A Multidimensional Dataset Based on Crowdsourcing for Analyzing and Detecting News Bias

The automatic detection of bias in news articles can have a high impact on society because undiscovered news bias may influence the political opinions, social views, and emotional feelings of readers. While various analyses and approaches to news bias detection have been proposed, large data sets with rich bias annotations on a fine-grained level are still missing. In this paper, we firstly aggregate the aspects of news bias in related works by proposing a new annotation schema for labeling news bias. This schema covers the overall bias, as well as the bias dimensions (1) hidden assumptions, (2) subjectivity, and (3) representation tendencies. Secondly, we propose a methodology based on crowdsourcing for obtaining a large data set for news bias analysis and identification. We then use our methodology to create a dataset consisting of more than 2,000 sentences annotated with 43,000 bias and bias dimension labels. Thirdly, we perform an in-depth analysis of the collected data. We show that the annotation task is difficult with respect to bias and specific bias dimensions. While crowdworkers\u27 labels of representation tendencies correlate with experts\u27 bias labels for articles, subjectivity and hidden assumptions do not correlate with experts\u27 bias labels and, thus, seem to be less relevant when creating data sets with crowdworkers. The experts\u27 article labels better match the inferred crowdworkers\u27 article labels than the crowdworkers\u27 sentence labels. The crowdworkers\u27 countries of origin seem to affect their judgements. In our study, non-Western crowdworkers tend to annotate more bias either directly or in the form of bias dimensions (e.g., subjectivity) than Western crowdworkers do

Targeting histone deacetylases to modulate graft-versus-host disease and graft-versus-leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL

Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

TonEBP (tonicity-responsive enhancer binding protein) is a transcriptional regulator whose expression is elevated in response to various forms of stress including hyperglycemia, inflammation, and hypoxia. Here we investigated the role of TonEBP in acute kidney injury (AKI) using a line of TonEBP haplo-deficient mice subjected to bilateral renal ischemia followed by reperfusion (I/R). In the TonEBP haplo-deficient animals, induction of TonEBP, oxidative stress, inflammation, cell death, and functional injury in the kidney in response to I/R were all reduced. Analyses of renal transcriptome revealed that genes in several cellular pathways including peroxisome and mitochondrial inner membrane were suppressed in response to I/R, and the suppression was relieved in the TonEBP deficiency. Production of reactive oxygen species (ROS) and the cellular injury was reproduced in a renal epithelial cell line in response to hypoxia, ATP depletion, or hydrogen peroxide. The knockdown of TonEBP reduced ROS production and cellular injury in correlation with increased expression of the suppressed genes. The cellular injury was also blocked by inhibitors of necrosis. These results demonstrate that ischemic insult suppresses many genes involved in cellular metabolism leading to local oxidative stress by way of TonEBP induction. Thus, TonEBP is a promising target to prevent AKI

Novel JAK inhibitors to reduce graft-versus-host disease after allogeneic hematopoietic cell transplantation in a preclinical mouse model

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases

Recombinant bone morphogenetic protein-2 and platelet-derived growth factor-BB for localized bone regeneration. Histologic and radiographic outcomes of a rabbit study

OBJECTIVES: Improvement in localized bone regeneration is needed to avoid the use of autogenous tissue. For that purpose, the use biologic mediators was proposed. The aim was to test whether or not one of two biologic mediators, recombinant human bone morphogenetic protein-2 (rhBMP-2) or recombinant platelet-derived growth factor (rhPDGF-BB), is superior to the other and to control groups for localized bone regeneration. MATERIALS AND METHODS: Four cylinders (height: 5 mm; diameter: 7 mm) were screwed on the parietal and frontal bones at the cranium in 12 rabbits. The cylinders either received (i) deproteinized bovine bone mineral (DBBM) mixed rhBMP-2 (DBBM/BMP-2), (ii) DBBM mixed with rhPDGF-BB (DBBM/PDGF), (iii) DBBM (DBBM), and (iv) empty control (control). Rabbits were euthanized at 2 and 8 weeks (n = 6, respectively). Conventional histomorphometric and micro-CT analyses were performed. Parametric linear mixed models were applied for the analyses with Bonferroni correction for the multiple group comparisons. RESULTS: The area of bone regeneration (histology; AAHisto ) at 2 weeks peaked for DBBM (41.91%) with statistically significantly greater values compared to DBBM/PDGF and the control group (P < 0.05). At 8 weeks, mean AAHisto values were 96.29% (DBBM/BMP-2), 46.37% (DBBM/PDFG), 39.66% (DBBM), and 35.98% (control) (DBBM/BMP-2 vs. all groups (P < 0.05)). At 8 weeks, bone regeneration was greatest for DBBM/BMP-2 (35.62%) with statistically significant differences compared to all other groups (P < 0.05). The area of bone regeneration (micro-CT; AAm-CT ) at 2 weeks amounted to 43.87% (DBBM/BMP-2), 42.81% (DBBM/PDFG), 48.71% (DBBM), and 0.96% (control). The control group demonstrated statistically significantly less AAm-CT compared to all groups (P < 0.05). At 8 weeks, mean AAm-CT values were 63.65% (DBBM/BMP-2), 50.21% (DBBM/PDFG), 44.81% (DBBM), and 4.57% (control) (P > 0.05). CONCLUSIONS: The use of rhBMP-2 significantly enhanced bone regeneration compared to all other groups including the group with rhPDGF-BB

Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC

In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics

Herbal extract THI improves metabolic abnormality in mice fed a high-fat diet

Target herbal ingredient (THI) is an extract made from two herbs, Scutellariae Radix and Platycodi Radix. It has been developed as a treatment for metabolic diseases such as hyperlipidemia, atherosclerosis, and hypertension. One component of these two herbs has been reported to have anti-inflammatory, anti-hyperlipidemic, and anti-obesity activities. However, there have been no reports about the effects of the mixed extract of these two herbs on metabolic diseases. In this study, we investigated the metabolic effects of THI using a diet-induced obesity (DIO) mouse model. High-fat diet (HFD) mice were orally administered daily with 250 mg/kg of THI. After 10 weeks of treatment, the THI-administered HFD mice showed reduction of body weights and epididymal white adipose tissue weights as well as improved glucose tolerance. In addition, the level of total cholesterol in the serum was markedly reduced. To elucidate the molecular mechanism of the metabolic effects of THI in vitro, 3T3-L1 cells were treated with THI, after which the mRNA levels of adipogenic transcription factors, including C/EBPα and PPARγ, were measured. The results show that the expression of these two transcription factors was down regulated by THI in a dose-dependent manner. We also examined the combinatorial effects of THI and swimming exercise on metabolic status. THI administration simultaneously accompanied by swimming exercise had a synergistic effect on serum cholesterol levels. These findings suggest that THI could be developed as a supplement for improving metabolic status

Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models

Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4+T-bet+ T cells, CD8+T-bet+ T cells, and CD4+FOXP3+ regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2- macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation

Transmembrane solute transport in the apicomplexan parasite Plasmodium

Apicomplexa are a large group of eukaryotic, single-celled parasites, with complex life cycles that occur within a wide range of different microenvironments. They include important human pathogens such as Plasmodium, the causal agent of malaria, and Toxoplasma, which causes toxoplasmosis most often in immunocompromised individuals. Despite environmental differences in their life cycles, these parasites retain the ability to obtain nutrients, remove waste products, and control ion balances. They achieve this flexibility by relying on proteins that can deliver and remove solutes. This reliance on transport proteins for essential functions makes these pathways excellent potential targets for drug development programmes. Transport proteins are frequently key mediators of drug resistance by their ability to remove drugs from their sites of action. The study of transport processes mediated by integral membrane proteins and, in particular, identification of their physiological functions and localisation, and differentiation from host orthologues has already established new validated drug targets. Our understanding of how apicomplexan parasites have adapted to changing environmental challenges has also increased through the study of their transporters. This brief introduction to membrane transporters of apicomplexans highlights recent discoveries focusing on Plasmodium and emphasises future directions