bluuebunny/crossref_metadata_2025_split huggingface dataset:
How big is a big effect size? A nonparametric measure of effect size when modeling cytokines
Authors: Qeadan Fares , Dwivedi Sunita , Erdei Esther , Beswick Ellen 
Published: January 2023

Abstract
Cytokines play a major role in driving immune responses in cancer and other diseases. There is a critical need to understand how they interact and regulate one another. In this study, we examine new approaches to understand meaningful networks between cytokines and their relevance to human disease.
Effect size (ES) is a way of assessing the difference between two groups with respect to a continuous measure such as cytokines. Its use, relative to p-values, gives easier understanding to whether a difference is actually clinically important or not. Results of a study can be statistically significant but still be too small to be of any practical value, or statistically insignificant but still be too large to not be of any practical value; especially when multiple comparisons adjustments are applied. As opposed to p-values, ES is independent of sample size, and thus has recently attracted the attention of researchers.
When modeling cytokines, we recommend the use of the A measure of stochastic superiority A = [#Y1 &gt; Y2) + 0.5#(Y1=Y2)]/n1n2, due to Delaney and Vargha (2002), which is appropriate for the nonparametric Wilcoxon Test. The ES of interest from this measure is A/1 – A which gives the odds that an individual in one group will score higher than an individual in the other group. Our simulation indicated that odds= 1.253, 1.763, and 2.500 are equivalent to Cohen’s d = 0.2 (small), 0.5 (medium), and 0.8 (large).
We applied this measure on a panel of 26 cytokines identified in 29 subjects (15 with Metastasis and 14 without Metastasis) with gastric cancer, and revealed 11 cytokines with large ES, five of which with non-significant Sidak adjusted p-values: (from largest to smallest) G-CSF, IL-6, IL-8, MCP-1, IL-10, TNF-a, GM-CSF, MIP-1a, IL-1b, MIP-1b, and VEGF.
BAFF antagonists designed by computer-aided drug design inhibited the interaction of BAFF with its receptors
Authors: Sun Jian , Zhang Xiaojuan , Zhen Zhao , Hao Xiafei 
Published: January 2023

Abstract
BAFF is a critical factor for B cell maturation and survival, and its overexpression is involved in pathogenesis of autoimmune diseases. As blockade of BAFF activity significantly improves the symptoms of autoimmune diseases such as SLE and RA, BAFF is a promising therapeutic target for treating these diseases. Currently, most BAFF antagonists are antibodies against BAFF or soluble BAFF receptor-IgG1 Fc fusion proteins. Small molecules such as peptides as antagonists to block the biological activity of cytokines have been investigated intensively. Based on the crystal structures of the protein–protein complexes, protein mimics can be designed as antagonists with computer-aided drug design (CADD) to block the cytokine-receptor interactions. Since the crystal structures of BAFF and its receptors are known, we designed BAFF antagonist peptides with CADD. The peptides could inhibit the binding of BAFF with its receptors BCMA, TACI and BR3. In addition, BAFF-binding peptides originated from CADD were compared to the peptide selected from the phage display library. Both kinds of peptides could inhibit the binding of BAFF to its receptors, a peptide from the phage display library showed two-fold inhibition effect on BAFF binding to its receptors. 3-copy vs 1-copy of peptides were also studied and the results indicated that increasing the copy numbers of peptides in peptide-Fc fusion proteins did not significantly enhance the bioactivities of the peptides. Therefore, BAFF antagonist peptides designed by CADD could bind to BAFF in a dose-dependent manner and inhibit BAFF biological activity significantly, which might be potential agents for autoimmune disease therapies.
Production and characterization of monoclonal antibodies specific for chicken interleukin-4
Authors: CHAUDHARI ATUL , Kim Woohyun , Lillehoj Hyun H. 
Published: January 2023

Abstract
Interleukin-4 is an important Th2 type cytokine in mammals which regulates growth and differentiation of B Lymphocytes. On the mammalian counterparts, the function of IL-4 orthologue in chickens (chIL-4) is less understood. Although the source of chIL-4 is not well established, it has been shown to have an integral role in mediating Th2 type immune responses in chickens. Despite its significant role, no monoclonal antibodies (mAbs) against chIL-4 have been developed till date. Therefore, in the present study we used recombinant yeast-expressed chIL-4 as an immunogen to develop mAbs against chIL-4 to establish the basis for understanding the function of chIL-4 in regulating Th2 mediated immune responses in chickens. We developed two mAbs against chIL-4 and characterized their specificity by western blot, enzyme linked immunosorbent assay (ELISA) and intracellular staining (ICS). These antibodies displayed specific binding with the recombinant chl-IL-4 as well as endogenous chIL-4 by western blot, ELISA and ICS. Further, these antibodies neutralized the inhibitory effect of chIL-4 on lipopolysaccharide (LPS)-induced nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) in avian macrophage-like HD11 cells, thus confirming that these antibodies can block the chIL-4 bioactivity. In conclusion, the mAbs developed in the present study can be useful for understanding the role of chIL-4 in the basic concept of Th1 versus Th2 T cell subsets in chickens.
Development of an Ultra-Sensitive Multiplex (6-plex) Cytokine Digital Immunoassay with fg/ml Sensitivity
Authors: Lambert Jeremy , Shan Dandan , Chang Lei , Rissin David , Nie Shuai , Hanlon David 
Published: January 2023

Abstract
The future of immuno-oncology treatment and autoimmune diagnostics will involve the detection and quantification of inflammatory biomarkers. As immunotherapy becomes a more common approach for treating cancer and inflammatory disease, cytokines will not only play a role in determining a patient’s disease diagnosis, prognosis, and potential treatment options, but also may serve as a primary index of a therapy’s effectiveness.
Incorporating these biomarkers into clinical practice, however, has been a challenge. Only a few cytokines have been studied in relation to inflammatory disease and immunotherapy, mainly because the biomarkers for these conditions are typically present in very small concentrations, and current research methods aren’t sensitive enough to detect them. It is critical that physicians have the ability to quantify these cytokines to track disease progression before and after treatment.
We present development and characterization of a multiplex digital immunoassay to simultaneously detect and quantify six inflammatory biomarkers (IL-10, IL-12p70, IL-17A, IL-6, TNFa, IFNg) with fg/ml sensitivity. This advanced approach reduces assay volume requirements for multiple sample types and may be sensitive enough to detect circulating disease biomarkers before symptoms appear. As a result, it could potentially provide physicians with a new capability to track disease progression, and the effectiveness of treatments against diseases, which they previously could not monitor with such precision.
Tristetraprolin family of RNA binding proteins post-transcriptionally regulate inflammation and metabolic responses in the liver
Authors: Patial Sonika , Blackshear Perry 
Published: January 2023

Abstract
Tristetraprolin family of RNA binding proteins, including tristetraprolin (TTP), zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2) regulate mRNA levels by binding to AU-rich elements on the 3′untranslated regions of specific mRNAs and enhancing their turnover. Global loss of TTP results in systemic inflammatory syndrome in mice; however, the physiological role of the other two TTP family members is unclear due to embryonic lethality of global knockout of ZFP36L1 and early post-natal death of global knockout of ZFP36L2. Here, using Cre-loxP technology, we independently and simultaneously (triple KO) deleted the three TTP family members in mouse liver and characterized the phenotype of the resulting mice strains using histopathological, immunohistochemical, clinical, and transcriptomic approaches. The triple KO mice exhibited chronic active peri-portal hepatitis, bile duct hyperplasia, and portal fibrosis. Immunohistochemically, increased numbers of T cells, B cells, macrophages, and neutrophils were detected within the peri-portal areas. Increased expression of heme-oxygenase-1, a marker of reactive oxygen species was also found. Clinically, serum levels of bile acids, bilirubin, and liver function enzymes were markedly elevated. Transcriptomic and bioinformatics analysis of liver RNA demonstrated novel potential liver specific inflammatory and metabolic mRNA targets of TTP family proteins that are post-transcriptionally regulated by TTP family proteins in both specific and redundant manner. In summary, our study provides strong evidence that TTP family of RNA binding proteins maintain immune and metabolic homeostasis in the liver.
Metabolomics analysis reveals differential T cell serine metabolism as a target in autoimmunity.
Authors: Andrejeva Gabriela , Wolf Melissa M. , Johnson Marc O. , Rutledge Alexandra C. , Codreanu Gabriela S. , Sherrod Stacy D. , Gutierrez Danielle , Rose Kristie L. , Norris Jeremy L. , Schey Kevin L. , McLean John A. , Rathmell Jeffrey C. 
Published: January 2023

Abstract
Inflammatory cytokines are key players in the pathogenesis of autoimmune disorders where their signaling leads to inappropriate balance between effector CD4 T-cells (Teff), Th1 and Th17, and the immunosuppressive regulatory T-cells (Treg). Each subset utilizes a distinctive metabolic program but how cytokines induce differential metabolic rewiring and what aspects of it are critical for the functioning and lineage stability of Teff subsets and Treg is not understood.
To delineate pathogenicity-associated metabolic programs, we performed global untargeted metabolomics mass spectrometry (MS) in in vitro cytokine-differentiated mouse Th1, Th17 and Treg cells with varying degrees of pathogenicity over time. Integrating our data-driven metabolic network with global proteomics profiling and cytokine secretion allowed us to examine metabolic pathways at metabolite-enzyme level. Metabolites at the interface of amino acid metabolism, particularly glutamine and serine, glycolysis, the TCA cycle and nucleotide synthesis were the most differentially changed. Serine limitation or pharmacological inhibition indicated differential coupling of serine/one-carbon metabolism to T-cell proliferation, lineage choices and the production of cytokines IL-17 or IFNγ. Furthermore, targeting this pathway promoted Treg lineage development in the presence of pathogenic cytokines and prevented loss of Treg transcription factor FoxP3 upon re-stimulation. In vivo, spinal cord infiltrating T-cells in murine experimental autoimmune encephalomyelitis had altered serine metabolic pathway. Our findings identify key areas of T-cell metabolism that may offer a new category of therapeutic targets for autoimmune and inflammatory disease.
Plasmacytoid dendritic cells inhibit Toxoplasma gondii infection induced cytokine storm
Authors: Zhou Wei , Wang Ding Ding , Tang Hua 
Published: January 2023

Abstract
Cytokine storm has serious harmfulness in infectious diseases, but its regulatory mechanism is not clear. The immunopathology is mediated by local overproduction of Th1-type cytokines during acute infection with Toxoplasma gondii (T. gondii). Because dendritic cells (DCs) are essential in the elicitation of these immune responses, we investigated the presence the role of plasmacytoid dendritic cells (pDCs) upon T. gondii infection. Towards this goal, we examined T. gondii infection of BDCA2-DTR mice, which specifically depleting this cell population. Here, we found that T. gondii infection reduced the number of pDCs, and depletion of pDCs in BDCA2-DTR mice were extremely susceptible to T. gondii infection, with decreased serum levels of IL-12, but increased serum levels of IFN-γ, IL-6 and TNF-α. In addition, depletion of pDCs also increased IFN-γ production by CD4+T cells, and resulted in an exacerbation of immunopathological damage caused by T. gondii infection. These results reveal that pDCs play a protective role during T. gondii infection by modulation of cytokine triggers immune response.
Natural Secretory Immunoglobulins Enhance Norovirus Infection
Authors: Turula Holly , Pry Alexandra , Wilke Carol A. , Fava Julianne , Wobus Christiane 
Published: January 2023

Abstract
Noroviruses are highly prevalent, enteric pathogens that cause significant morbidity, mortality and economic losses world-wide. Murine norovirus (MNV) exploits M-cells to cross the follicle-associated epithelium (FAE) and infect underlying populations of immune cells. Secretory immunoglobulins (SIg) are a first line of mucosal defense. However, whether natural, non-specific SIg can protect against norovirus infection remains unknown. SIg are secreted into the gut lumen via the polymeric immunoglobulin receptor (pIgR) where they bind to antigen and are transported back across the FAE via M-cells. To determine if natural SIg influence MNV pathogenesis, we used pIgR-deficient animals which lack SIg in the intestinal lumen. Contrary to other enteric pathogens, acute MNV replication was significantly reduced in the gastrointestinal tract of pIgR-deficient animals compared to controls, despite increased target cells (DC, Macrophages, B cells). Also, natural SIg did not alter MNV FAE binding or FAE crossing into the lymphoid follicle. Further analysis revealed enhanced baseline levels of inflammatory molecules known to inhibit viral infection, interferon gamma (IFNɣ) and inducible nitric oxide synthase (iNOS), in the small intestine of naive pIgR-deficient animals compared to controls. Removing the microbiota equalized IFNɣ and iNOS levels as well as MNV infection in germ-free pIgR KO mice compared to germ-free controls. Future studies will determine if neutralization of IFNɣ is sufficient to enhance MNV infection in pIgR KO mice. Taken together, these findings suggest a model whereby SIg sensing reduces pro-inflammatory, antiviral molecules which facilitates intestinal homeostasis but thereby promotes MNV infection.
Exploring anti-viral and immunomodulatory activities of Regenerating Islet-Derived proteins
Authors: De Luna Xavier , Hsieh I-Ni , White Mitchell , Hartshorn Kevan L. 
Published: January 2023

Abstract
The Regenerating Islet Derived Protein 3 (REG3) family are classified as antimicrobial peptides typically expressed in the gut epithelia of mammals, and help maintain host-bacteria homeostasis in our gastrointestinal tract. However, recent data has shown that the peptides are expressed in respiratory epithelia as well and play an important role in host defense in the lung against gram positive bacteria. The expression of one of the REG peptides in the lung is suppressed by IAV infection in mice and this contributes to bacterial superinfections which complicate influenza. REG3 peptides are classified as C-type lectins and our lab focuses on anti-microbial peptides as well as C-type lectins (mannose-binding lectin and surfactant protein D) and their function against Influenza A virus. Here I will be describing the previously unknown effects REG3 family of peptides on IAV infection. Preliminary data I have generated indicate that REG3 peptides inhibit the infectivity of IAV. I have compared the activity two different REG3 peptides and gained preliminary evidence that they not only inhibit viral infectivity but disrupt viral membranes (using electron microscopy) and alter viral interactions with epithelial cells using confocal microscopy. Of interest, the peptides also increase uptake of IAV by neutrophils and also increase neutrophil respiratory burst responses to the virus. These data suggest that REG proteins have significant and previously unknown effects to inhibit viral infectivity but also can modulate responsiveness of phagocyte to viruses
TLR3 of murine astrocytes is cleaved into several forms upon stimulation of cells with synthetic dsRNA
Authors: Mielcarska Matylda Barbara , Bossowska-Nowicka Magdalena , Gregorczyk Karolina Paulina , Wyzewski Zbigniew , Toka Felix Ngosa 
Published: January 2023

Abstract
TLR3 (Toll-like receptor 3) belongs to the subfamily of TLRs that reside in the endosomal compartment of the cell. It recognizes dsRNA (double-stranded RNA) of viruses and initiates a signaling pathway leading to generation of antiviral molecules such as type I interferons. Precursor TLR3 present in mammalian cells has a size of approximately 110 kDa, however, recent findings show that the TLR3 may also occur in two progeny forms: C-terminal and N-terminal, appearing after cleavage of TLR3 in specific conditions by cysteine proteases – cathepsins. Furthermore, cleaved and/or associated TLR3 molecules may represent the primary form of the receptor and are capable of binding the TLR3 ligand. Our results show that in C8D1A murine astrocyte cell line, cleavage of TLR3 is time- and dose-dependent upon stimulation with poly(I:C) (polyinosinic:polycytidylic acid, synthetic dsRNA analogue). The cleavage process promotes and increases expression of the progeny receptor forms. Presentation of TLR3 in such manner may modulate the level of response to viral dsRNA, especially in central nervous system cells, however, this requires further investigation.
STAT reporter cell line systems as a tool for cancer therapeutic target screening.
Authors: Lee Hyun-Ku , Singh Gita , Singh Sujay 
Published: January 2023

Abstract
Signal transducer and activator of transcription (STAT) proteins as cytoplasmic transcription factors respond to cytokines and growth factors that mediate downstream signaling. STATs are closely related with cancers as they are frequently found to be dysregulated in primary tumors, leading to enhanced survival of tumors and increased angiogenesis. Among seven STAT family members, STAT3, STAT4 and STAT5 are considered to primarily promote cancer development and progression, while STAT1 may function either as a tumor suppressor or tumor promoter. STAT3, 4 and 5 are persistently activated in many human cancer cell lines, leading to increased cancer cell survival. Several studies demonstrate that inhibition of STAT3 or STAT5 signaling decreases cancer cell proliferation leading to apoptosis. Taken together, these indicate that STAT proteins can be ideal targets for anti-cancer therapy, and so it is crucial to develop assay systems that can identify inhibitors targeting those pro-tumorigenic STATs. Hence we developed the four reporter cell lines, each of which stably expresses STAT1-, STAT3-, STAT4-, or STAT5-response element that controls an optimized Renilla luciferase reporter gene upon stimulation. Functional activity of each cell line was evaluated through dose response of various cytokines such as IFNs, IL-3 and IL-6. One of the STAT inhibitors, curcumin as well as other putative STAT suppressors were utilized to characterize how each STAT can differentially respond to each test molecule and how its response can affect the host cells.
Epigallocatechin-3-gallate prevents Non-alcoholic fatty liver disease by modulating liver function, lipid profiles and M1/M2 macrophage polarization
Authors: Paglicawan Laura Q. , Du Yong , Soomro Sanam , Baig Sahar , Vanarsa Kamala , Mohan Chandra 
Published: January 2023

Abstract

Background
Here, we examine the therapeutic efficacy of Epigallocatechin-3-gallate, the most potent catechin in green tea, on nonalcoholic fatty liver disease (NAFLD), a growing epidemic in humans.

Methods
NAFLD was induced by high-fat diet (HFD) with 30% fructose in drinking water for 8 weeks. Mice were divided into 3 groups: model group (MD; no EGCG), low dose EGCG group (LE, 20 mg/kg/d) and high dose EGCG group (HE, 50 mg/kg/d). Liver histology, serum lipid prolife, liver function as well as liver M1/M2 polarization were evaluated.

Results
At the end of the experiment, the mean body weight of LE and HE mice were 39.7g and 45.7g, while it was 51.9g in the MD group (P&lt; 0.05). Similarly, liver weights in the LE and HE groups (means = 1.44g, and 1.68g, respectively) were lower than that in MD (2.94g, P &lt; 0.01). Liver dysfunction observed in the MD group (mean AST=133.2 U/L and ALT=183.4 U/L), was significantly improved in both LE (44.8 U/L, 86.8 U/L, respectively, P &lt; 0.001) and HE groups (83.63 U/L, 117.6 U/L, respectively P &lt; 0.05). Serum cholesterol, HDL, triglyceride levels were increased in the MD group, but lowered in both LE and HE mice (p&lt;0.01). Hepatic FACS, RT-PCR and IHC studies demonstrated that the HE group had lower F4/80+ CD86+ (0.3 ×103 vs 1.5 × 104), F4/80+ MHC II+ (0.7 ×104 vs 1.3 × 104), and higher F4/80+ CD206+(2.96 ×104 vs 0.3 × 104), F4/80+ CD23+ (1.27 ×104 vs 0.65 × 104) hepatic infiltration, accompanied by down-regulated CD68 and up-regulated CD163 mRNA expression.

Conclusion
EGCG subdued NAFLD despite consumption of HDF and high fructose water, marked by improved liver function and serum lipid profile, as well as M1/M2 polarization. EGCG should be investigated as a therapeutic modality in human NAFLD.
The intracellular target of the antimicrobial peptide thanatin
Authors: Jackson Karen E. , Miller-White Tiffany 
Published: January 2023

Abstract
Thanatin is an inducible 21-residue antimicrobial peptide (AMP) derived from the insect Podisus maculiventris. Thanatin and its analogs have bactericidal activity against gram-positive and gram-negative bacteria, including antibiotic resistant strains. Due to the lack of hemolytic action, thanatin is a good candidate for therapeutic use, as evidenced by its ability to fight sepsis in mice. However, the mode of action of thanatin remains unexplored. Introduction of the respiratory poison carbonyl cyanide m-chlorophenyl hydrazone (CCCP) inhibits AMP induced death, suggesting that the bacterial respiratory pathway is targeted. In this study, biotinylated S-thanatin was used to determine a minimum inhibitory concentration (MIC) in Escherichia coli. Biotinylated S-thanatin showed comparable killing activity to the non-biotinylated peptide, 8μg/mL vs. 4μg/mL, respectively. Next, the killing activity of biotinylated S-thanatin was determined for cultures of E. coli grown under anaerobic, aerobic and respiratory dependent conditions. Anaerobic growth was shown to inhibit thanatin-induced microbial death, and respiratory dependent increased sensitivity. Currently, we are using biotinylated S-thanatin in an affinity purification assay to isolate the intracellular target to be analyzed using matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy.