Antiphospholipid antibodies as potential predictors of disease severity and poor prognosis in systemic lupus erythematosus-associated thrombocytopenia: results from a real-world CSTAR cohort study.

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<100 × 109/L. Demographic characteristics, platelet count, clinical manifestations, disease activity, and autoantibody profiles were collected at baseline. Relapse was defined as the loss of remission. Bone marrow aspirate reports were also collected. RESULTS: A total of 350 SLE-TP patients with complete follow-up data, 194 (55.4%) were aPLs positive. At baseline, SLE-TP patients with aPLs had lower baseline platelet counts (61.0 × 109/L vs. 76.5 × 109/L, P<0.001), and a higher proportion of moderate to severe cases (24.2% vs. 14.1% ; 18.0% vs. 8.3%, P<0.001). SLE-TP patients with aPLs also had lower platelet counts at their lowest point (37.0 × 109/L vs. 51.0 × 109/L, P = 0.002). In addition, thean increasing number of aPLs types was associated with a decrease in the baseline and minimum values of platelets ( P<0.001, P = 0.001). During follow-up, SLE-TP carrying aPLs had a higher relapse rate (58.2% vs. 44.2%, P = 0.009) and a lower complete response (CR) rate. As the types of aPLs increased, the relapse rate increased, and the CR rate decreased. Furthermore, there was no significant difference in the ratio of granulocytes to red blood cells (G/E), the total number of megakaryocyte and categories. CONCLUSION: SLE-TP patients with positive aPLs had more severe disease a lower remission rate but a higher relapse rate.

Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice.

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 ß-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).

Effect of e-learning program for improving nurse knowledge and practice towards managing pressure injuries: A systematic review and meta-analysis.

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.

Sub-picosecond tunable mid-infrared light source for driving high-efficiency optical rectification.

Optical rectification (OR) is a popular way to generate coherent terahertz radiation. Here, we develop a sub-picosecond mid-infrared (mid-IR) light source with a tailored wavelength and pulse duration for enhancing the OR efficiency. Numerical simulations for a LiNbO3-based OR with tilted pulse-front excitation are first conducted to determine the optimal parameters of pump wavelength and pulse duration, demonstrating that the OR efficiency pumped by 4-µm sub-picosecond (0.5-0.6 ps) pulses is approximately twice the value with 0.8-µm pump at the same conditions. Guided by the simulation results, we build a BaGa4Se7-based optical parametric chirped-pulse amplification system with 1030-nm thin-disk pump and broadband mid-IR seeds. The output performances of >200-µJ pulse energy, ∼600-fs pulse duration and 1-kHz pulse repetition rate are achieved in a spectral range tunable from 3.5 to 5 µm. The large energy scalability and high parameter tunability make the light source attractive to high-efficiency OR in various materials.

Serial synthesis of mid-infrared optical parametric amplifiers for enlarging a gain bandwidth.

Broadband optical parametric amplifiers (OPAs) require a group-velocity matching between the signal and the idler. For mid-infrared OPAs, however, the group-velocity matching is usually difficult to meet, rendering a limited gain bandwidth. Here, we report a serial synthesis of bandwidth-limited OPAs to provide a broad gain bandwidth. In a proof-of-principle experiment, two mid-IR OPAs based on KTA crystals with different phase-matching angles are sequentially employed to amplify different spectral regions of a broad seed pulse centered at 3.1 µm. Compared to the traditional two-stage OPA, here the gain bandwidth is nearly doubled, resulting in a much shorter compressed pulse. Such a serial synthesis approach, independent of a nonlinear crystal and an interaction wavelength, particularly suits for enlarging the gain bandwidth of OPAs when broadband amplification is impossible to achieve by a single crystal.

Association Study Identified HLA-DQA1 as a Novel Genetic Risk of Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE). However, the genetic signatures of SLE-associated PAH have not been well studied. We aimed to identify genetic variants implicated in SLE-associated PAH susceptibility within the major histocompatibility complex (MHC) region and assess the contribution to clinical outcomes. METHODS: A total of 172 patients with SLE-associated PAH confirmed by right heart catheterization, 1,303 patients with SLE without PAH, and 9,906 healthy controls were included. Deep sequencing of the MHC region was performed to identify alleles, single-nucleotide polymorphisms, and amino acids. We compared patients with SLE-associated PAH with patients with SLE without PAH and healthy controls. Clinical association study was conducted to explore the contribution to phenotypes. RESULTS: A total of 19,881 genetic variants were identified within the MHC region. HLA-DQA1*03:02 was identified as a novel genetic variant associated with SLE-associated PAH in the discovery cohort (P = 5.68 × 10-12 ) and authenticated in an independent replication cohort (P = 1.30 × 10-9 ). The strongest associated amino acid position was mapped to HLA-DQα1 in the region affecting MHC/peptide-CD4+ T cell receptor affinity and antigen binding. Clinical association study demonstrated that patients with SLE-associated PAH with HLA-DQA1*03:02 had significantly lower rates of target role achievement (P = 0.005) and survival (P = 0.04). CONCLUSION: This study, based on the largest cohort of SLE-associated PAH, is the first to investigate how MHC region genetic variants contribute to SLE-associated PAH susceptibility. HLA-DQA1*03:02 is a novel genetic risk factor and a prognostic factor in SLE-associated PAH. Patients with SLE with this allele require regular monitoring and careful follow-up for early diagnosis and interventions for potential PAH.

Mid-infrared quasi-parametric chirped-pulse amplification based on Sm:LGN crystals.

We numerically demonstrate highly efficient mid-infrared quasi-parametric chirped-pulse amplification (QPCPA) based on a recently developed Sm3+-doped La3Ga5.5Nb0.5O14 (Sm:LGN) crystal. At pump wavelength around 1 µm, the broadband absorption of Sm3+ on idler pulses can enable QPCPA for femtosecond signal pulses centered at 3.5 or 5 µm, with a conversion efficiency approaching the quantum limit. Due to suppression of back conversion, such mid-infrared QPCPA exhibits robustness against phase-mismatch and pump-intensity variation. The Sm:LGN-based QPCPA will provide an efficient approach for converting currently well-developed intense laser pulses at 1 µm to mid-infrared ultrashort pulses.

The diagnostic and prognostic value of growth differentiation factor-15 in systemic lupus erythematosus-associated pulmonary arterial hypertension.

Growth-differentiation factor (GDF)-15 is a member of transforming growth factor-ß-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 < 0.001). Patients with GDF-15 > 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.

Maximizing CRISPRi efficacy and accessibility with dual-sgRNA libraries and optimal effectors.

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.

A metabolically engineered bacterium controls autoimmunity and inflammation by remodeling the pro-inflammatory microenvironment.

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.

Immunosuppressive therapy in patients with connective tissue disease-associated pulmonary arterial hypertension: A systematic review.

OBJECTIVES: It is currently accepted that inflammation plays an important role in the pathogenesis of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). However, the efficacy of immunosuppressive therapy remains anecdotal. The objective of this systematic review was to evaluate the efficacy of immunosuppressive therapy in patients with CTD-PAH and to further assess whether response differs between CTD subtypes and clinical features. METHODS: We systematically searched studies reporting the treatment response of immunosuppressants and biological agents in CTD-PAH from PUBMED, EMBASE, the Cochrane Library, and Scopus. Studies had to report treatment regime and response criteria. The risk of bias was assessed using the Newcastle-Ottawa scale. RESULTS: Seven independent cohorts, 1 trial, and 1 case-series encompassing 439 patients with CTD-PAH were included. Patients were divided into 2 groups according to the therapeutic regimen. There were 146 patients in the immunosuppressants group with better heart function at baseline and 52.1% (76/146) of them were responders. There were 236 patients treated with immunosuppressants combined with PAH-specific therapy who showed more severity at baseline and 41.1% (97/236) of them were responders. Among different CTD subtypes, patients with systemic lupus erythematosus-associated PAH (SLE-PAH) showed a better response to immunosuppressants (response rate 48.1%). What is more, 1 randomized controlled trial showed the potential therapeutic value of rituximab (n = 57) in CTD-PAH patients. CONCLUSIONS: Current studies support the use of immunosuppressive therapy in CTD-PAH, especially in SLE-PAH. Further studies on biological agents and the therapeutic effect of different immunosuppressants are still needed.

The role of anti-ribosomal P autoantibodies in the prediction of neuropsychiatric damage in systemic lupus erythematosus based on CSTAR cohort (XIV).

OBJECTIVES: To identify the predictive value of anti-ribosomal P protein (anti-RibP) antibodies on the accrual of neuropsychiatric damage in systemic lupus erythematosus (SLE) patients in a large cohort in the Chinese SLE Treatment and Research group (CSTAR) database. METHODS: This single-center prospective study was conducted based on data from the CSTAR registry. At baseline, we collected demographic characteristics, autoantibody profiles, clinical manifestations, disease activity status, and organ damage. Follow-up data were collected by reviewing clinical records and telephone interviews. Anti-RibP antibodies were identified by immunoblot containing all three native RibP (P0, P1, P2) antigenic proteins. RESULTS: Of 2395 SLE patients with complete follow-up data, 659 (27.5%) were anti-RibP antibody positive. At baseline, positive anti-RibP antibodies were associated with a higher proportion of neurological involvement (𝑃 < 0.05). During follow-up, patients with positive anti-RibP antibodies were more likely to accumulate neuropsychiatric damage (adjusted HR = 3.8, 95% CI 2.7-57), p < 0.001). What is more, the cumulative probability of new-onset neurological involvement increased gradually in anti-RibP antibody-positive patients. CONCLUSION: Anti-RibP antibodies can provide information about not only organ involvement at baseline, but also neuropsychiatric damage accrual and new-onset neurological involvement during follow-up. We suggested that anti-RibP antibody detection should be done in the newly diagnosed SLE patients to predict organ involvement and even the accumulation of neuropsychiatric damage. KEY POINTS: • Positive anti-RibP antibodies were associated with baseline neurological involvement. • Baseline positive anti-RibP antibodies can predict the neuropsychiatric damage accrual and new-onset neurological involvement.

TCQA, A Natural Caffeoylquinic Acid Derivative Attenuates H2O2-Induced Neuronal Apoptosis by Suppressing Phosphorylation of MAPKs Signaling Pathway.

1,3,5-Tri-O-caffeoyl quinic acid is a caffeoylquinic acid derivative isolated from the roots of Arctium lappa L. Our previous studies have revealed that the ethyl acetate extract of the roots of A. lappa L. and the caffeoylquinic acids contained in it possess antioxidant properties, especially 1,3,5-tri-O-caffeoyl quinic acid. The present study aimed to investigate the protective effects of 1,3,5-tri-O-caffeoyl quinic acid against hydrogen peroxide-induced oxidative stress and explore the underlying mechanism. We found that 1,3,5-tri-O-caffeoyl quinic acid prevented the decline of cell viability and excessive release of lactate dehydrogenase induced by hydrogen peroxide. In addition, Hoechst 33 342 staining and Annexin V-PI double staining showed that 1,3,5-tri-O-caffeoyl quinic acid inhibited hydrogen peroxide-induced neuronal cell apoptosis. 1,3,5-Tri-O-caffeoyl quinic acid reduced the excessive production of intracellular reactive oxygen species, decreased the malondialdehyde content, and improved the activity of superoxide dismutase. Furthermore, 1,3,5-tri-O-caffeoyl quinic acid restored the loss of mitochondrial membrane potential in SH-SY5Y cells induced by hydrogen peroxide. 1,3,5-Tri-O-caffeoyl quinic acid downregulated the overexpression of proapoptotic proteins, including Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3 as well as promoted the expression of the antiapoptotic protein Bcl-2. Moreover, the phosphorylation of mitogen-activated protein kinases induced by hydrogen peroxide was inhibited by 1,3,5-tri-O-caffeoyl quinic acid. Pretreatment with 1,3,5-tri-O-caffeoyl quinic acid also promoted the activation of phosphorylated Akt. Taken together, these findings suggest that 1,3,5-tri-O-caffeoyl quinic acid exerts protective effects against hydrogen peroxide-induced neuronal apoptosis. In addition, inhibition of the mitogen-activated protein kinase signaling pathway and the activation of Akt are implicated in the antioxidant activity of 1,3,5-tri-O-caffeoyl quinic acid, giving new insight in searching for a compound with antioxidant activity for the treatment of oxidative stress-associated neurological diseases.

Magnetic covalent organic framework nanocomposites as a new adsorbent for the determination of polycyclic aromatic hydrocarbons in water and food samples.

A magnetic covalent organic framework nanocomposite (Fe3O4@COF(Tp-NDA)) was synthesized via a solvothermal method, used as a magnetic adsorbent for the extraction of polycyclic aromatic hydrocarbons (PAHs) from lake water, tea, coffee, and fried chicken, and detected using a high performance liquid chromatography-ultraviolet detector. The synthesized magnetic adsorbent was characterized via transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, N2 adsorption-desorption isotherm analysis and vibrating sample magnetometry. Parameters that affected the extraction conditions and desorption conditions were optimized. Adsorption equilibrium could be attained within 3 min. The prepared magnetic material could be reused 10 times. The limits of detection and quantification were 0.05-0.25 µg L-1 and 0.17-0.83 µg L-1, respectively. The recovery was 74.6-101.8% with a relative standard deviation of below 4.2%. The method was successfully used to detect PAHs in various samples.

MODELING INTER-KINGDOM REGULATION OF INFLAMMATORY SIGNALING IN HUMAN INTESTINAL EPITHELIAL CELLS.

The human gastrointestinal (GI) tract is colonized by a highly diverse and complex microbial community (i.e., microbiota). The microbiota plays an important role in the development of the immune system, specifically mediating inflammatory responses, however the exact mechanisms are poorly understood. We have developed a mathematical model describing the effect of indole on host inflammatory signaling in HCT-8 human intestinal epithelial cells. In this model, indole modulates transcription factor nuclear factor κ B (NF-κB) and produces the chemokine interleukin-8 (IL-8) through the activation of the aryl hydrocarbon receptor (AhR). Phosphorylated NF-κB exhibits dose and time-dependent responses to indole concentrations and IL-8 production shows a significant down-regulation for 0.1 ng/mL TNF-α stimulation. The model shows agreeable simulation results with the experimental data for IL-8 secretion and normalized NF-κB values. Our results suggest that microbial metabolites such as indole can modulate inflammatory signaling in HTC-8 cells through receptor-mediated processes.

Roles of inflammation factors in melanogenesis (Review).

The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its occurrence is not yet known, prevention and treatment are troublesome. Previous studies have confirmed that α­melanocyte­stimulating hormone, stem cell factor and other factors can promote melanogenesis­related gene expression through the activation of signaling pathways. Recent studies have revealed that a variety of inflammatory mediators can also participate in the regulation of melanogenesis in melanocytes. In this review, we summarized that interleukin­18, interleukin­33, granulocyte­macrophage colony stimulating factor, interferon­Î³, prostaglandin E2 have the effect of promoting melanogenesis, while interleukin­1, interleukin­4, interleukin­6, interleukin­17 and tumor necrosis factor can inhibit melanogenesis. Further studies have found that these inflammatory factors may activate or inhibit melanogenesis­related signaling pathways (such as protein kinase A and mitogen activated protein kinase) by binding to corresponding receptors, thereby promoting or inhibiting the expression of melanogenesis­related genes and regulating skin pigmentation processes. This suggests that the development of drugs or treatment methods from the perspective of regulating inflammation can provide new ideas and new targets for the treatment of pigmented dermatosis. This review outlines the current understanding of the inflammation factors' roles in melanogenesis.

The Long Noncoding RNA UCA1 Negatively Regulates Melanogenesis in Melanocytes.

The long noncoding RNA UCA1 was first discovered in bladder cancer and is known to regulate the proliferation and migration of melanoma. However, its role in melanogenesis is unclear. In this study, we aimed to explore the role and mechanism of UCA1 in melanogenesis. Our findings showed that the expression of UCA1 was negatively correlated with melanin content in melanocytes and pigmented nevus. Overexpression of UCA1 in melanocytes decreased melanin content and the expression of melanogenesis-related genes, whereas knockdown of UCA1 in melanocytes had the opposite effect. High-throughput sequencing revealed that microphthalmia-associated transcription factor (MITF), an important transcription factor affecting melanogenesis, was also negatively correlated with the expression of UCA1. Furthermore, the transcription factor CRE-binding protein (CREB), which promotes MITF expression, was negatively regulated by UCA1. The cAMP/protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways, which are upstream of the CREB/MITF/melanogenesis axis, were activated or inhibited in response to silencing or enhancing UCA1 expression, respectively. In addition, enhanced UCA1 expression downregulates the expression of melanogenesis-related genes induced by UVB in melanocytes. In conclusion, UCA1 may negatively regulate the CREB/MITF/melanogenesis axis through inhibiting the cAMP/PKA, ERK, and JNK signaling pathways in melanocytes. UCA1 may be a potential therapeutic target for the treatment of pigmented skin diseases.