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1.
Adv Mater ; : e2000208, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32147886

RESUMO

Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR-Cas9 plasmid for ß-catenin knockout to reverse tumor immunosuppression is constructed. The multi-functionalized delivery vector is decorated with aptamer-conjugated hyaluronic acid and peptide-conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT-NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective ß-catenin knockout and suppress Wnt/ß-catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death-ligand 1 (PD-L1) downregulation in edited tumor cells not only releases the PD-1/PD-L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti-tumor immunity.

2.
Crit Care ; 24(1): 75, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131879

RESUMO

BACKGROUND: Although current guidelines for AKI suggested against the use of furosemide in AKI management, the effect of furosemide on outcomes in real-world clinical settings remains uncertain. The aim of the present study was to investigate the association between furosemide administration and outcomes in critically ill patients with AKI using real-world data. METHODS: Critically ill patients with AKI were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score (PS) matched analysis was used to match patients receiving furosemide to those without diuretics treatment. Linear regression, logistic regression model, and Cox proportional hazards model were used to assess the associations between furosemide and length of stay, recovery of renal function, and in-hospital and 90-day mortality, respectively. RESULTS: A total of 14,154 AKI patients were included in the data analysis. After PS matching, 4427 pairs of patients were matched between the patients who received furosemide and those without diuretics treatment. Furosemide was associated with reduced in-hospital mortality [hazard ratio (HR) 0.67; 95% CI 0.61-0.74; P < 0.001] and 90-day mortality [HR 0.69; 95% CI 0.64-0.75; P < 0.001], and it was also associated with the recovery of renal function [HR 1.44; 95% CI 1.31-1.57; P < 0.001] in over-all AKI patients. Nevertheless, results illustrated that furosemide was not associated with reduced in-hospital mortality in patients with AKI stage 0-1 defined by UO criteria, AKI stage 2-3 according to SCr criteria, and in those with acute-on-chronic (A-on-C) renal injury. CONCLUSIONS: Furosemide administration was associated with improved short-term survival and recovery of renal function in critically ill patients with AKI. Furosemide was especially effective in patients with AKI UO stage 2-3 degree. However, it was not effective in those with AKI SCr stage 2-3 and chronic kidney disease. The results need to be verified in randomized controlled trials.

3.
Sci Rep ; 10(1): 3963, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127629

RESUMO

The diversity of pathogens associated with acute respiratory infection (ARI) makes diagnosis challenging. Traditional pathogen screening tests have a limited detection range and provide little additional information. We used total RNA sequencing ("meta-transcriptomics") to reveal the full spectrum of microbes associated with paediatric ARI. Throat swabs were collected from 48 paediatric ARI patients and 7 healthy controls. Samples were subjected to meta-transcriptomics to determine the presence and abundance of viral, bacterial, and eukaryotic pathogens, and to reveal mixed infections, pathogen genotypes/subtypes, evolutionary origins, epidemiological history, and antimicrobial resistance. We identified 11 RNA viruses, 4 DNA viruses, 4 species of bacteria, and 1 fungus. While most are known to cause ARIs, others, such as echovirus 6, are rarely associated with respiratory disease. Co-infection of viruses and bacteria and of multiple viruses were commonplace (9/48), with one patient harboring 5 different pathogens, and genome sequence data revealed large intra-species diversity. Expressed resistance against eight classes of antibiotic was detected, with those for MLS, Bla, Tet, Phe at relatively high abundance. In summary, we used a simple total RNA sequencing approach to reveal the complex polymicrobial infectome in ARI. This provided comprehensive and clinically informative information relevant to understanding respiratory disease.

4.
Life Sci ; : 117553, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32194081

RESUMO

AIMS: Enhancer of zeste homolog 2 (EZH2) is associated with ulcerative colitis development. However, the mechanism of EZH2 in ulcerative colitis progression remains unclear. MAIN METHODS: Lipopolysaccharide (LPS)-treated Caco-2 cells and dextran sodium sulfate (DSS)-treated mice were used as model of ulcerative colitis. The levels of EZH2, angiopoietin-like 4 (ANGPTL4) and cyclic adenosine monophosphate response element-binding protein 1 (CREB1) were tested via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell viability and apoptosis was measured via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide or flow cytometry. The abundances of inflammatory cytokines were examined via qRT-PCR and enzyme-linked immunosorbent assay. The association between EZH2 and ANGPTL4 was explored via chromatin immunoprecipitation. The colon damage in DSS-treated mice was investigated by colon length, histological analysis, inflammatory response and apoptosis. KEY FINDINGS: LPS induced viability inhibition, inflammatory response and apoptosis in Caco-2 cells. EZH2 expression was increased but ANGPTL4 and CREB1 levels were decreased in LPS-challenged Caco-2 cells. Overexpression of ANGPTL4 or CREB1 suppressed LPS-induced damage in Caco-2 cells. EZH2 could target ANGPTL4 to mediate CREB1 expression. Inhibition of EZH2 suppressed LPS-caused injury. Moreover, knockdown of ANNGPTL4 or CREB1 attenuated the role of EZH2 inhibition. DSS caused the reduced colon length and increased inflammatory response as well as apoptosis. EZH2 expression was up-regulated but ANGPTL4 and CREB1 expression were down-regulated in DSS-treated mice. SIGNIFICANCE: Inhibition of EZH2 declined LPS-induced injury in Caco-2 cells by mediating ANGPTL4 and CREB1, indicating the potential of EZH2 in treatment of ulcerative colitis.

5.
J Zhejiang Univ Sci B ; 21(3): 204-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32133798

RESUMO

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32173448

RESUMO

Copper can be accumulated in water through excessive sewage discharge or residual algaecide to generate toxic effect to aquatic animals. In this study, the juvenile of Pacific white shrimp, Litopenaeus vannamei was exposed to 0 (control), 0.05, 0.1, 0.2, 0.5 or 1 mg Cu2+ L-1 for 30 days. Growth, immune function, anti-oxidative status and gut microbiota were evaluated. Weight gain and specific growth rate of L. vannamei were significantly decreased with the increase of ambient Cu2+. Enlarged lumen and ruptured cells were found in the hepatopancreas of shrimp in the 0.5 or 1 mg Cu2+ L-1 treatment. Total hemocyte counts of shrimp in 0.5 or 1 mg Cu2+ L-1 were significantly lower than in the control. The hemocyanin concentration was also significantly increased in 0.2 or 0.5 mg Cu2+ L-1. Lysozyme contents were reduced in shrimp when Cu2+ exceeded 0.2 mg L-1. Meanwhile, activities of superoxide dismutase and glutathione peroxidase were increased in the hepatopancreas and the activity of Na+-K+ ATPase was decreased in the gills with increasing Cu2+. The mRNA expressions of immune deficiency, toll-like receptor and caspase-3 were all significantly higher in the hepatopancreas in 0.05 mg Cu2+ L-1 than in the control. For the diversity of intestinal microbes, Bacteroidetes significantly decreased in 1 mg Cu2+ L-1 at the phylum level. KEGG pathway analysis demonstrates that 1 mg L-1 Cu2+ can significantly alter metabolism, cellular processes and environmental information processing. This study indicates that the concentration of 1 mg L-1 Cu can negatively impact growth, hemolymph immunity, anti-oxidative capacity and gut microbiota composition of L. vannamei.

7.
J Glob Antimicrob Resist ; 21: 13-15, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32119991

RESUMO

OBJECTIVES: This study aimed to determine the genetic environment of antimicrobial resistance genes (ARGs) in Erysipelothrix rhusiopathiae strain ZJ isolated from a pig with symptoms of swine erysipelas in China. METHODS: Illumina MiSeq (200× coverage) and PacBio RS II (100× coverage) platforms were used for genome sequencing. ARGs and prophages were identified using ResFinder 3.0 and PHASTER, respectively. A conjugation experiment, induced prophage infection and long-term passage assay were performed to determine the transferability and stability of ARGs in this strain. RESULTS: The assembled circular genome of E. rhusiopathiae ZJ was 1 945 689 bp with a GC content of 36.48%; no plasmid sequence was detected. Eleven acquired ARGs were identified in the genome. A novel integrative and conjugative element (ICE) encoding a multidrug resistance (MDR) gene cluster [aadE-apt-spw-lsa(E)-lnu(B)-aadE-sat4-aphA3] was identified in strain ZJ. A prophage Φ1605 harbouring mef(A)-msr(D) and tet(M) was also found in this strain, which can take a circular form and can be induced by mitomycin C to infect E. rhusiopathiae G4T10 for ARG transfer. CONCLUSION: To our knowledge, this is the first report of a complete genome sequence of E. rhusiopathiae carrying multiple ARGs obtained from a pig farm. This is the first identification of a novel chimeric ICE carrying a MDR gene cluster and a prophage carrying ARGs in E. rhusiopathiae, which will provide a valuable reference to understand the potential transfer mechanism of MDR gene clusters carried by ICEs and prophages in Gram-positive bacteria.

8.
Fish Shellfish Immunol ; 100: 137-145, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32151686

RESUMO

Cobalt (Co) is an important component of vitamin B12, but is toxic to aquatic animals at a high level. In this study, the Pacific white shrimp, Litopenaeus vannamei were exposed to three Co concentrations (0, 100, and 1000 µg/L) for 4 weeks. The survival and condition factor in shrimp exposed to the Co treatments were not different from the control, but the shrimp exposed to 100 µg Co/L gained more weight than in other two groups, and the shrimp exposed to 1000 µg Co/L gained less weight than in other groups. The SOD and GSH-PX activities were higher in shrimp exposed to 100 µg Co/L, but lower in the shrimp exposed to 100 µg Co/L compared with the control, respectively. The MDA contents in the hepatopancreas decreased in the 100 µg Co/L, but increased in the 1000 µg Co/L. The serum lysozyme decreased with ambient cobalt, was lower in the shrimp exposed to 1000 µg Co/L than in other two groups. The expression of C-type lectin 3 was down-regulated by Co concentrations. The Toll and immune deficiency in shrimp exposed to 100 µg Co/L was higher than in other two groups. The mucin-1 was lower in the 1000 µg Co/L group than in other two groups, but mucin-2 and mucin-5AC were higher in the 1000 µg Co/L group than in the control. With increasing Co concentration, Shannon and Simpson indexes of the intestinal microbial communities were decreased. The abundance of pathogenic bacteria (Ruegeria and Vibrio) increased in both Co groups. This study indicates that chronic exposure to waterborne cobalt could affect growth, cause oxidative stress, stimulate the immune response, damage intestinal histology, and reshape intestinal microbiota community L. vannamei.

9.
J Anim Sci ; 98(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32161959

RESUMO

Accumulating evidences indicate that plant extracts and probiotics are effective antioxidant substitutes which play important roles in animal production. However, the comparative study of the mechanism underlying the antioxidant property of Illicium verum extracts (IVE) and probiotics with added glucose oxidase (PGO) on piglets remains to be explored. This study evaluated the difference and the interaction effect of IVE and PGO on serum, liver, and jejunum antioxidant capacity of weaned piglets. A total of 32 weaned piglets (Duroc × Landrace × Yorkshire) at the age of 28 d with an average body weight of 14.96 ± 0.32 kg were randomly divided into four treatments with eight replicates per treatment in a 2 × 2 factorial arrangement. Treatments included basal diet (IVE-PGO-), basal diet + 1,000 mg/kg PGO (IVE-PGO+), basal diet + 500 mg/kg IVE (IVE+PGO-), and basal diet + 500 mg/kg IVE + 1,000 mg/kg PGO (IVE+PGO+). All the piglets were housed individually for the 42-d trial period after 7-d adaptation. The piglets were euthanized at the end of the experiment and the liver and jejunum samples were taken and subjected to immunohistochemistry, Western blotting, as well as antioxidant and qRT-PCR analysis. Significant interactions were observed between IVE and PGO for total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) in serum (42 d), liver, and jejunum; malondialdehyde (MDA) in serum (21 d); and mRNA and protein expression of kelch sample related protein-1 (Keap1) and nuclear factor erythroid-2 related factor (Nrf2)/Keap1 in the liver and jejunum (P < 0.05). Both IVE and PGO improved (P < 0.05) T-SOD and GSH-Px in the serum (42 d), liver, and jejunum, and the mRNA and protein expression of Nrf2 and Nrf2/Keap1 in the liver and jejunum, but decreased (P < 0.05) MDA in the serum (21 d) and the mRNA and protein expression of Keap1 in the liver and jejunum. Immunohistochemical results confirmed that IVE and PGO enhanced the positive reactions of Nrf2 but weakened Keap1 in both the liver and jejunum. In conclusion, the results confirmed that IVE (500 mg/kg) and PGO (1,000 mg/kg) can improve the antioxidant capacity of weaned piglets and that the interaction effect between IVE and PGO is significant. At the same time, the fact that IVE and PGO activate the Nrf2/Keap1 in the liver and jejunum signaling pathway suggests that they play an important role in the ameliorative antioxidant capacity of weaned piglets. Therefore, the combination of IVE and PGO could be recommended as a new potential alternative to antibiotics in piglets' diets.

10.
Fitoterapia ; 143: 104556, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32194169

RESUMO

Sophora flavescens Ait (Ku-Shen in Chinese) is a popular traditional Chinese herbal medicine in China for a long history. It shows significant pharmacological activities in the treatment of dysentery, eczema, fever, jaundice, vulvar swelling, gastrointestinal hemorrhage and inflammatory disorders. Alkaloids and flavonoids have been identified as virtual components, especially isoprenoid flavanonols are a class of characteristic compounds for S. flavescens. However, few studies have focused on isoprenoid flavonoids analyses and no comprehensive review has yet been published. In the current review, we systematically summarized the isoprenoid flavonoids, a total of 55 compounds have been isolated from S. flavescens, particularly an isoprenyl and a lavandulyl group in backbone structures. Further pharmacological activities, qualitative and quantitative chemical analyses research will contribute to the development of natural isoprenoid flavonoid products in S. flavescens.

11.
Phytomedicine ; 69: 153185, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32120244

RESUMO

BACKGROUND: Dihydroquercetin (DHQ) is an antifibrotic agent. However, whether DHQ can prevent renal fibrosis remains unknown. PURPOSE: This study aimed to investigate the effects of DHQ on tubulointerstitial fibrosis and its underlying mechanisms in unilateral ureteral obstruction (UUO) mice in vivo and NRK-49F cells in vitro. METHODS: In vivo, UUO mice received vehicle or DHQ treatment. In vitro, NRK-49F cells were pretreated with DHQ and exposed to transforming growth factor-ß1 (TGF-ß1). Changes in fibroblast activation, collagen synthesis, oxidative stress, and related signaling pathways were assessed by immunohistochemical staining, Western blot analysis, real-time reverse transcription-PCR, and fluorescence microscopy. RESULTS: UUO induced tubular atrophy, inflammation, fibroblast differentiation into myofibroblast, and collagen deposition, whereas DHQ ameliorated these effects. UUO also resulted in decreased levels of nuclear factor-erythroid-2-related factor 2 (Nrf2), catalase, and heme oxygenase-1, but increased H2O2 and malondialdehyde levels. DHQ treatment corrected these changes. In vitro, the intracellular Nrf2 level of NRK-49F exposed to TGF-ß1 decreased. However, DHQ rescued intracellular Nrf2 level and promoted nuclear translocation of Nrf2. DHQ scavenged TGF-ß1-induced accumulation of reactive oxygen species, inhibited TGF-ß1-induced Smad3 phosphorylation, and prevented TGF-ß1-induced fibroblast activation and collagen synthesis in NRK-49F. Nrf2 knockdown could suppress the DHQ-mediated inhibitory effects on oxidative stress, Smad3 phosphorylation, fibroblast activation, and collagen deposition. Furthermore, DHQ ameliorated established renal fibrosis in UUO mice. CONCLUSIONS: DHQ posed remarkable preventive and therapeutic effects on UUO-induced renal fibrosis and suppressed fibroblast activation by reducing oxidative stress and Smad3 phosphorylation via Nrf2 signaling. This study provided a mechanistic basis for the clinical application of DHQ in renal fibrosis treatment.

12.
Genome Biol Evol ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32108236

RESUMO

Iron-sulfur (Fe-S) clusters play important roles in electron transfer, metabolic and biosynthetic reactions, and the regulation of gene expression. Understanding the biogenesis of Fe-S clusters is therefore relevant to many fields. In the complex process of Fe-S protein formation, the A-type assembly protein (ATAP) family, which consists of several subfamilies, plays an essential role in Fe-S cluster formation and transfer, and is highly conserved across the tree of life. However, the taxonomic distribution, motif compositions and the evolutionary history of the ATAP subfamilies are not well understood. To address these problems, our study investigated the taxonomic distribution of 321 species from a broad cross-section of taxa. Then, we identified common and specific motifs in multiple ATAP subfamilies to explain the functional conservation and nonredundancy of the ATAPs, and a novel, essential motif was found in Eumetazoa IscA1, which has a newly found magnetic function. Finally, we used phylogenetic analytical methods to reconstruct the evolution history of this family. Our results show that two types of ErpA proteins (non-proteobacteria-type ErpA1 and proteobacteria-type ErpA2) exist in bacteria. The ATAP family, consisting of seven subfamilies, can be further classified into two types of ATAPs. Type-I ATAPs include IscA, SufA, HesB, ErpA1 and IscA1, with an ErpA1-like gene as their last common ancestor (LCA), while type-II ATAPs consist of ErpA2 and IscA2, duplicated from an ErpA2-like gene. During the mitochondrial endosymbiosis, IscA became IscA1 in eukaryotes and ErpA2 became IscA2 in eukaryotes, respectively.

13.
Chem Commun (Camb) ; 56(17): 2642-2645, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32021998

RESUMO

A nickel-catalyzed tandem reaction of N-vinylamides with arylboronic acids and bromodifluoroacetate has been developed. The use of amide carbonyl as a chelating group efficiently furnishes a series of protected α,α-difluoro-γ-amino acid esters. The reaction can also extend to bromoacetate and 2-bromomalonate. The advantages of this protocol are high functional group tolerance and a broad substrate scope, including a variety of N-vinylamides. In particular, the use of removable amide carbonyl groups provides potential opportunities for applications in peptide chemistry and protein engineering.

14.
Phys Chem Chem Phys ; 22(7): 3921-3926, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32016236

RESUMO

Owing to their unique properties, thiolate-protected gold clusters (denoted as Aun(SR)m) have attracted intense research interest both experimentally and theoretically. The superatom complex (SAC) and superatom network (SAN) models are significantly well-known concepts to explain the electronic stability of Aun(SR)m. Based on the structural characters of Aun(SR)m, the tetrahedral Au4 unit was found to be an elementary building block and used to design a series of tetrahedron-network clusters. In this work, we first build a Au22(µ4-S)(SH)12 cluster consisting of a network of four non-conjugated tetrahedral Au4 units and confirm that it is a local minimum on the potential energy surface by density functional theory calculations. Chemical bonding analysis by the AdNDP method reveals that the electronic structure of Au22(µ4-S)(SH)12 follows the SAN (4 × 2e) model. Based on the structural character of the Au22(µ4-S)(SH)12 cluster, we utilize the diamond lattice as a template to construct a stable Au4S crystal in which each S atom binds to four Au4 superatoms. The computational results demonstrate that the structure has rather good dynamic and thermal stabilities, and it is an indirect semiconductor with a band gap of 2.68 eV at the HSE06 level. Chemical bonding analysis performed by the SSAdNDP method reveals that the Au4S can be seen as a SAN crystal. These bonding patterns and properties of the solid provide references for further investigation of cluster-assembled materials.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32092018

RESUMO

Deep convolutional neural networks have been widely used in numerous applications, but their demanding storage and computational resource requirements prevent their applications on mobile devices. Knowledge distillation aims to optimize a portable student network by taking the knowledge from a well-trained heavy teacher network. Traditional teacher-student-based methods used to rely on additional fully connected layers to bridge intermediate layers of teacher and student networks, which brings in a large number of auxiliary parameters. In contrast, this article aims to propagate information from teacher to student without introducing new variables that need to be optimized. We regard the teacher-student paradigm from a new perspective of feature embedding. By introducing the locality preserving loss, the student network is encouraged to generate the low-dimensional features that could inherit intrinsic properties of their corresponding high-dimensional features from the teacher network. The resulting portable network, thus, can naturally maintain the performance as that of the teacher network. Theoretical analysis is provided to justify the lower computation complexity of the proposed method. Experiments on benchmark data sets and well-trained networks suggest that the proposed algorithm is superior to state-of-the-art teacher-student learning methods in terms of computational and storage complexity.

16.
J Agric Food Chem ; 68(11): 3456-3465, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32096633

RESUMO

In this study, the role and mechanism of pterostilbene (Pts) in mast cell degranulation in vitro and in vivo were investigated. The results showed that Pts inhibited mast cell-mediated local passive allergic reactions in mice. In addition, treatment with Pts reduced both histamine release and calcium influx in rat peritoneal mast cells and RBL-2H3 cells and reduced IgE-mediated mast cell activation. Furthermore, the mechanism underlying Pts inhibition of mast cell signaling was probed via studying the effects of Pts on liver kinase B1 (LKB1), including the use of the LKB1 activator metformin and siRNA knockdown of LKB1. The data showed that Pts reduced the release of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, leukotriene C4, and prostaglandin D2 in mast cells by activating the LKB1/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Furthermore, Pts inhibited phosphorylation of FcεRI and FcεRI-mediated degranulation in RBL-2H3 cells. These effects were attenuated after LKB1 knockdown. Taken together, Pts could inhibit FcεRI signaling through activation of the LKB1/AMPK signaling pathway in IgE-mediated mast cell activation. Thus, Pts might be an effective therapeutic agent for mast cell-mediated allergic diseases.

17.
Ann Intern Med ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32066146

RESUMO

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Design: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). Setting: North America. Participants: Adults with known cardiovascular disease and diabetes or metabolic syndrome. Intervention: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Measurements: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. Results: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). Limitation: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. Conclusion: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. Primary Funding Source: National Institutes of Health.

18.
Genes (Basel) ; 11(2)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053967

RESUMO

The Apollo butterfly, Parnassius glacialis, is one of the most charming members of its genus and includes two subspecies locally distributed in montane areas of south-central China and Japan. In this study, we investigated the genetic structure and demographic history of P. glacialis by analyzing partial sequences of four mitochondrial genes and nuclear single nucleotide polymorphisms (SNPs) via genotyping-by-sequencing (GBS) of samples from nearly the entire known distributional range in China. The mitochondrial DNA (mtDNA) data demonstrated that a total of 39 haplotypes were present, and the species was estimated to have diverged about 0.95 million years ago during the middle Pleistocene transition into two main clades that likely formed during the Kunlun-Huanghe tectonic movement. The two clades then dispersed independently in distinct geographic areas alongside the mountainous routes in central and southern China, most likely driven by the Pleistocene glacial-interglacial cycles. Nuclear SNP analysis was generally congruent with mtDNA results at the individual level. A minor incongruence of genetic structures that was detected between mtDNA and nuclear SNP data from the Laojunshan and Tiantangzhai populations was likely due to secondary contact and male-biased dispersal. Our work demonstrates that complicated dispersal-vicariance evolutionary processes likely led to the current geographic distribution of P. glacialis in China, particularly the uplift of the Qinghai-Tibet Plateau and related climatic oscillations during the Quaternary period.

19.
Child Dev ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31960956

RESUMO

This study investigated the longitudinal associations between children's early mathematics and their home numeracy environment (HNE). Chilean children from families who varied widely in socioeconomic status were assessed at the beginning and end of prekindergarten in 2016 (N = 419, Mage  = 4:7 [years:months]), and at the end of kindergarten in 2017 (N = 368, Mage  = 5:10). Children whose parents provided frequent operational numeracy activities (e.g., learning simple sums) at prekindergarten showed better arithmetic performance and growth in nonsymbolic and symbolic number comparison at the end of kindergarten. Parents' knowledge of number-related games predicted children's arithmetic skills and growth in nonsymbolic number comparison. These findings underscore the persistent relations between the HNE and the development of children's mathematical skills.

20.
Ying Yong Sheng Tai Xue Bao ; 31(1): 319-325, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31957410

RESUMO

Investigating the composition of food sources with stable isotope method can provide direct evidence for the top-down control in the coastal wetland. In this study, we examined food source and feeding habit of Helice tientsinensis of common reed (Phragmites australis) vegetation in high marsh of Yellow River Delta. The results showed that the density of crab was (5.5±1.5) ind·m-2, with the behavior of climbing P. australis to feed on the leaves at night. Under the same indoor experimental condition, H. tientsinensis showed feeding preference on fresh leaves of P. aus-tralis. The stable isotope food source analysis showed that the leaves of P. australis were one of the important food sources of H. tientsinensis in the field. There were temporal variations in the proportion of fresh leaves [May: (6.4±4.9)%, July: (5.8±4.9)%, September: (12.5±8.8)%] and dead leaves [May: (12.4±7.8)%, July: (15.5±9.9)%, September: (15.1±9.4)%]. Therefore, H. tientsinensis could inhibit P. australis's growth and affect litter decomposition through feeding disturbance behavior.


Assuntos
Braquiúros , Áreas Alagadas , Animais , China , Hábitos , Poaceae , Rios
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