Summary
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with abnormal T cell immune responses. We hypothesized that aberrant expression of microRNAs (miRNAs) in T cells may ...contribute to the pathogenesis of SLE. First, we analysed the expression profiles of 270 human miRNAs in T cells from five SLE patients and five healthy controls and then validated those potentially aberrant‐expressed miRNAs using real‐time polymerase chain reaction (PCR). Then, the expression of mRNAs regulated by these aberrant‐expressed miRNAs was detected using real‐time PCR. Finally, miRNA transfection into Jurkat T cells was conducted for confirming further the biological functions of these miRNAs. The initial analysis indicated that seven miRNAs, including miR‐145, miR‐224, miR‐513‐5p, miR‐150, miR‐516a‐5p, miR‐483‐5p and miR‐629, were found to be potentially abnormally expressed in SLE T cells. After validation, under‐expressed miR‐145 and over‐expressed miR‐224 were noted. We further found that STAT1 mRNA targeted by miR‐145 was over‐expressed and apoptosis inhibitory protein 5 (API5) mRNA targeted by miR‐224 was under‐expressed in SLE T cells. Transfection of Jurkat cells with miR‐145 suppressed STAT1 and miR‐224 transfection suppressed API5 protein expression. Over‐expression of miR‐224 facilitates activation‐induced cell death in Jurkat cells. In the clinical setting, the increased transcript levels of STAT1 were associated significantly with lupus nephritis. In conclusion, we first demonstrated that miR‐145 and miR‐224 were expressed aberrantly in SLE T cells that modulated the protein expression of their target genes, STAT1 and API5, respectively. These miRNA aberrations accelerated T cell activation‐induced cell death by suppressing API5 expression and associated with lupus nephritis by enhancing signal transducer and activator of transcription‐1 (STAT)‐1 expression in patients with SLE.
This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic ...circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner.
Fatty liver disease is commonly associated with obesity, insulin resistance and diabetes. Severe fatty liver is sometimes accompanied by steatohepatitis and may lead to the development of ...hepatocellular carcinoma. At present, there is no effective treatment for non-alcoholic fatty liver disease (NAFLD); thus, recent investigations have focused on developing effective therapeutics to treat this condition. This study aimed to evaluate the effects of kefir on the hepatic lipid metabolism of ob/ob mice, which are commonly used to model fatty liver disease.
In this study, we used leptin receptor-deficient ob/ob mice as an animal disease model of NAFLD. Six-week-old ob/ob mice were orally administered the dairy product kefir (140 mg kg(-1) of body weight (BW) per day) for 4 weeks. The data demonstrated that kefir improved fatty liver syndrome on BW, energy expenditure and basal metabolic rate by inhibiting serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) activities (P<0.05) and by decreasing the triglyceride (TG) and total cholesterol (TC) contents of the liver (P<0.05). Oral kefir administration also significantly reduced the macrovesicular fat quantity in liver tissue. In addition, kefir markedly decreased the expression of the genes sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (P<0.05) but not the expression of peroxisome proliferator-activated receptor α (PPARα) or hepatic carnitine palmitoyltransferase-1α (CPT1α) in the livers of ob/ob mice.
On the basis of these results, we conclude that kefir improves NAFLD on BW, energy expenditure and basal metabolic rate by inhibiting the lipogenesis pathway and that kefir may have the potential for clinical application to the prevention or treatment of NAFLD.
Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not ...fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.
This article shows how the concept of reliability of composite scores, as defined in classical test theory, can be extended to the context of multilevel modeling. In particular, it discusses the ...contributions and limitations of the various level-specific reliability indices proposed by Geldhof, Preacher, and Zyphur (2014), denoted as ω̃b
and ω̃w (and also αãb and α̃w). One major limitation of those indices is that they are quantities for latent, unobserved level-specific composite scores, and are not suitable for observed composites at different levels. As illustrated using simulated data in this article, ω̃b can drastically overestimate the true reliability of between-level composite scores (i.e., observed cluster means). Another limitation is that the development of those indices did not consider the recent conceptual development on construct meanings in multilevel modeling (Stapleton & Johnson, 2019; Stapleton, Yang, & Hancock, 2016). To address the second limitation, this article defines reliability indices (ω2l, ωb, ωw, α2l, αb, αw) for three types of multilevel observed composite scores measuring various multilevel constructs: individual, configural, shared, and within-cluster. The article also shows how researchers can obtain sample point and interval estimates using the derived formulas and the provided R and Mplus code. In addition, a large-scale national data set was used to illustrate the proposed methods for estimating reliability for the three types of multilevel composite scores, and practical recommendations on when different indices should be reported are provided.
Translational Abstract
Reporting of reliability information of measures on the studied sample is a basic requirement in psychological research. For multilevel data-data that have a hierarchical structure such as students nested within schools and survey participants nested within neighborhoods, previous research commonly used the between-level and within-level composite reliability proposed by Geldhof, Preacher, and Zyphur (2014). However, this article shows that the previously proposed between-level composite reliability can provide overly optimistic reliability coefficient because it ignores one major source of error, namely the sampling error of cluster means. To obtain more accurate reliability information for multilevel data, this article proposes alternative reliability indices that correctly account for the different sources of measurement error. The computation of the between-level indices also takes into account whether the construct being measured is an aggregate of individual characteristics (e.g., mean student achievement of a school) or an inherent group-level characteristic (e.g., school climate). I illustrate the proposed indices using a large-scale national data set with four items measuring students' attitudes toward mathematics. Software code in the R and the Mplus software was provided so that applied researchers can use to compute the proposed indices for their data and the corresponding confidence intervals.
The strong coupling between antiferromagnetism and ferroelectricity at room temperature found in BiFeO3 generates high expectations for the design and development of technological devices with novel ...functionalities. However, the multi-domain nature of the material tends to nullify the properties of interest and complicates the thorough understanding of the mechanisms that are responsible for those properties. Here we report the realization of a BiFeO3 material in thin film form with single-domain behaviour in both its magnetism and ferroelectricity: the entire film shows its antiferromagnetic axis aligned along the crystallographic b axis and its ferroelectric polarization along the c axis. With this we are able to reveal that the canted ferromagnetic moment due to the Dzyaloshinskii-Moriya interaction is parallel to the a axis. Furthermore, by fabricating a Co/BiFeO3 heterostructure, we demonstrate that the ferromagnetic moment of the Co film does couple directly to the canted moment of BiFeO3.
TONs of copper fun: There is considerable interest in developing catalysts to harness the abundant natural supply of methane for various industrial applications. Two tricopper complexes capable of ...mediating efficient oxidation of methane to methanol under ambient conditions were tested: a biomimetic tricopper complex (see figure) and a tricopper‐peptide species derived from the particulate methane monooxygenase (pMMO) protein.
The genus of Nocardia is rapidly expanding and the species distribution varies with different geographical locations. We retrospectively reviewed the laboratory records of the bacteriology laboratory ...at National Taiwan University Hospital from January 1998 to June 2008 to identify patients with nocardiosis. During the study period, 164 isolates of Nocardia spp. were identified from 134 patients but only 113 patients had Nocardia infection. Nocardia brasiliensis (n = 54) was the most common pathogen, followed by N. asteroides (n = 36), N. farcinica (n = 7), N. flavorosea (n = 4), N. otitidiscaviarum (n = 3), N. nova (n = 3), N. beijingensis (n = 2) and one each of N. puris, N. jinanensis and N. takedensis. The major types of infection were cutaneous infection (56.6%), pulmonary infection (33.6%) and disseminated infection (7.1%). Eighty-eight patients received sulfonamide-containing antibiotic and eight of 100 patients with available data on outcomes died during the episode of nocardiosis. In conclusion, the clinical and microbiological manifestations of Nocardiosis vary with the different Nocardia species. Accurate identification of the species is crucial to make the diagnosis.
Clostridium innocuum can cause extraintestinal infection in patients with underlying diseases. The role of C. innocuum in antibiotic-associated diarrhoea (AAD) remains unknown.
Clinical information ...of 103 patients from whom C. innocuum was isolated was reviewed. We carried out cellular and animal experiments to examine the pathogenic potential of C. innocuum in AAD.
Eighty-eight per cent (91/103) of the 103 patients received antibiotics within 2 weeks of diarrhoea onset. Patients were further classified into two groups, severe colitis and diarrhoea, according to clinical severity level. The mortality rate was 13.6% (14/103) among the patients from whom C. innocuum was isolated. The lowest concentrations at which 90% of the isolates were inhibited for metronidazole and vancomycin were 0.5 and 16 mg/L, respectively. All isolates tested were susceptible to metronidazole but resistant to vancomycin. Nineteen randomly selected isolates (ten from severe colitis group, nine from diarrhoea group) were subjected to further in vitro cellular examinations. The level of cytotoxicity to Vero cells was significantly higher in isolates from the severe colitis group at both 24 and 48 hours after inoculation (24 and 48 hours, p 0.042 and 0.033, respectively). We observed apoptotic changes that subsequently led to cell death in C. innocuum–infected Vero cells. Tissue damages, necrotic changes and oedema were observed in the mouse ileal loop infected by C. innocuum.
Vancomycin-resistant C. innocuum may play a potential role as a causative agent of AAD. The clinical manifestations of AAD caused by C. innocuum were diarrhoea or severe colitis, including pseudomembranous colitis.
This study surveyed the characteristics of white matter (WM) micro-integrity in patients who were diagnosed with major depressive disorder (MDD) without co-morbidities.
A total of 44 patients with ...MDD and 27 normal controls were enrolled in our study. Diffusion tensor imaging images of patients and controls were pre-processed and analysed to estimate differences in WM micro-integrity between patients and controls by performing comparisons of the values obtained from fractional anisotropy (FA). FA outputs of patients and controls were compared by a non-parametric permutation-based method with global brain volume, age and gender as covariates. In addition, the between-group differences of radial diffusivity (RD) and axial diffusivity (AD) were assessed to explain the alterations in FA values. Correlations between clinical variables (such as depression severity, anxiety severity, illness duration) and FA values were also estimated in each group and across both groups.
The patients with MDD had significantly lower FA values than the controls, for the left superior longitudinal fasciculus (SLF) and the right anterior thalamic radiation (ATR). The reductions in FA values occurred in combination with elevated RD values in the bilateral SLF and decreased AD values in the bilateral ATR. FA values were negatively correlated with depression severity in the SLF and with illness duration in the right SLF and ATR.
MDD patients had significant alterations in the WM micro-integrity of the left SLF and the right ATR.
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