitive single-molecule arrays (Simoa). IA showed an anti-inflammatory effect in an in vitro astrocyte injury model. Conclusion: Our data suggest that essential aromatic amino acid tryptophan metabolites IA in the serum or CSF may serve as a novel promising biomarker to monitor and predict the activity and severity of NMOSD disease. Supplying or enhancing IA function can promote anti-inflammatory responses and may have therapeutic benefits.

Generalized Rapid Synthesis of Supported Nanocluster Catalyst for Mild Hydrogenation of Phenol toward KA Oil.

Homogeneous and nanometric metal clusters with unique electronic structures are promising for catalysis, however, common synthesis techniques for metal clusters suffer from large size and even metal nanocrystals attributing to their high surface energy and unsaturated configurations. Herein, a generalized rapid annealing strategy for synthesizing a series of supported metal clusters as superior catalysts is developed. Remarkably, TiO2 supported platinum nanoclusters (Pt NC/TiO2 ) exhibits the excellent catalytic activity to realize phenol hydrogenation under mild conditions. The complete phenol conversion rate and 100% selectivity toward KA oil are achieved in aqueous solution at room temperature and normal pressure. Semi-continuous scale up production of KA oil is successfully performed under mild conditions. Such excellent performance mainly originates from the partial reconstruction of Pt NC/TiO2 in aqueous phenol solution. Considering that the phenol can be produced from lignin, this study underpins a facile, sustainable, and economical route to synthesize nylon from biomass.

Targeting chemoattractant chemokine (C-C motif) ligand 2 derived from astrocytes is a promising therapeutic approach in the treatment of neuromyelitis optica spectrum disorders.

Introduction: Aquaporin-4 immunoglobulin G (AQP4-IgG)-induced astrocytes injury is a key mechanism in the pathogenesis of neuromyelitis spectrum disorder (NMOSD), and although CCL2 is involved, its specific role has not been reported. We aimed to further investigate the role and potential mechanisms of CCL2 in AQP4-IgG-induced astrocyte injury. Methods: First, we evaluated CCL2 levels in paired samples of subject patients by automated microfluidic platform, Ella®. Second, we knock down astrocyte's CCL2 gene in vitro and in vivo to define the function of CCL2 in AQP4-IgG-induced astrocyte injury. Third, astrocyte injury and brain injury in live mice were assessed by immunofluorescence staining and 7.0T MRI, respectively. Western blotting and high-content screening were conducted to clarify the activation of inflammatory signaling pathways, and changes in CCL2 mRNA and cytokine/chemokines were measured by qPCR technique and flow cytometry, respectively. Results: There were greatly higher CSF-CCL2 levels in NMOSD patients than that in other non-inflammatory neurological diseases (OND) groups. Blocking astrocyte CCL2 gene expression can efficiently mitigate AQP4-IgG-induced damage in vitro and in vivo. Interestingly, prevention of CCL2 expression could decrease other inflammatory cytokines released, including IL-6 and IL-1ß. Our data suggest that CCL2 involves in the initiation and plays a pivotal role in AQP4-IgG-damaged astrocytes. Discussion: Our results indicate that CCL2 may serve as a promising candidate target for inflammatory disorder therapy, including NMOSD.

Aligned Nanofibrous Net Deposited Perpendicularly on Microridges Supports Endothelium Formation and Promotes the Structural Maturation of hiPSC-Derived Cardiomyocytes.

Cell alignment widely exists in various in vivo tissues and also plays an essential role in the construction of in vitro models, such as vascular endothelial and myocardial models. Recently, microscale and nanoscale hierarchical topographical structures have been drawing increasing attention for engineering in vitro cell alignment. In the present study, we fabricated a micro-/nanohierarchical substrate based on soft lithography and electrospinning to assess the synergetic effect of both the aligned nanofibrous topographical guidance and the off-ground culture environment provided by the substrate on the endothelium formation and the maturation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The morphology, proliferation, and barrier formation of human umbilical vein endothelial cells (HUVECs) as well as the alignment, cardiac-specific proteins, and maturity-related gene expression of hiPSC-CMs on the aligned-nanofiber/microridge (AN-MR) substrate were studied. Compared with the glass slide and the single-aligned nanofiber substrate, the AN-MR substrate enhanced the proliferation, alignment, and cell-cell interaction of HUVECs and improved the length of the sarcomere and maturation-related gene expression of hiPSC-CMs. Finally, the response of hiPSC-CMs on different substrates to two typical cardiac drugs (isoproterenol and E-4031) was tested and analyzed, showing that the hiPSC-CMs on AN-MR substrates were more resistant to drugs than those in other groups, which was related to the higher maturity of the cells. Overall, the proposed micro-/nanohierarchical substrate supports the in vitro endothelium formation and enhances the maturation of hiPSC-CMs, which show great potential to be applied in the construction of in vitro models and tissue engineering.

Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways.

Glucagon has emerged as a key regulator of extracellular amino acid (AA) homeostasis. Insufficient glucagon signaling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other AA sensors in α cell proliferation has not been described. Here, using both genders of mouse islets and glucagon receptor (gcgr)-deficient zebrafish (Danio rerio), we show α cell proliferation requires activation of the extracellular signal-regulated protein kinase (ERK1/2) by the AA-sensitive calcium sensing receptor (CaSR). Inactivation of CaSR dampened α cell proliferation, which was rescued by re-expression of CaSR or activation of Gq, but not Gi, signaling in α cells. CaSR was also unexpectedly necessary for mTORC1 activation in α cells. Furthermore, coactivation of Gq and mTORC1 induced α cell proliferation independent of hyperaminoacidemia. These results reveal another AA-sensitive mediator and identify pathways necessary and sufficient for hyperaminoacidemia-induced α cell proliferation.

Real-time monitoring of mercury(II) in water and food samples using a quinoline-based ionic probe.

Herein, a novel ionic fluorescent probe for mercury(II) detection is presented consisting of a functional quinoline-based IL. Interestingly, the probe displayed high sensitivity (0.8 nM) and selectivity through the regulation function of electrostatic attraction, where its performance was significantly superior to that of quinoline probes without negative charge. Furthermore, the probe was found to exhibit two different fluorescent signals and colorimetric signals in the presence of different concentrations of mercury(II), which was consistent with the reaction mechanisms of the generation of large conjugated systems and the formation of anion-mercury(II) complexes. Moreover, this probe could be further loaded on a simple filter paper to serve as a visual paper sensor due to its adequate response time of less than 5 s. This regulation function strategy of electrostatic attraction has excellent potential for use in the precise detection of targeted analytes in real complex samples with improved accuracy and selectivity.

CXCL1/CXCR2 is involved in white matter injury in neonatal rats via the gut-brain axis.

BACKGROUND: This study aimed to investigate whether CXCL1/CXCR2 mediates intestinal injury or white matter injury by delivering inflammatory mediators through the gut-brain regulation axis. METHODS: Neonatal SD rats, regardless of sex, were administered 3% dextran sulfate sodium via intragastric administration at different time points to construct necrotizing enterocolitis (NEC) models. Meanwhile, hypoxia and ischemia were induced in 3 day-old SD rats to construct hypoxic-ischemic brain injury (HIBI) and NEC + HIBI models, without gender discrimination. Hematoxylin-eosin staining was used to observe pathological changes in neonatal rat intestinal and brain tissues. Western blotting detected CXCL1 and CXCR2 expression in NEC, HIBI, and NEC + HIBI rat intestinal and brain tissues. RESULTS: Compared with normal rats, pathological damage to periventricular white matter was observed in the NEC group. In addition to the increased mortality, the histopathological scores also indicated significant increases in brain and intestinal tissue damage in both HIBI and NEC + HIBI rats. Western blotting results suggested that CXCL1 and CXCR2 expression levels were upregulated to varying degrees in the intestinal and brain tissues of NEC, HIBI, and NEC + HIBI neonatal rats compared to that in the normal group. Compared with the HIBI group, the expression of CXCL1 and CXCR2 continued to increase in NEC + HIBI rats at different time points. CONCLUSIONS: CXCL1/CXCR2 may be involved in white matter injury in neonatal rats by delivering intestinal inflammatory mediators through the gut-brain axis.