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Abstract Background To investigate the role of antiphospholipid antibodies (aPLs) in the disease severity and prognosis of SLE-related thrombocytopenia (SLE-TP). Methods This multicenter prospective study was conducted based on data from the CSTAR registry. TP was defined as a platelet count

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).

Abstract Aim The aim of this review was to determine the effectiveness of the e‐learning programs for improving the knowledge and professional practices of nursing personnel in managing pressure injuries patients. Design Systematic review and meta‐analysis. Methods Systematic search was done in EMBASE, SCOPUS, Cochrane library, MEDLINE, Google Scholar, ScienceDirect and Clinicaltrials.gov databases until August 2022. Meta‐analysis was carried out using random‐effects model, and the results were reported as pooled standardized mean differences (SMD), or odds ratios (OR) with 95% confidence intervals (CIs). Results Eight studies were included in the analysis. Most of the studies had higher risk of bias. The pooled SMD for knowledge score and for the classification skill were 1.40 (95%CI: 0.45–2.35; I2 = 93.1%) and 1.75 (95%CI: 0.94–3.24; I2 = 78.3%) respectively. The pooled OR for the classification skills was 1.75 (95%CI: 0.94–3.24; I2 = 78.3%). Patient or Public Contribution No patient or public contribution.

Abstract Growth‐differentiation factor (GDF)‐15 is a member of transforming growth factor‐β‐related cytokine and may respond to right ventricular overload. The objective of this article was to assess the diagnosis and prognostic value of GDF‐15 in systemic lupus erythematosus‐associated pulmonary arterial hypertension (SLE‐PAH). Serum samples were obtained from 65 patients with SLE‐PAH, 51 sex and age matched patients of SLE without PAH (SLE‐non‐PAH), and 32 healthy controls. Serum GDF‐15 level was detected by enzyme‐linked immunosorbent assay and the optimal cut‐off point was determined by receiver operating characteristic curve. The primary end‐point was death from any cause and the secondary end‐point was target goal achievement (TGA). Cox regression analyses and Kaplan−Meier method were performed to identify the prognostic value of GDF‐15. Serum GDF‐15 levels were significantly higher in SLE‐PAH patients (1112.14 ± 781.80 pg/mL) than SLE‐non‐PAH patients (810 ± 408 pg/mL) and healthy controls (442 ± 139 pg/mL) at baseline. The optimal cut‐off value of GDF‐15 in the diagnosis of SLE‐PAH was 733 pg/mL (AUC = 0.84). In patients with SLE‐PAH, GDF‐15 level was associated with 6 min walking distance (ρ = −0.385, p = 0.017) and higher serum N terminal‐pro brain natriuretic peptide (NT‐proBNP) (ρ = 0.605, p 733 pg/mL were more likely to death (adjusted hazard ratio [HR] = 4.01, 95% confidence intervals [CI]: 1.23−6.27, p = 0.041) and less likely to achieve treatment goal (adjusted HR = 0.57, 95% CI: 0.23−0.79, p = 0.028). In addition, patients with simultaneous elevation of GDF‐15 and NT‐proBNP showed lower proportion of TGA (p = 0.046). In conclusion, GDF‐15 is a new and promising biomarker of development and prognosis in SLE‐PAH. The combination of GDF‐15 and NT‐proBNP may provide more accurate prognostic information.

CRISPR interference (CRISPRi) enables programmable, reversible, and titratable repression of gene expression (knockdown) in mammalian cells. Initial CRISPRi-mediated genetic screens have showcased the potential to address basic questions in cell biology, genetics, and biotechnology, but wider deployment of CRISPRi screening has been constrained by the large size of single guide RNA (sgRNA) libraries and challenges in generating cell models with consistent CRISPRi-mediated knockdown. Here, we present next-generation CRISPRi sgRNA libraries and effector expression constructs that enable strong and consistent knockdown across mammalian cell models. First, we combine empirical sgRNA selection with a dual-sgRNA library design to generate an ultra-compact (1–3 elements per gene), highly active CRISPRi sgRNA library. Next, we compare CRISPRi effectors to show that the recently published Zim3-dCas9 provides an excellent balance between strong on-target knockdown and minimal non-specific effects on cell growth or the transcriptome. Finally, we engineer a suite of cell lines with stable expression of Zim3-dCas9 and robust on-target knockdown. Our results and publicly available reagents establish best practices for CRISPRi genetic screening.

Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR::tnaA) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (Treg) cells. We demonstrated that treatment with Bm∆vjbR::tnaA polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Treg cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting Treg cell function.

Summary: The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors. : Dysbiosis of the intestinal microbiota is an emerging factor contributing to the progression of fatty liver disease. Krishnan et al. utilize metabolomics and biochemical assays in conjunction with animal and cell culture models to identify microbiota-dependent metabolites that engage a host receptor to affect liver inflammatory responses under lipid loading. Keywords: nonalcoholic fatty liver disease, gut microbiota, metabolomics, indole-3-acetate, inflammation, aryl hydrocarbon receptor

Synthetic microvascular networks are essential to enable in vitro studies of cell biology, biophysics, hemodynamics, and drug discovery, as well as in applications involving tissue engineering and artificial vasculature. But current limitations make it challenging to construct networks incorporating a hierarchy of microchannel diameters that possess cell-favored circular cross-sectional topographies. We report a new approach that overcomes these limitations by employing pressure-assisted expansion of biocompatible degradable poly(lactic acid) (PLA) substrates. This single-step process is straightforward and highly controllable, making it possible to simultaneously shape the interior topology of branched 3D and pseudo-3D microchannel networks across wide range of diameters. We further demonstrate in vitro culture of confluent endothelial cell monolayers in microchannel networks treated by this process, suggesting potential as a tool to help generate bio-mimicking vascular-like environments.