Cannabinoids, endocannabinoids and marijuana activate two well‐characterized cannabinoid receptors (CB‐Rs), CB1‐Rs and CB2‐Rs. The expression of CB1‐Rs in the brain and periphery has been well ...studied, but neuronal CB2‐Rs have received much less attention than CB1‐Rs. Many studies have now identified and characterized functional glial and neuronal CB2‐Rs in the central nervous system. However, many features of CB2‐R gene structure, regulation and variation remain poorly characterized in comparison with the CB1‐R. In this study, we report on the discovery of a novel human CB2 gene promoter transcribing testis (CB2A) isoform with starting exon located ca 45 kb upstream from the previously identified promoter transcribing the spleen isoform (CB2B). The 5′ exons of both CB2 isoforms are untranslated 5′UTRs and alternatively spliced to the major protein coding exon of the CB2 gene. CB2A is expressed higher in testis and brain than CB2B that is expressed higher in other peripheral tissues than CB2A. Species comparison found that the CB2 gene of human, rat and mouse genomes deviated in their gene structures and isoform expression patterns. mCB2A expression was increased significantly in the cerebellum of mice treated with the CB‐R mixed agonist, WIN55212‐2. These results provide much improved information about CB2 gene structure and its human and rodent variants that should be considered in developing CB2‐R‐based therapeutic agents.
Elevated expression of Siglec-1 on circulating monocytes has been reported in some inflammatory and autoimmune diseases, but its expression and role in RA has not been elucidated. The aims of this ...study were to determine the expression of Siglec-1 in peripheral blood and to explore its role in mononuclear cell reactivity to autoantigen in RA.
Siglec-1 protein and mRNA levels in 42 RA patients, 39 OA patients, 28 SLE patients and 42 normal controls were determined by flow cytometry and quantitative RT-PCR, respectively. In addition, 10 patients with active RA received DMARDs for 12 weeks and the frequencies of Siglec-1-positive cells and the 28-joint DAS (DAS28) were assessed before and after therapy. Furthermore, TNF-α, IFN-γ and type II collagen were used to up-regulate Siglec-1. Peripheral blood mononuclear cells (PBMCs) from different groups were stimulated with mitogens or antigens and cell proliferation and cytokine production were determined.
The protein and mRNA levels of Siglec-1 on PBMCs and monocytes in RA patients were significantly higher than those in OA patients and healthy controls. Moreover, the expression of Siglec-1 protein on PBMCs was positively correlated with DAS28, ESR, high-sensitivity CRP and IgM-RF, but not with anti-CCP antibody. Interestingly, Siglec-1 expression was decreased in parallel with the decrease in the DAS28 after 12 weeks of anti-rheumatic treatment. Furthermore, TNF-α, IFN-γ and type II collagen can up-regulate Siglec-1 in PBMCs. Elevated PBMC proliferation and proinflammatory cytokine production to collagen stimulation in RA patients decreased when Siglec-1 was inhibited by anti-Siglec-1 antibodies.
Elevated Siglec-1 expression in PBMCs and monocytes can potentially serve as a biomarker for monitoring disease activity in RA. Siglec-1 may also play a proinflammatory role in stimulating lymphocyte proliferation and activation in RA.
Monte Carlo (MC) simulation production plays an important role in physics analysis of the Alpha Magnetic Spectrometer (AMS-02) experiment. To facilitate the metadata retrieving for data analysis ...among millions of database records, we developed a monitoring tool to analyse and visualize the production status and progress. In this paper, we discuss the workflow of the monitoring tool and present its features and technical details.
This study puts forward a new concept, "population urbanization level forecast - driving factor analysis - urban spatial planning analysis" for achieving efficient and intensive development of ...urbanization considering human-land harmony. We analyzed big data for national economic and social development, studied the development trends of population urbanization and its influencing factors using the grey system model in Chengmai county of Hainan province, China. In turn, we calculated the population of Chengmai coming years based on the forecasting urbanization rate and the corresponding amount of urban construction land, and evaluated the urban spatial planning with GIS spatial analysis method in the study area. The result shows that the proposed concept is feasible for evaluation of urban spatial planning, and is meaningful for guiding the rational distribution of urban space, controlling the scale of development, improving the quality of urbanization and thus promoting highly-efficient and intensive use of limited land resource.
Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T ...cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC.
Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model.
Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFβR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFβ-Smad signaling.
CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC.
Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.
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•CD103+ TRM cells are the dominant population of PDC-E2-specific autoreactive cytotoxic T cells in livers of patients with PBC.•CD103+ TRM cells exhibit cytotoxicity against autologous cholangiocytes in PBC.•Upon antigenic stimulation, metabolic reprogramming and DNA damage response of CD103+ TRM cells is orchestrated by NUDT1.•NUDT1-dependent DNA damage resistance promotes long-term survival of CD103+ TRM cells via PARP1-TGFβ-Smad axis.
Perioperative multimodal analgesia can prevent chronic pain after breast cancer surgery. This study aimed to investigate the efficacy of combined perioperative oral pregabalin and postoperative ...esketamine in preventing chronic pain after breast cancer surgery.
Ninety patients undergoing elective breast cancer surgery were randomized into the combined pregabalin and esketamine group (EP group) and the general anesthesia alone group (Control group). The EP group received 150 mg of oral pregabalin 1 h before surgery and twice daily for seven days postoperatively, and a patient-controlled analgesia pump after surgery that delivered 100 μg sufentanil + 1.25 mg/kg esketamine + 4 mg tropisetron in 100 mL saline solution intravenously. The Control group received placebo capsules before and after the surgery and routine postoperative analgesia (100 μg sufentanil + 4 mg tropisetron in 100 mL saline solution). The primary outcome was the incidence of chronic pain three and six months after surgery. Secondary outcomes included acute postoperative pain, postoperative opioid consumption, and incidence of adverse events.
The incidence of chronic pain in the EP group was significantly lower than in the Control group three (14.3% vs 46.3%,
= 0.005) and six (7.1% vs 31.7%,
= 0.009) months postoperatively. The rest numerical rating scale (NRS) pain scores 1-3 days postoperatively and coughing NRS pain scores 1-7 days postoperatively in the EP group were significantly lower than in the Control group (all
˂ 0.05). The cumulative sufentanil consumption in the EP group during postoperative 0-12, 12-24, and 24-48, 0-24, and 0-48 hours were significantly lower than in the Control group (all
˂ 0.05).
Combined perioperative oral pregabalin and postoperative esketamine effectively prevented chronic pain after breast cancer surgery, improved acute postoperative pain, and reduced postoperative opioid consumption.
The assimilation efficiency (AE), efflux rate, and release budget of Cd, Cr(III), Se(IV), and Zn by a freshwater zooplankton Daphnia magna were measured under different food concentrations. The AEs ...of trace elements by Daphnia on two algal diets (Chlamydomonas reinhardtii and Scenedesmus obliquus) were 30-77% for Cd, 8-44% for Cr, 24-58% for Se, and 7-66% for Zn at food concentrations ranging from 0.136 to 7.50 mg carbon L-1. Metal AEs increased significantly with decreasing food concentrations, with a maximum increase of 5.5 and 4.0x for Zn and Cr, respectively. AEs were generally on the order of Cd > Se > Zn > Cr. Efflux rate constants, determined during 7 d depuration after 8 d of exposure to metals in the dissolved phase or dietary phase, were 0.012-0.216 d-1, with the highest efflux for Zn, followed by Cr > Se > Cd. The relative contribution of different routes of metal loss to the overall metal loss was also quantitatively assessed during the 7-d depuration period. Metals differed substantially in their routes of release from Daphnia. In general, metal excretion into the dissolved phase was the most important route for metal loss. Molting represented nearly 50-70% and 20-70% of daily metal efflux for Cd and Zn, respectively, following aqueous exposure within the first 4 d but was <20 and <30%, respectively, following food exposure. Release by offspring production contributed substantially to Se efflux by the animals. Up to 44-67% and 16-47% of Se was lost from the animals through reproductive allocation on a daily basis following uptake from the aqueous and dietary phases, respectively. The major routes of Cr efflux were by excretion and feces egestion. Our study suggested that trace metal assimilation and regeneration in Daphnia may play an important role in the biogeochemical fates of metals in lake systems.
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