bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of MHCI antigen presentation sabotage by cowpox encoded protein CPXV203 (168.18)
Authors: McCoy William , Wang Xiaoli , Yokoyama Wayne , Hansen Ted , Fremont Daved 
Published: January 2023

Abstract
Viral dissemination can be greatly facilitated by immune evasion proteins that subvert MHCI antigen presentation, thereby conferring the ability to evade cytotoxic T-lymphocyte (CTL) detection and clearance. Surprisingly, ablation of MHCI-specific immune evasion proteins has been reported to be dispensable for both immediate and latent MCMV and RhCMV infections, while murine infection by the equivalent mutant cowpox virus (ΔCPXV012, ΔCPXV203) showed attenuated virulence in a CTL-dependent manner. Here we show that the cowpox virus encoded CPXV203 protein inhibits MHCI surface expression by directly binding mature MHCI heterodimers, thus bridging MHCI to the KDEL receptor (KDELR) rescue pathway via the viral protein’s C-terminal ER-retention sequence (KTEL). Similar to KDELR/KDEL binding, CPXV203/MHCI binding was found to be pH-dependent, insuring high-affinity association of KDELR/CPXV203/MHCI in the Golgi for retrieval to the ER. Ensuing structural studies of CPXV203/MHCI revealed that CPXV203 binds MHCI through conserved tapasin, CD8, & NKR interaction sites. Mutagenesis of the CPXV203/MHCI interface followed by cellular & biophysical studies identified the critical importance of CPXV203 recognition of the MHCI α3 domain and CPXV203 histidines that confer pH-dependent binding. These studies clarify mechanistically how CPXV203 coordinates with CPXV012 to effectively block antigen presentation through the targeting of distinct MHCI assembly states.
Ecto-5'-nucleotidase (CD73) regulates host inflammatory responses and bacterial persistence during murine Salmonellosis (169.10)
Authors: Alam Mohammad , Kuo Jennifer , Pereira Marion , Gaines Dennis , Bigley Elmer , Ernst Peter , Williams Kristina 
Published: January 2023

Abstract
Salmonella spp. is responsible for the vast majority of foodborne illnesses in the US. Adenosine is an antiinflammatory mediator that limits tissue damage during inflammation. Surface enzymes CD39 & CD73 mediate the synthesis of extracellular adenosine & can regulate immune responses. We studied the expression of CD39 & CD73 in liver & spleen after infection of C57BL/6 mice with Salmonella enterica serotype Typhimurium (ST) & evaluated the role of CD73 after oral infection of wildtype & CD73-KO mice, in regulating immune responses & bacterial persistence. Liver & spleen cytokine mRNA expression was tested by RT-PCR. Cytokines were assayed by ELISA from cultured supernatant of activated splenocytes. Splenocyte-derived Th cells were tested for intracellular cytokines by FACS. Inflammatory responses in infected CD73-/- mouse livers were tested in H&E sections. Bacterial count was done from liver tissues. After ST infection of wildtype mice, both CD39 & CD73 transcript levels declined in spleen & liver. Splenocytes from ST-infected CD73-/- mice produced significantly more IFN-γ & IL17a. Infected CD73-/- mice had higher expressions of IFN-γ & TNF-α mRNA in liver. Histological examinations of liver sections showed significantly greater number of “inflammatory-foci”. Liver bacterial load was significantly lower in CD73-/-mice. CD73 expression contributes to adenosine accumulation that attenuates inflammation during Salmonellosis & may impair immunity to favor bacterial persistence.
Linking IL-17 signaling to TRAF6 transcriptome activities during OC-or-/DDOC-mediated osteoclastogenesis (169.15)
Authors: Liu Yenchun , Chiang Min Shyuan , Wang Yan Hsiung , Teng Yen Tung 
Published: January 2023

Abstract
RANKL/RANK-OPG regulates osteoclastogenesis; whereas TRAF6 is an adaptor-protein associated -with bone-loss. Here, we investigate how these signal-interactions work between RANKL/RANK and cytokines’ to activate TRAF6-transcriptome and osteoclastogenesis in-vitro/in-vivo. Methods: A 1.1-kb mTRAF6-promoter-region was cloned into pCR-BluntII-TOPO-vector. Later, purified CD11c+dendritic-cell-derived osteoclasts(DDOC) & RAW264.7 stably transfected with pGL4-mTRAF6-Luc are stimulated in the presence/absence of RANKL/cytokines (i.e., IL-17, etc.) in-vitro, then measured the transcription via luciferase-activity, and correlated with mRNA/protein expressions by RT-PCR & western-blots, respectively, and TRAP-mediated resorptive pits (p&lt;0.05). Further, EMSA-vs.-ChIP assays are employed to reveal transcriptional binding-motifs on mTRAF6-promoter. The results showed that: i) 1.1-kb of mTRAF6-promoter-upstream contain critical binding-motifs stimulated by RANKL and osteotropic cytokines; ii) while RANKL/IL-17 both mediate positive signaling on mTRAF6-transcriptome, IL-17 of different-dose also inhibited its responses; iii) there are 3-or-4 transcription binding-motifs critical for osteoclatsogenesis; iv) IL-17-depletion leads to inhibition of alveolar-bone-loss induced by anaerobes in diabetic-NOD -mice in-vivo. Conclusion: These findings suggest that RANKL can work alone or interactively with IL-17 (or TNF-α) via mTRAF6-transcriptome-machinery on OCp/DDOC-mediated bone -loss.
Effect of Statins in influenza (169.22)
Authors: Ghosh Sanjukta , Ezquerro Fernando , Kobzik Lester 
Published: January 2023

Abstract
Excessive inflammatory immune responses are a major cause of influenza morbidity and mortality. Some epidemiological studies find reduced mortality from influenza in patients on statins. This suggests that the anti-inflammatory properties of these drugs could be useful. We first tested the effect of acute administration of 100 mg/kg pravastatin i.p. per day for 3 days, starting either at 1 day prior to, 2 days after, or 6 days post infection. For all three regimens, we observed increased, not decreased, mortality compared to control groups (infection alone). We then sought to better model the epidemiologic data in which a majority of patients are taking statins before hospitalization for influenza. We used longer-term administration (10 days) prior to influenza of pravastatin or simvastatin, followed by continued therapy for 7 days after infection. Chronic statin treatment of mice suppressed early inflammatory responses measured in lung lavage at 36 hours (decreased TNF release by ~50%, and reduced protein leakage), but did not change these parameters later in the course (days 3 and 7). Long-term pretreatment with statin, continued through first week of influenza, did not result in the enhanced mortality observed with the acute treatments. The potential benefit, if any, of the early anti-inflammatory effect of statins in long-term users remains to be determined.
The innate immune response to cytomegalovirus: the kick-start (170.1)
Authors: Verma Shilpi , Fukuyama Satoshi , Ware Carl , Benedict Chris 
Published: January 2023

Abstract
Like all herpesviruses, cytomegalovirus (CMV, a β-herpesvirus) persists for the lifetime of its host. Primary infection is sub-clinical in healthy individuals, but can cause serious disease when immunity is compromised or naïve. We have previously shown the initial type I Interferon (IFNαβ) produced by the splenic stroma within hours after mouse CMV (MCMV) infection is dependent on lymphotoxin (LT)-LTβR signaling. We now show it is splenic marginal zone (MZ) stromal cells that are initially infected by MCMV and produce this initial IFNαβ. This “first wave” of IFNαβ is critical to restrict MCMV production from the MZ stroma, inhibiting the earliest measurable viral burst by 100-1000 fold. NK cells are key controllers of MCMV in the first few days of infection, but their role in restricting this first burst of MCMV is unclear. Depleting NK cells revealed them to contribute to initial control of MCMV production from the MZ stroma. Additional studies revealed NK cells can mediate their earliest effector function(s) independently of both IFNαβ and Ly49H, a key NK activating receptor that binds the MCMV m157 protein. Strikingly, the levels of MCMV produced from MZ stroma at the earliest time measurable are the highest observed at any subsequent time point prior to immune control of MCMV. These results highlight the importance of both IFNαβ and NK cells in controlling initial MCMV replication and spread, establishing a baseline for MCMV production over the course of acute infection.
FIV infection activates Regulatory T cells expressing GARP-bound TGFb complexes which suppress T helper cells and may contribute to immune dysfunction (170.12)
Authors: Miller Michelle , Tompkins Mary 
Published: January 2023

Abstract
Here we identify on feline Treg cells Glycoprotein A Repititions Predominant (GARP), a cell surface anchor for TGFb, as a functional protein in Treg-mediated suppression. We demonstrate co-precipitation of mature TGFb with GARP from feline CD4+CD25+ cells. The GARP:TGFb complex is expressed on the surface of highly effective suppressors, as depletion of these cells from the Treg pool reduces suppression of CD4+CD25- targets as measured by IL2 inhibition. In vitro activation of CD4+CD25+ cells upregulates surface GARP:TGFb as measured by flow cytometry. Surface phenotyping of PBMCs from noninfected or chronically FIV-infected cats reveals a higher percent of GARP+TGFb+ Tregs and of TGFbRII+ T helper targets in FIV+ cats. At days 3 or 6 post in vitro FIV infection CD4+CD25+ cells upregulate GARP:TGFb and CD4+CD25- upregulate TGFbRII. In vivo infection studies were performed and expression of GARP, TGFb or TGFbRII was evaluated on PBMC for 13 weeks post infection. Acute FIV infection generated increased GARP:TGFb expression on CD4+CD25+ cells one week post infection and a corresponding increase in TGFbRII on CD4+CD25- consistent with in vitro study results. We conclude that GARP: TGFb is increased on the surface of Treg cells during acute FIV and contributes to the CD4+ T cell anergy via ligation of TGFbRII on the surface of CD4+CD25- T helpers. We hypothesize that FIV infects Treg cells in vivo, resulting in activation of these suppressor cells and chronic T helper dysfunction.
Immunomodulatory role of acute cigarette smoke exposure in pdmH1N1 and H9N2 infection (170.14)
Authors: Han Yan , Ling Manto , Mao Huawei , Tu Wenwei , Lau Yulung 
Published: January 2023

Abstract
Cigarette smoke has both immune-activating and suppressing activities. Mouse studies have demonstrated that smoke exposure increases the expressions of some factors likely to be important in the antiviral defense. However, there is no report about the role of cigarette smoke in 2009 pandemic H1N1 (pdmH1N1) and avian influenza A H9N2 (H9N2/G1) infection. In this study, C57/B6N mice were whole body exposed to 4% cigarette smoke 4 hours per day for 21 days and then infected with pdmH1N1 or H9N2 virus. Some mice were exposed to room air in parallel as the control group. Mortality, weight changes, lung virus loads and inflammatory cytokines and chemokines were analyzed. For pdmH1N1 infection, although no significant difference in the lung virus loads was shown between the two groups, smoke exposure group had a significantly lower mortality than the air exposure group, which may be caused by the lower inflammatory response in the smoke exposure group than in the air exposure group at day 5 post virus infection. Similarly, after H9N2 virus infection, the mice in smoke exposure group displayed a significantly milder disease, as evidenced by a less weight loss, as well as lower inflammatory response compared to the air exposure group. Our study provided the first in vivo evidence that acute cigarette smoke exposure may modulate the effect of influenza A virus infection. The underlying mechanism is under investigation.
Pathogenesis of Newly Discovered Severe Fever with Thrombocytopenia Syndrome Bunyavirus in Mice (170.19)
Authors: Jin Cong , Liang Mifang , Ning Junyu , Gu Wen , Jiang Hong , Zhu Hua , Qin Chuan , Li Dexin 
Published: January 2023

Abstract
Severe fever with thrombocytopenia syndrome (SFTS) was an emerging zoonotic disease identified since 2009 in multiple provinces in China. A novel phlebovirus in the family Bunyaviridae was demonstrated as the etiological agent of SFTS and named as severe fever with thrombocytopenia syndrome bunyavirus (SFTSV). However, lacking of knowledge on pathology and pathogenic mechanisms of SFTSV in human underscores the need to study pathogenesis of SFTSV using an animal model. The infectious C57/BL6 mouse model with hallmark symptoms of thrombocytopenia and leukocytopenia was established. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. Intriguingly, viral replication was only found in the spleen, which suggested spleen as the principle target organ of SFTSV. Focusing on spleen, we found that the number of macrophages and platelets dramatically increased in the infected spleen, and SFTSV co-localized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to human platelets and facilitated the phagocytosis of platelets by human macrophages, which in combination with in vivo findings suggests that the SFTSV-induced thrombocytopenia was caused by clearance of circulating virus-bound platelets promoted by splenic macrophages. Thus, the study elucidated pathology and pathogenic mechanisms of thrombocytopenia in a murine model which resembles human SFTS disease.
Human High Mobility Group Box 1 Induced Human Lung Fibroblasts Migration Through Activation PI3 kinase, MAPK, and NF-κB Signaling Pathway (173.31)
Authors: Lee Chen-Chen , Tsai Yi-Ru 
Published: January 2023

Abstract
High mobility group box 1(HMGB1) is a nuclear protein that involves the interactions with DNA and chromatin regulation and transcription. HMGB1 is also a cytokine that can activate monocytes neutrophils involving in inflammation. In this study, we want to investigate the role of HMGB1 on cell migration on human fibroblast cell line -WI-38. After treated with HMGB1 1, 10, 100 ng/ml for 24h, we did not found obviously cytoxicity and proliferation effect on WI-38 cells by MTT and BrdU incorporation assay, respectively. We found that HMGB1 induced cell migration on WI38 by dose-dependent manner and caused MMP9 activation but not MMP2. Using specific inhibitor of protein kinases, we observed that extracellular signal related kinase (ERK) inhibitor- PD98059(2μM), c-Jun N-terminal kinase (JNK) inhibitor - SB203580(2μM), p38 mitogen activated protein kinase (p38) inhibitor-SP600125(2μM), phosphoinositide 3-kinase (PI3 kinase) inhibitor- LY294002(2μM), and NF-κB inhibitor-Bay117082(1μM) all showed the inhibition effect on HMGB1 induced WI-38 cells migration. We also found that HMGB1 induced ERK, JNK and p38 activated and increased the nucleus β-catenin expression by time-dependently. In the future, we will further investigate the mechanisms of HMGB1-induced cell migration on WI-38 including HMGB1 membrance receptors activation and related signaling pathway.
Putative roles of specific T cells in progression of obesity-associated inflammation in adipose tissue. (173.36)
Authors: Taniguchi Kaori , Miyazaki Toru 
Published: January 2023

Abstract
The metabolic syndrome is known as a chain of illness, triggered by obesity followed by diabetes, hepatic steatosis and atherosclerosis. It is well known that adipose tissues in obesity are in a state of chronic inflammation, and that such inflammatory state is tightly associated with multiple metabolic disorders. Accumulating evidence has shown that the inflammation is mainly lead by the recruitment of macrophages into adipose tissues. Although it has recently been suggested that T cells may also play a role in establishment of inflammation in adipose tissue during the early phase of obesity, specificity and roles of them are poorly understood. In order to solve this issue, we first kinetically analyzed the repertoire of T cells recruited into adipose tissues along with the progression of obesity in mice. Interestingly, the adipose tissue T cells in mice fed with high fat diet for 9 wks harbored restricted repertoires of T cell receptor (TCR), indicating the presence of specific antigen(s) derived from fat tissues in obese individuals. Until now, we have created TCR transgenic mice in which majority of T cells may respond to a particular antigen exposed in obese adipose tissue. Our study will clarify the precise role of T cells in metabolic syndrome, and will contribute to development of a new therapeutic strategy.
Effects of bee venom-PLA2 on Regulatory T cells in asthma mice model (173.37)
Authors: Park Soojin , Choi Taewon , Lee Gihyun , Shin Minkyu Shin , Hong Moochang , Bae Hyunsu 
Published: January 2023

Abstract
CD4+CD25+Foxp3+ regulatory T cell (Treg) plays an important role in immune tolerance which can reduce inflammation and allergic reactions through its inhibitory functions. Bee venom (BV) has been widely used in the treatment of chronic inflammatory diseases such as Rheumatoid Arthritis. In this study, we hypothesized that phospholipase A2 (PLA2), major constituent of BV, could increase Treg expression and treat OVA-induced allergic asthma in mice. In vitro study, the percentage of Treg increased significantly by PLA2 treatment in CD4+T cell compared to saline treatment. In OVA induced allergic asthma model, PLA2-treatment significantly suppressed eosinophil and lymphocyte infiltration in BALF. In addition, PLA2 inhibited the production of IL-4, IL-13, INF-γ, IgE and OVA-specific IgE, along with suppressing airway hyper-responsiveness. Furthermore, CD4+CD25+Foxp3+ population was significantly increased by PLA2 treatment. Interestingly, these anti-asthmatic effects by PLA2 were totally abolished by Treg depletion via anti-CD25 antibody injection, suggesting pharmaceutical action of PLA2 was medicated by Treg. Our data suggest that PLA2 inhibits OVA-induced allergic airway inflammation by modulating Treg function.
Cleavage of the CD11b extracellular domain by the leukocyte serprocidins is critical for neutrophil detachment during chemotaxis (173.7)
Authors: Zen Ke , Guo Yalan , Bian Zhen , Liu Yuan 
Published: January 2023

Abstract
The β(2)-integrin CD11b/CD18 mediates the firm adhesion of neutrophils (PMNs) to epithelial monolayers, a key step in PMN transepithelial migration. To complete the transmigration process, adherent PMNs must detach from epithelial surfaces to move forward. The mechanism that governs the detachment of adherent PMNs, however, is not clear. Here, we present evidence that cleavage of the CD11b extracellular domain containing the ligand-binding I-domain by 3 structural and functional related serine proteases (elastase, proteinase-3 and cathepsin G) serves as a novel mechanism for PMN detachment after the initial cell adhesion. Kinetic studies showed that the cleavage of CD11b is positively correlated with PMN detachment and subsequent transmigration. Moreover, the results demonstrated that elastase, proteinase-3 and cathepsin G all cleaved the purified, functionally active form of CD11b in a pattern similar to the CD11b shedding that occurs during PMN transmigration. Their cleavage sites on purified CD11b were located at (761)Thr-Ala(762) (elastase/proteinase-3) and (760)Phe-Thr(761) (cathepsin G), respectively. CD11b cleavage and PMN detachment and chemotaxis, were impaired in elastase/cathepsin G-deficient Beige mice; this defect could be restored by the addition of extracellular elastase. By illustrating CD11b shedding by elastase, proteinase-3 and cathepsin G as a novel mechanism for PMN detachment, our study provides novel therapeutic targets for controlling inflammation.
Enhanced Claudin-9 expression is associated with lung cancer metastasis (173.8)
Authors: Sharma Rajesh , Jala Venkatakrishna , Satpathy Shuchismita , Haribabu Bodduluri 
Published: January 2023

Abstract
Typical metastasis models utilize intravenous injection of tumor cells, thus bypass the egression of malignant cells an obligatory step in metastasis of spontaneous cancers. We herein utilized a unique metastasis model by in vivo passaging the Lewis lung carcinoma (3LL) cells and maintaining them in vivo with 7-11 days of intermittent culture in between passages. When injected subcutaneously parental 3LL cells have minimal metastasis, while in vivo passaged cells show robust metastasis. Most interestingly, parental and passed cell lines if injected i.v., yielded similar metastatic burden suggesting that egression from the primary tumor is facilitated by in vivo passaging. Microarray analysis of RNA from these cells as well as the primary tumors derived from each revealed several novel markers associated with increased metastasis. Expression of a tight junction protein “claudin 9” is highly up regulated in passaged 3LL lines. Enhanced expression of claudin-9 in passaged 3LL lines and tumors derived from these cells was confirmed by real time PCR and Western blot as well as immuno-fluorescence microscopy. Passaged 3LL cells exhibited greater motility and invasiveness relative to parental 3LL cells. Taken together, these data indicate distinct association of claudin 9 expression with metastatic phenotype and suggest that claudin 9 may serve as a biomarker and a potential therapeutic target for preventing lung cancer metastasis.
Single cell network profiling (SCNP) assay allows for the identification of heterogeneity in the activation of multiple signaling pathways in distinct human B cell subsets (174.12)
Authors: Longo Diane , Conroy Andy , Louie Brent , Wang Ena , Pos Zoltan , Marincola Francesco , Hawtin Rachael , Cesano Alessandra 
Published: January 2023

Abstract
The specific functions of phenotypically defined B cell subsets in the regulation of protective immune responses and the pathogenesis of immune-mediated diseases is incompletely understood. SCNP is a multi-parametric flow cytometry based approach that simultaneously measures intracellular signaling in multiple cell subsets in heterogeneous tissues. In this study, SCNP was applied to examine 34 signaling nodes (paired modulator/intracellular readout) in B cell subsets (CD27-IgM+IgD+ naïve B cells, total CD27+ memory B cells, CD27+IgM-IgD- switched memory B cells, CD27+IgM+IgD+ IgM memory B cells) in peripheral blood mononuclear cells from 6 healthy donors. Signaling responses in B cell subsets were masked when the total B cell population was analyzed. Specifically, a higher responsiveness was observed in the memory B cell subset relative to the naïve; 14 signaling nodes showed statistically significant differences between these subsets (p&lt;.05, paired Wilcoxon test) of which 12 displayed stronger activation in response to CD40L, SDF1α, PMA, IFNα, IFNγ, IL10 and IL27 modulation in the memory B cells. 11 signaling nodes differed significantly in IgM memory vs. switched memory B cells (p&lt;.05, paired Wilcoxon test); 7/11 displayed stronger activation in response to CpG, R848, thapsigargin, IFNγ and IL10 modulation in IgM memory B cells. An increased understanding of B cell subset signaling may allow for the development of more effective B cell targeted therapies.