bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia
Authors: Gosmann Christina , Mattarollo Stephen R. , Bridge Jennifer A. , Frazer Ian H. , Blumenthal Antje 
Published: July 2014

Abstract
Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3+ T cells, predominantly CD4+ T cells in human, and CD4+ and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.
Caspase-8 Modulates Dectin-1 and Complement Receptor 3–Driven IL-1β Production in Response to β-Glucans and the Fungal Pathogen, Candida albicans
Authors: Ganesan Sandhya , Rathinam Vijay A. K. , Bossaller Lukas , Army Kelly , Kaiser William J. , Mocarski Edward S. , Dillon Christopher P. , Green Douglas R. , Mayadas Tanya N. , Levitz Stuart M. , Hise Amy G. , Silverman Neal , Fitzgerald Katherine A. 
Published: July 2014

Abstract
Inflammasomes are central mediators of host defense to a wide range of microbial pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR), pyrin domain–containing 3 (NLRP3) inflammasome plays a key role in triggering caspase-1–dependent IL-1β maturation and resistance to fungal dissemination in Candida albicans infection. β-Glucans are major components of fungal cell walls that trigger IL-1β secretion in both murine and human immune cells. In this study, we sought to determine the contribution of β-glucans to C. albicans–induced inflammasome responses in mouse dendritic cells. We show that the NLRP3–apoptosis-associated speck-like protein containing caspase recruitment domain protein–caspase-1 inflammasome is absolutely critical for IL-1β production in response to β-glucans. Interestingly, we also found that both complement receptor 3 (CR3) and dectin-1 play a crucial role in coordinating β-glucan–induced IL-1β processing as well as a cell death response. In addition to the essential role of caspase-1, we identify an important role for the proapoptotic protease caspase-8 in promoting β-glucan–induced cell death and NLRP3 inflammasome-dependent IL-1β maturation. A strong requirement for CR3 and caspase-8 also was found for NLRP3-dependent IL-1β production in response to heat-killed C. albicans. Taken together, these results define the importance of dectin-1, CR3, and caspase-8, in addition to the canonical NLRP3 inflammasome, in mediating β-glucan– and C. albicans–induced innate responses in dendritic cells. Collectively, these findings establish a novel link between β-glucan recognition receptors and the inflammatory proteases caspase-8 and caspase-1 in coordinating cytokine secretion and cell death in response to immunostimulatory fungal components.
Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury
Authors: Feng Dechun , Wang Yan , Wang Hua , Weng Honglei , Kong Xiaoni , Martin-Murphy Brittany V. , Li Yongmei , Park Ogyi , Dooley Steven , Ju Cynthia , Gao Bin 
Published: July 2014

Abstract
Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with IL-22 protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (Cyp2E1) and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF-1α, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for 2 wk. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease, but are also helpful to identify novel therapeutic targets for the treatment of AILI.
Rapid Remodeling of Tight Junctions during Paracellular Diapedesis in a Human Model of the Blood–Brain Barrier
Authors: Winger Ryan C. , Koblinski Jennifer E. , Kanda Takashi , Ransohoff Richard M. , Muller William A. 
Published: July 2014

Abstract
Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that, at the tight junctions of the blood–brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed 10-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte–endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.
Noncanonical NF-κB Activation Mediates STAT3-Stimulated IDO Upregulation in Myeloid-Derived Suppressor Cells in Breast Cancer
Authors: Yu Jinpu , Wang Yue , Yan Fang , Zhang Peng , Li Hui , Zhao Hua , Yan Cihui , Yan Fan , Ren Xiubao 
Published: July 2014

AbstractImmunotherapy for cancer treatment is achieved through the activation of competent immune effector cells and the inhibition of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). Although MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSC-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer–suppressing T cell function through STAT3-dependent IDO upregulation. In this study we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by coculturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical NF-κB pathway, including increased NF-κB–inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase α and p100, and RelB-p52 nuclear translocation. Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. IL-6 was found to stimulate STAT3-dependent, NF-κB–mediated IDO upregulation in MDSCs. Furthermore, significant positive correlation between the numbers of pSTAT3+ MDSCs, IDO+ MDSCs, and NIK+ MDSCs was observed in human breast cancers. These results demonstrate a STAT3/NF-κB/IDO pathway in breast cancer–derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer.
IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells
Authors: Mizui Masayuki , Koga Tomohiro , Lieberman Linda A. , Beltran Jessica , Yoshida Nobuya , Johnson Mark C. , Tisch Roland , Tsokos George C. 
Published: July 2014

Abstract
IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Faslpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant adeno-associated virus resulted in reduced mononuclear cell infiltration and pathology of various tissues, including skin, lungs, and kidneys. In parallel, we noted a significant decrease of IL-17–producing CD3+CD4−CD8− double-negative T cells and an increase in CD4+CD25+Foxp3+ immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive double-negative (DN) T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122+ cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy, whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17–producing DN T cells and expanding Treg.
Compensatory Mechanisms Allow Undersized Anchor-Deficient Class I MHC Ligands To Mediate Pathogenic Autoreactive T Cell Responses
Authors: Lamont Deanna , Mukherjee Gayatri , Kumar P. Rajesh , Samanta Dibyendu , McPhee Caroline G. , Kay Thomas W. H. , Almo Steven C. , DiLorenzo Teresa P. , Serreze David V. 
Published: July 2014

Abstract
Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell–cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell–specific ligand for AI4 as an unusually short H-2Db–binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14–20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14–20 shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4’s promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14–20 with improved H-2Db–binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease.
Yaklaşma iniş sistemlerinde ileri teknolojiler
Authors: Ataş Sefer , Koç Osman , Çiftçibaşi Mehmet Emre , Kilinç Mustafa , Altin Deniz , Özdemir Başak Gonca , Yeşilyurt Alper 
Published: July 2014

Özet21. yüzyılda dünyanın ulaştığı teknolojik seviye, yaklaşma iniş sistemleri konusunda yeni bir çağ başlatmıştır. Tüm dünyada sivil ve askeri hava araçlarının iniş ve kalkışlarında halen kullanılan Hassas Yaklaşma Radarı ve Aletli İniş Sistemi gibi sistemler, orta ve uzun vadede uydu sinyallerini kullanan yeni sistemlerle güncellenecektir. Söz konusu yeni sistemlerin geliştirilmesinde çevresel şartların etkilerini azaltarak sinyal kalitesini artıracak çeşitli yer kesimi ve hava aracı aviyonik birimlerinin ve ilgili algoritmaların geliştirilmesi gerekmektedir. Türkiye ve tüm dünya için yeni bir araştırma konusu olan söz konusu sistemlerde, mevcut ve gelecekteki uydu kümeleriyle birlikte çalışabilirlik önem arz etmektedir. Bu çalışmada uydu tabanlı yaklaşma iniş teknolojilerine genel bakışla birlikte sistemlere yönelik teknik bilgiler verilmiş, Uydu Tabanlı Destek Sistemi (UTDS) ve Yer Tabanlı Destek Sistemi (YTDS)’nin örnek uygulamalar ile birlikte askeri kullanımda sağladıkları operasyonel avantajlar detaylandırılmış, ileri teknolojilerin kullanıldığı yaklaşma türleri hakkında genel bilgiler verilmiş, İHA’larda UTDS/YTDS kullanımı ve otomatik kalkış ve iniş desteğinin önemi ile birlikte operasyonel kullanımı etkileyen faktörlere ve askeri ve sivil yaklaşma iniş sistemlerinin birlikte çalışabilirliğine yer verilerek Türkiye’nin gelecekte iyi bir konumda olması için yapılması gereken çalışmalar ve taslak UTDS/YTDS yol haritası sunulmuştur.
Global Case Fatality of Bacterial Meningitis During an 80-Year Period
Authors: van Ettekoven Cornelis N. , Liechti Fabian D. , Brouwer Matthijs C. , Bijlsma Merijn W. , van de Beek Diederik 
Published: August 2024

ImportanceThe impact of vaccination, antibiotics, and anti-inflammatory treatment on pathogen distribution and outcome of bacterial meningitis over the past century is uncertain.ObjectiveTo describe worldwide pathogen distribution and case fatality ratios of community-acquired bacterial meningitis.Data SourcesGoogle Scholar and MEDLINE were searched in January 2022 using the search terms bacterial meningitis and mortality.Study SelectionIncluded studies reported at least 10 patients with bacterial meningitis and survival status. Studies that selected participants by a specific risk factor, had a mean observation period before 1940, or had more than 10% of patients with health care–associated meningitis, tuberculous meningitis, or missing outcome were excluded.Data Extraction and SynthesisData were extracted by 1 author and verified by a second author. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Random-effects models stratified by age (ie, neonates, children, adults), Human Development Index (ie, low-income or high-income countries), and decade and meta-regression using the study period’s year as an estimator variable were used.Main Outcome and MeasureCase fatality ratios of bacterial meningitis.ResultsThis review included 371 studies performed in 108 countries from January 1, 1935, to December 31, 2019, describing 157 656 episodes. Of the 33 295 episodes for which the patients’ sex was reported, 13 452 (40%) occurred in females. Causative pathogens were reported in 104 598 episodes with Neisseria meningitidis in 26 344 (25%) episodes, Streptococcus pneumoniae in 26 035 (25%) episodes, Haemophilus influenzae in 22 722 (22%), other bacteria in 19 161 (18%) episodes, and unidentified pathogen in 10 336 (10%) episodes. The overall case fatality ratio was 18% (95% CI, 16%-19%), decreasing from 32% (95% CI, 24%-40%) before 1961 to 15% (95% CI, 12%-19%) after 2010. It was highest in meningitis caused by Listeria monocytogenes at 27% (95% CI, 24%-31%) and pneumococci at 24% (95% CI, 22%-26%), compared with meningitis caused by meningococci at 9% (95% CI, 8%-10%) or H influenzae at 11% (95% CI, 10%-13%). Meta-regression showed decreasing case fatality ratios overall and stratified by S pneumoniae, Escherichia coli, or Streptococcus agalactiae (P &amp;lt; .001).Conclusions and RelevanceIn this meta-analysis with meta-regression, declining case fatality ratios of community-acquired bacterial meningitis throughout the last century were observed, but a high burden of disease remained.
Short‐term impact of vitamin K2 supplementation on biochemical parameters and lipoprotein fractions
Authors: Barna Milos , Dunovska Katerina , Cepova Jana , Werle Julia , Prusa Richard , Bjørklud Geir , Melichercik Pavel , Kizek Rene , Klapkova Eva 
Published: August 2024

AbstractThis study explored the short‐term effects of vitamin K2 (VK2) supplementation on biochemical parameters (vitamin D, vitamin E, vitamin A, alkaline phosphatase, calcium, phosphorus (P), magnesium, metallothionein, triglycerides, cholesterol, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), and lipoprotein fractions (albumin, HDL, very low‐density lipoprotein (VLDL), LDL, and chylomicrons). A short‐term experiment (24 h, six probands) was performed to track changes in VK2 levels after a single‐dose intake (360 µg/day). Liquid chromatography–tandem mass spectrometry was used to monitor vitamin K levels (menaquinone‐4 (MK‐4), menaquinone‐7 (MK‐7), and vitamin K1 [VK1]) with a limit of detection of 1.9 pg/mL for VK1 and 3.8 pg/mL for the two forms of VK2. Results showed that MK‐7 levels significantly increased within 2–6 h post‐administration and then gradually declined. MK‐4 levels were initially low, showing a slight increase, whereas VK1 levels rose initially and then decreased. Biochemical analyses indicated no significant changes in sodium, chloride, potassium, calcium, magnesium, albumin, or total protein levels. A transient increase in P was observed, peaking at 12 h before returning to baseline. Agarose gel electrophoresis of lipoprotein fractions revealed distinct chylomicron bands and variations in VLDL and HDL mobility, influenced by dietary lipids and VK2 supplementation. These findings suggest effective absorption and metabolism of MK‐7 with potential implications for bone metabolism and cardiovascular health.
Rhinovirus characteristics associated with viremia in childhood asthma
Authors: Lejeune Stéphanie B. , Deschildre Antoine , Morel Constance L. , Béghin Laurent R. , Drumez Elodie , Pichavant Muriel , Gosset Philippe , Engelmann Ilka ,   VIRASTHMA2 Study Group
Published: August 2024

AbstractAlthough rhinoviruses play a major role in exacerbations of childhood asthma, the presence of rhinovirus (RV) RNA in plasma, referred to as viremia, has been investigated in a few studies. The aim of the study was to investigate the presence of rhinovirus viremia at the time of asthma exacerbation and to describe the molecular characteristics of rhinoviruses associated with viremia. We conducted an observational, prospective, multicenter study in eight pediatric hospitals (VIRASTHMA2). Preschool‐aged recurrent wheezers (1–5 years) hospitalized for a severe exacerbation were included. Reverse‐transcription polymerase chain reaction (RT‐PCR) and molecular typing for RV/enteroviruses (EV) were performed on nasal swabs and plasma. Plasma specimens were available for 105 children with positive RT‐PCR for RV/EV in respiratory specimens. Thirty‐six (34.3%) had positive viremia. In plasma, 28 (82.4%) of the typable specimens were RV‐C, five (14.7%) were EV‐D68, and one was RV‐A (2.9%). In all cases, the RV/EV type was identical in the plasma and respiratory specimens. In conclusion, RV/EV viremia is frequent in severe exacerbations of preschool recurrent wheezers, particularly in RV‐C infections.
A reporter virus particle seroneutralization assay for tick‐borne encephalitis virus overcomes ELISA limitations
Authors: Ackermann‐Gäumann Rahel , Dentand Alexis , Lienhard Reto , Saeed Mohsan , Speiser Daniel E. , MacDonald Margaret R. , Coste Alix T. , Cagno Valeria 
Published: August 2024

AbstractTick‐borne encephalitis (TBE) virus is the most prevalent tick‐transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA‐based detection of specific antibodies in the patient serum. However, cross‐reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)‐based SNT in which the infectivity is measured by luminescence and that can be performed under BSL‐2 conditions. The RVP‐based SNT for TBEV exhibited a highly significant correlation with the traditional virus‐based SNT (R2 = 0.8637, p < 0.0001). The RVP‐based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%–97.4%) and specificity of 100% (95% CI: 81.6%–100%). We also tested the cross‐reactivity of serum samples in RVP‐based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV‐positive by ELISA but negative by RVP‐based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP‐based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies.
A tri‐axial acceleration‐based behaviour template for translocated birds: the case of the Asian houbara bustard
Authors: Chopra Kareemah , Wilson Rory P. , Shepard Emily L. C. , Sorato Enrico , Hingrat Yves 
Published: August 2024

Understanding the behaviours and time budgets of translocated animals post‐release has the potential to improve rearing and release protocols, and therefore survival rate. Otididae (bustards) inhabit open landscapes across the Middle East and Asia, are highly mobile on the ground and have similar lifestyles and body plans. The Asian houbara Chlamydotis macqueenii is a bustard of conservation concern inhabiting the Middle East to Central Asia and is frequently reared in captivity for population management. We deployed tri‐axial accelerometers on 20 captive Asian houbaras in two seasons to catalogue basic behaviours, provide a template applicable to other bustard species and examine seasonal differences in behaviour. We created Boolean algorithms to define the following behaviours using raw acceleration data and derived metrics: stationary, eating/drinking and locomotion. We used video recordings to cross‐validate the algorithms, yielding recalls from 95 to 97%, and precisions between 97 and 98%. Houbaras spent significantly more time ‘stationary' and less time on ‘locomotion' in summer (June) compared to spring (March). Simple Boolean algorithms proved useful in identifying several behaviours and have the potential to be applicable to other bustard species, in captivity and in the wild post‐release.Keywords: accelerometer, animal behaviour, Asian houbara bustard, captive breeding, conservation translocation