Miracle-dz/UniFAR-FTUs huggingface dataset:
Interleukin-33 in Systemic Sclerosis: Expression and Pathogenesis

Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions as a traditional cytokine and nuclear factor. It is proposed to have an “alarmin” role. IL-33 mediates biological effects by interacting with the ST2 receptor and IL-1 receptor accessory protein, particularly in innate immune cells and T helper 2 cells. Recent articles have described IL-33 as an emerging pro-fibrotic cytokine in the immune system as well as a novel potential target for systemic sclerosis. Here, we review the available information and focus on the pleiotropic expression and pathogenesis of IL-33 in systemic sclerosis, as well as the feasibility of using IL-33 in clinical applications.
Anti-biofilm effects of gold and silver nanoparticles synthesized by the Rhodiola rosea rhizome extracts

Abstract Bacterial biofilm represents a major problem in medicine. They colonize and damage medical devices and implants and, in many cases, foster development of multidrug-resistant microorganisms. Biofilm development starts by bacterial attachment to the surface and the production of extracellular polymeric substances (EPS). The EPS forms a structural scaffold for dividing bacterial cells. The EPS layers also play a protective role, preventing the access of antibiotics to biofilm-associated microorganisms. The aim of this work was to investigate the production nanoparticles that could be used to inhibit biofilm formation. The applied production procedure from rhizome extracts of Rhodiola rosea is simple and environmentally friendly, as it requires no additional reducing, stabilizing and capping agents. The produced nanoparticles were stable and crystalline in nature with an average diameter of 13–17 nm for gold nanoparticles (AuNPs) and 15–30 nm for silver nanoparticles (AgNPs). Inductively coupled plasma mass spectrometry analysis revealed the concentration of synthesized nanoparticles as 3.3 and 5.3 mg/ml for AuNPs and AgNPs, respectively. Fourier-transform infrared spectroscopy detected the presence of flavonoids, terpenes and phenols on the nanoparticle surface, which could be responsible for reducing the Au and Ag salts to nanoparticles and further stabilizing them. Furthermore, we explored the AgNPs for inhibition of Pseudomonas aeruginosa and Escherichia coli biofilms. AgNPs exhibited minimum inhibitory concentrations of 50 and 100 µg/ml, against P. aeruginosa and E. coli, respectively. The respective minimum bactericidal concentrations were 100 and 200 µg/ml. These results suggest that using the rhizome extracts of the medicinal plant R. rosea represents a viable route for green production of nanoparticles with anti-biofilm effects. Graphical Abstract A schematic representation of the green synthesis, characterization and biofilm inhibition application of nanoparticles produced by extracts of R. rosea.
The toxin from a ParDE toxin‐antitoxin system found in Pseudomonas aeruginosa offers protection to cells challenged with anti‐gyrase antibiotics

Toxin‐antitoxin systems are mediators of diverse activities in bacterial physiology. For the ParE‐type toxins, their reported role of gyrase inhibition utilized during plasmid‐segregation killing indicates they are toxic. However, their location throughout chromosomes leads to questions about function, including potential non‐toxic outcomes. The current study has characterized a ParDE system from the opportunistic human pathogen Pseudomonas aeruginosa (Pa). We identified a protective function for this ParE toxin, PaParE, against effects of quinolone and other antibiotics. However, higher concentrations of PaParE are themselves toxic to cells, indicating the phenotypic outcome can vary based on its concentration. Our assays confirmed PaParE inhibition of gyrase‐mediated supercoiling of DNA with an IC50 value in the low micromolar range, a species‐specificity that resulted in more efficacious inhibition of Escherichia coli derived gyrase versus Pa gyrase, and overexpression in the absence of antitoxin yielded an expected filamentous morphology with multi‐foci nucleic acid material. Additional data revealed that the PaParE toxin is monomeric and interacts with dimeric PaParD antitoxin with a KD in the lower picomolar range, yielding a heterotetramer. This work provides novel insights into chromosome‐encoded ParE function, whereby its expression can impart partial protection to cultures from selected antibiotics.
Circulating mir‐320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk

miRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. Little is known on the origin of circulating miRNAs and their relationship with the tumor microenvironment in lung cancer. Here, we focused on the cellular source and relative contribution of different cell types to circulating miRNAs composing our risk classifier of lung cancer using in vitro/in vivo models and clinical samples. A cell‐type specific expression pattern and topography of several miRNAs such as mir‐145 in fibroblasts, mir‐126 in endothelial cells, mir‐133a in skeletal muscle cells was observed in normal and lung cancer tissues. Granulocytes and platelets are the major contributors of miRNAs release in blood. miRNAs modulation observed in plasma of lung cancer subjects was consistent with de‐regulation of the same miRNAs observed during immunosuppressive conversion of immune cells. In particular, activated neutrophils showed a miRNA profile mirroring that observed in plasma of lung cancer subjects. Interestingly mir‐320a secreted by neutrophils of high‐risk heavy‐smokers promoted an M2‐like protumorigenic phenotype through downregulation of STAT4 when shuttled into macrophages. These findings suggest a multifactorial and nonepithelial cell‐autonomous origin of circulating miRNAs associated with risk of lung cancer and that circulating miRNAs may act in paracrine signaling with causative role in lung carcinogenesis and immunosuppression.
Genome-Wide Analysis of mRNAs and lncRNAs of Intramuscular Fat Related to Lipid Metabolism in Two Pig Breeds

Background/Aims: Long non-coding RNAs (lncRNAs) can regulate adipogenesis and lipid accumulation. Intramuscular fat deposition appears to vary in different pig breeds, and the regulation mechanism has not yet been fully elucidated at molecular level. Moreover, little is known about the function and profile of lncRNAs in intramuscular fat deposition and metabolism in pig. The aim of this study was thus to explore the regulatory functions of lncRNAs in intramuscular fat deposition. Methods: In this study, Laiwu (LW) pig and Large White (LY) pig with significant difference in fat deposition were selected for use. RNA-seq technology and bioinformatics methods were used to comparatively analyze the gene expression profiles of intramuscular fat between LW and LY pigs to identify key mRNAs and lncRNAs associated with lipid metabolism and adipogenesis. Real-time fluorescence-based quantitative PCR was applied to verify the expression level of the differentially expressed mRNAs and lncRNAs. Results: A total of 513 mRNAs and 55 lncRNAs were differentially expressed between two pig breeds. By co-expression network construction as well as cis- and trans-regulated target gene analysis, 31 key lncRNAs were identified. Gene Ontology and KEGG pathway analyses revealed that differentially expressed genes and lncRNAs were mainly involved in the biological processes and pathways related to adipogenesis and lipid metabolism. Conclusion: XLOC_046142, XLOC_004398 and XLOC_015408 may target MAPKAPK2, NR1D2 and AKR1C4, respectively, and play critical regulatory roles in intramuscular adipogenesis and lipid accumulation in pig. XLOC_064871 and XLOC_011001 may play a role in lipid metabolism-related disease via regulating TRIB3 and BRCA1. This study provides a valuable resource for lncRNA study and improves our understanding of the biological roles of lipid metabolism- related genes and molecular mechanism of intramuscular fat metabolism and deposition.
Chokeberry Extract and Its Active Polyphenols Suppress Adipogenesis in 3T3-L1 Adipocytes and Modulates Fat Accumulation and Insulin Resistance in Diet-Induced Obese Mice

Berries of Aronia melanocarpa (chokeberry) are known to be a rich source of biologically active polyphenols. In the present study, the effects of seven anti-adipogenic polyphenolic phytochemicals isolated from A. melanocarpa methanol extract on adipogenic transcription factors were investigated. Amygdalin and prunasin were found to inhibit 3T3-L1 adipocyte differentiation by suppressing the expressions of PPARγ (peroxisome proliferator-activated receptor γ), C/EBPα (CCAAT/enhancer binding protein α), SREBP1c (sterol regulatory element binding protein 1c), FAS (fatty acid synthase), and aP2 (adipocyte fatty-acid–binding protein). A. melanocarpa extract-treated (100 or 200 mg/kg/day on body weight) high fat diet (HFD)-induced obese mice showed significant decreases in body weight, serum triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) levels and improved insulin sensitivity as compared with HFD controls. This research shows A. melanocarpa extract is potentially beneficial for the suppression of HFD-induced obesity.
Novel Agents for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is “3 + 7” regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors’ opinion.
Global Brain That Makes You Think Twice

In this position paper we introduce our approach to positive computing by developing and integrating meth-ods for future assistant and companion agents which could help us a) avoid making mistakes due to biases caused by insufﬁcient knowledge, b) be more empathic and righteous, c) be more sensitive and thoughtful. We present text processing techniques for automatic discovery of possible reasoning errors and provide hints to make users doubt their beliefs when there is a possibility of harm. We present existing sources and methods, discuss on how natural language processing technologies could contribute to various aspects of well-being by giving examples of systems we develop, and describe the strengths and weaknesses of our approach.
Bacillus thuringiensis Suppresses the Humoral Immune System to Overcome Defense Mechanism of Plutella xylostella

Background: Plutella xylostella has become a notorious pest of cruciferous crops all over the world. Delta-endotoxins of Bacillus thuringiensis are widely used insecticidal proteins for controlling P. xylostella. However, the interaction mechanism of B. thuringiensis with the immune system of P. xylostella, at the genomic level, is still unclear. This study explored the immune response of P. xylostella to B. thuringiensis, at different time intervals, 6 h, 12 h, 18 h, 24 h, and 36 h, by using RNA-Sequencing (RNA-Seq) and RT-qPCR. Results: In total, 167 immunity-related genes were identified and placed into different families, including pattern recognition receptors (PRRs), signal modulators, immune pathways (Toll, IMD, and JAK/STAT), and immune effectors. It is worth mentioning that the analyses of the differentially expressed immunity-related genes revealed that most of the differentially expressed genes (DEGs) (87, 56, 76, 67, and 73 genes) were downregulated in P. xylostella following B. thuringiensis oral infection at 6 h, 12 h, 18 h, 24 h, and 36 h. Interestingly, our RNA-Seq analysis also revealed reduced expression of antimicrobial peptides, that play a vital role in the humoral immune system of P. xylostella. Conclusion: This study demonstrates that B. thuringiensis plays a novel role in controlling P. xylostella, by suppressing the immune system.
IR-A/IGF-1R-mediated signals promote epithelial-mesenchymal transition of endometrial carcinoma cells by activating PI3K/AKT and ERK pathways

ABSTRACT Background Obesity is a risk factor for endometrial cancer (EC). However, it is not known how insulin receptor isoform A (IR-A) and insulin-like growth factor 1 receptor (IGF-1R), cognate receptors for insulin and IGFs, respectively, regulate malignant behaviors of EC. In this study, we examined the biological effects of IR-A/IGF-1R, explored the downstream signaling cascades, and assessed the therapeutic potential of targeting IR-A/IGF-1R in vivo. Methods The expression levels of IR-A and IGF-1R were examined by qRT-PCR and Western blotting. Upon down-regulating IR-A and/or IGF-1R by sh-IR-A and/or sh-IGF-1R, respectively, cell migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) were examined by wound healing, transwell invasion, flow cytometry, and Western blotting, respectively. Furthermore, the effect of sh-IR-A and/or sh-IGF-1R on phosphatidylinositide 3-kinases (PI3K)/AKT and ERK pathways was measured by Western blotting. Lastly, we monitored xenograft growth and EMT in vivo. Results Both IR-A and IGF-1R were significantly up-regulated in EC cells. Knockdown of IR-A or IGF-1R alone was sufficient to reduce migration and invasion, enhance apoptosis, and inhibit EMT of EC cells, and the most significant alterations were observed in cells co-transfected with sh-IR-A+ sh-IGF-1R. These phenotypes were associated with inactivating PI3K/AKT and ERK signaling by sh-IR-A and/or sh-IGF-1R. Consistent with in vitro findings, sh-IR-A or sh-IGF-1R significantly inhibited xenograft growth and EMT in vivo. Conclusion IR-A and IGF-1R-mediated signals, by activating PI3K/AKT and ERK pathways, can induce multiple malignant phenotypes of EC cells. Therefore, targeting IR-A or IGF-1R may provide therapeutic benefits for EC.
Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles

Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
Detailed Characterization of Early HIV-1 Replication Dynamics in Primary Human Macrophages

Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV-1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the detection of reverse transcriptase (RT) products with droplet digital PCR (ddPCR) revealed that early replication was delayed in primary human monocyte-derived macrophages of several donors and peaked late after infection. Direct imaging of reverse-transcription and pre-integration complexes (RTC/PIC) by click-labeling of newly synthesized DNA further confirmed our findings and showed a concomitant shift to the nuclear stage over time. Altering the entry pathway enhanced infectivity but did not affect kinetics of viral replication. The addition of viral protein X (Vpx) enhanced productive infection and accelerated completion of reverse transcription and nuclear entry. We propose that sterile alpha motif (SAM) and histidine/aspartate (HD) domain-containing protein 1 (SAMHD1) activity lowering deoxyribonucleotide triphosphate (dNTP) pools is the principal factor delaying early HIV-1 replication in macrophages.
Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats

Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.
Diagnostic performance of a new anti-carbamylated protein assay in rheumatic diseases

Autoantibodies play an essential role in the diagnosis and prognosis of rheumatoid arthritis (RA), a systemic autoimmune disease. Recently, several novel autoantibody systems have been identified in rheumatoid arthritis (RA) (1), including antibodies against carbamylated proteins (CarP) whose predictive and prognostic value have been established (2–4). In this study, we evaluated the analytical and diagnostic performance of a new antiCarP assay for RA in a US rheumatic disease cohort. Anti-CarP antibodies were measured using an enzymelinked immunosorbent assay (ELISA) (QUANTA Lite® CarP, research use only; InovaDiagnostics, SanDiego, CA, USA) following the manufacturer’s protocol. In brief, calibrator and diluted subject sera/plasma were added to carbamylated foetal calf serum-boundwells and incubated for 1 h at room temperature. Unbound antibodies were washed away and an enzyme-labelled anti-human immunoglobulin G (IgG) conjugate was added. After another hour of
SGK1-FoxO1 Signaling Pathway Mediates Th17/Treg Imbalance and Target Organ Inflammation in Angiotensin II-Induced Hypertension

It has been demonstrated that serum/glucocorticoid regulated kinase 1 (SGK1) and the downstream transcription factor forkhead box O1 (FoxO1) plays a critical role in the differentiation of T helper 17 cells/regulatory T cells (Th17/Treg). In the present study, we hypothesized that this SGK1-FoxO1 signaling pathway is involved in Th17/Treg imbalance and target organ damage in angiotensin II (AngII)-induced hypertensive mice. Results show that SGK1 inhibitor EMD638683 significantly reversed renal dysfunction and cardiac dysfunction in echocardiography as indicated by decreased blood urine nitrogen and serum creatinine in AngII-infused mice. Flow cytometric assay shows that there was significant Th17/Treg imbalance in spleen and in renal/cardiac infiltrating lymphocytes as indicated by the increased Th17 cells (CD4+-IL17A+ cells) and decreased Treg cells (CD4+-Foxp3+). Consistently, real-time PCR shows that Th17-related cytokines including IL-17A, IL-23, and tumor necrosis factor α (TNF-α) was increased and Treg-related cytokine IL-10 was decreased in renal and cardiac infiltrating lymphocytes in AngII-infused mice. Meanwhile, SGK1 protein level, as well as its phosphorylation and activity, was significantly increased in spleen in AngII-infused rats. Furthermore, it was found that splenic phosphorylated FoxO1 was significantly increased, whereas total FoxO1 in nuclear preparation was significantly decreased in AngII-infused mice, suggesting that increased FoxO1 phosphorylation initiate its translocation from cytoplasm to nucleus. Notably, all changes were significantly inhibited by the treatment of EMD638683. These results suggest that SGK1 was involved in Th17/Treg imbalance and target organ damage in AngII-induced hypertension.
Challenges and opportunities for antibiotic stewardship among preterm infants

Antibiotic stewardship programmes aim to optimise antimicrobial use to prevent the emergence of resistance species and protect patients from the side effects of unnecessary medication. The high incidence of systemic infection and associated mortality from these infections leads neonatal providers to frequently initiate antibiotic therapy and make empiric antibiotic courses one of the main contributors of antibiotic use in the neonatal units. Yet, premature infants are also at risk for acute life-threatening complications associated with antibiotic use such as necrotising enterocolitis and for long-term morbidities such as asthma. In this review, we discuss specific aspects of antibiotic use in the very low birthweight preterm infants, with a focus on empiric use, that provide opportunities for stewardship practice. We discuss strategies to risk-stratify antibiotic initiation for the risk of early-onset sepsis, optimise empiric therapy duration and antibiotic choice in late-onset sepsis, and standardise decisions for stopping empiric therapy. Lastly, review the evolving role of biomarkers in antibiotic stewardship.