bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conventional NK Cells Can Produce IL-22 and Promote Host Defense in Klebsiella pneumoniae Pneumonia
Authors: Xu Xin , Weiss Ido D. , H. Zhang Hongwei , Singh Satya P. , Wynn Thomas A. , Wilson Mark S. , Farber Joshua M. 
Published: January 2014

Abstract
It was reported that host defense against pulmonary Klebsiella pneumoniae infection requires IL-22, which was proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22−/− mice had decreased survival compared with wild-type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2−/− mice did not differ from wild-type mice in survival or levels of IL-22 in the lungs postinfection with K. pneumoniae. In contrast, K. pneumoniae–infected Rag2−/−Il2rg−/− mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells in host defense and production of IL-22. Unlike NK cell–like innate lymphoid cells that produce IL-22 and display a surface phenotype of NK1.1−NKp46+CCR6+, lung NK cells showed the conventional phenotype, NK1.1+NKp46+CCR6−. Mice depleted of NK cells using anti–asialo GM1 showed decreased survival and higher lung bacterial counts, as well as increased dissemination of K. pneumoniae to blood and liver, compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within 1 d postinfection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild-type and Rag2−/− mice. Our data suggest that, during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.
Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy
Authors: Brenndörfer Erwin Daniel , Brass Anette , Karthe Juliane , Ahlén Gustaf , Bode Johannes Georg , Sällberg Matti 
Published: January 2014

Abstract
Ribavirin has proven to be a key component of hepatitis C therapies both involving IFNs and new direct-acting antivirals. The hepatitis C virus–mediated interference with intrahepatic immunity by cleavage of mitochondrial antiviral signaling protein (MAVS) and T cell protein tyrosine phosphatase (TCPTP) suggests an avenue for compounds that may counteract these effects. We therefore studied the effects of ribavirin, with or without inhibition of the nonstructural (NS)3/4A protease, on intrahepatic immunity. The intrahepatic immunity of wild-type and NS3/4A-transgenic mice was determined by Western blot, ELISA, flow cytometry, and survival analysis. Various MAVS or TCPTP constructs were injected hydrodynamically to study their relevance. Ribavirin pretreatment was performed in mice expressing a functional or inhibited NS3/4A protease to analyze its effect on NS3/4A-mediated changes. Intrahepatic NS3/4A expression made mice resistant to TNF-α–induced liver damage and caused an alteration of the intrahepatic cytokine (IFN-γ and IL-10) and chemokine (CCL3, CCL17, CCL22, CXCL9, and CXCL11) profiles toward an anti-inflammatory state. Consistent with this, the number of intrahepatic Th1 cells and IFN-γ+ T cells in NS3/4A-transgenic mice decreased, whereas the amount of Th2 cells increased. These effects could be reversed by injection of uncleavable TCPTP but not uncleavable MAVS and were absent in a mouse expressing a nonfunctional NS3/4A protease. Importantly, the NS3/4A-mediated effects were reversed by ribavirin treatment. Thus, cleavage of TCPTP by NS3/4A induces a shift of the intrahepatic immune response toward a nonantiviral Th2-dominated immunity. These effects are reversed by ribavirin, supporting that ribavirin complements the effects of direct-acting antivirals as an immunomodulatory compound.
CD19 and CD32b Differentially Regulate Human B Cell Responsiveness
Authors: Karnell Jodi L. , Dimasi Nazzareno , Karnell Fredrick G. , Fleming Ryan , Kuta Ellen , Wilson Mildred , Wu Herren , Gao Changshou , Herbst Ronald , Ettinger Rachel 
Published: January 2014

AbstractB cell activation is regulated by a variety of signals. CD19 positively regulates B cell activation, augmenting signals delivered through the BCR complex. In contrast, CD32b contains an ITIM and negatively regulates BCR signaling. Importantly, there are drugs currently in clinical trials and preclinical development that cross-link CD32b to molecules within the BCR complex. We wanted to address how single engagement versus cotargeting these molecules affects human B cell function. When B cells from healthy individuals were activated by signals that mimic a T cell response (IL-21 costimulation), ligation of CD32b, but not CD19, inhibited B cell expansion and plasma cell (PC) differentiation. In contrast, when B cells were activated through TLR, anti-CD19, but not anti-CD32b, blunted the response. However, when both CD19 and CD32b were coengaged by a bispecific anti-CD19×CD32b Ab, both types of stimuli were potently inhibited. Cross-linking CD19 with CD32b also inhibited Ab-independent functions of B cells, such as HLA upregulation, cytokine production, and the ability of B cells to prime CD4+ T cells. Finally, although cross-linking CD19 and CD32b inhibited PC differentiation of primary B cells, it did not alter Ig production from pre-established PCs. These data elucidate the mechanism by which a complex set of signals determines the fate of B cell responsiveness. Although signals through CD19 influence TLR-driven activation, CD32b impacts the magnitude of the response following IL-21 costimulation. Therefore, simultaneous targeting of multiple surface molecules may be a necessary approach to comprehensively modulate B cell activation in vivo.
Induction of Endotoxin Tolerance by Pathogenic Neisseria Is Correlated with the Inflammatory Potential of Lipooligosaccharides and Regulated by MicroRNA-146a
Authors: Liu Mingfeng , John Constance M. , Jarvis Gary A. 
Published: January 2014

Abstract
In this article, we report that retreatment of human monocytic THP-1 cells and primary monocytes with pathogenic Neisseria or with purified lipooligosaccharides (LOS) after previous exposure to LOS induced immune tolerance, as evidenced by reduced TNF-α and IL-1β cytokine expression. LOS that we have previously shown to vary in their potential to activate TLR4 signaling, which was correlated with differences in levels of lipid A phosphorylation, had similarly variable ability to induce tolerance. Efficacy for induction of tolerance was proportional to the level of lipid A phosphorylation, as LOS from meningococcal strain 89I with the highest degree of phosphorylation was the most tolerogenic following retreatment with LOS or whole bacteria, compared with LOS from gonococcal strains 1291 and GC56 with reduced levels of phosphorylation. Hydrogen fluoride treatment of 89I LOS to remove phosphates rendered the LOS nontolerogenic. Tolerance induced by the more highly inflammatory meningococcal LOS was correlated with significantly greater downregulation of p38 activation, greater induction of the expression of A20 and of microRNA-146a, and greater reductions in IL-1R–associated kinase 1 and TRAF6 levels following LOS retreatment of cells. The role of miR-146a in regulation of induction of TNF-α was confirmed by transfecting cells with an inhibitor and a mimic of miR-146a. Our results provide a mechanistic framework for understanding the variable pathophysiology of meningococcal and gonococcal infections given that after an initial exposure, greater upregulation of microRNA-146a by more highly inflammatory LOS conversely leads to the suppression of immune responses, which would be expected to facilitate bacterial survival and dissemination.
Flagellin Induces Antibody Responses through a TLR5- and Inflammasome-Independent Pathway
Authors: López-Yglesias Américo Harry , Zhao Xiaodan , Quarles Ellen K. , Lai Marvin A. , VandenBos Tim , Strong Roland K. , Smith Kelly D. 
Published: January 2014

Abstract
Flagellin is a potent immunogen that activates the innate immune system via TLR5 and Naip5/6, and generates strong T and B cell responses. The adaptor protein MyD88 is critical for signaling by TLR5, as well as IL-1Rs and IL-18Rs, major downstream mediators of the Naip5/6 Nlrc4-inflammasome. In this study, we define roles of known flagellin receptors and MyD88 in Ab responses generated toward flagellin. We used mice genetically deficient in flagellin recognition pathways to characterize innate immune components that regulate isotype-specific Ab responses. Using purified flagellin from Salmonella, we dissected the contribution of innate flagellin recognition pathways to promote Ab responses toward flagellin and coadministered OVA in C57BL/6 mice. We demonstrate IgG2c responses toward flagellin were TLR5 and inflammasome dependent; IgG1 was the dominant isotype and partially TLR5 and inflammasome dependent. Our data indicate a substantial flagellin-specific IgG1 response was induced through a TLR5-, inflammasome-, and MyD88-independent pathway. IgA anti-FliC responses were TLR5 and MyD88 dependent and caspase-1 independent. Unlike C57BL/6 mice, flagellin-immunized A/J mice induced codominant IgG1 and IgG2a responses. Furthermore, MyD88-independent, flagellin-induced Ab responses were even more pronounced in A/J MyD88−/− mice, and IgA anti-FliC responses were suppressed by MyD88. Flagellin also worked as an adjuvant toward coadministered OVA, but it only promoted IgG1 anti-OVA responses. Our results demonstrate that a novel pathway for flagellin recognition contributes to Ab production. Characterization of this pathway will be useful for understanding immunity to flagellin and the rationale design of flagellin-based vaccines.
Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB × NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation
Authors: Der Evan , Dimo Joana , Trigunaite Abhishek , Jones Justin , Jørgensen Trine N. 
Published: January 2014

Abstract
Systemic lupus erythematosus is an autoimmune disease characterized by elevated production of autoreactive Abs. The disease has a much higher prevalence in women than in men. Although testosterone has been shown to be protective in the disease, and estrogens exacerbating, the discrepancy in prevalence between men and women is still not well understood and the mechanism behind it is unknown. We have recently described that male (New Zealand black [NZB] × New Zealand white [NZW])F1 mice have higher levels of Gr1+CD11b+ cells, and that these cells suppress autoantibody production in vivo. In this article, we extend our findings to show that similarly to humans, female lupus-prone (NZB × NZW)F1 mice also respond with stronger Ab responses to thymus-dependent Ag immunization than male littermates. Furthermore, the presence or absence of Gr1-expressing cells not only control Ag-specific Ab responses in male, but not female, (NZB × NZW)F1 mice, but also significantly alter the activation and differentiation of CD4+ T cells in vitro and in vivo. In particular, we found that Gr1+ cells from male (NZB × NZW)F1 mice suppress the differentiation and effector function of CXCR5+PD-1+ T follicular helper cells, thereby controlling germinal center formation and plasma cell differentiation. This new finding strongly supports efforts to develop new drugs that target myeloid cell subsets in a number of T and B cell–mediated diseases with a female predominance.
Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation
Authors: Wang Yetao , Hu Lei , Tong Xiaomei , Ye Xin 
Published: January 2014

Abstract
The casein kinase 1 (CK1) plays an important role in various biological processes by phosphorylating its target proteins. In this study, we demonstrate that CK1γ1 inhibits RNA virus–mediated activation of retinoic acid–inducible gene I (RIG-I) signaling by affecting the stability of NF-κB subunit p65. First, we found that ectopic expression of CK1γ1 inhibits RIG-I pathway–mediated activation of IFN-β, whereas knockdown of CK1γ1 potentiates the activation of IFN-β and NF-κB induced by Sendai virus (SeV). We then revealed that CK1γ1 interacts with p65 and specifically enhances its phosphorylation at Ser536 induced by SeV. By using an in vitro kinase assay, we confirmed that CK1γ1 can phosphorylate p65 at Ser536. We also showed that the kinase dead mutants CK1γ1K73A and CK1γ1N169A did not inhibit SeV-induced activation of IFN-β and NF-κB, suggesting that the kinase activity of CK1γ1 is critical for its inhibitory effect on RIG-I signaling. Additionally, we found that CK1γ1 also has the similar effect on TLR signaling. Further analysis indicated that CK1γ1 phosphorylates p65 and consequently promotes its degradation by ubiquitin E3 ligases CUL2 and COMMD1. These results revealed a novel negative regulatory manner of CK1γ1 on innate immune signaling.
CXCL1 but Not IL-6 Is Required for Recurrent Herpetic Stromal Keratitis
Authors: West Devin M. , Del Rosso Chelsea R. , Yin Xiao-Tang , Stuart Patrick M. 
Published: January 2014

Abstract
Herpetic stromal keratitis (HSK) is characterized by an inflammatory response that includes neutrophils, macrophages, NK cells, and T cells. The factors that are responsible for this inflammation are proinflammatory cytokines and chemokines. Many of these factors have been defined for primary disease, but relatively few have been investigated during recurrent HSK. The present study was designed to determine the role that two of these factors, IL-6 and CXCL1, play during recurrent HSK. Results clearly indicate that unlike primary disease, IL-6 plays no role in recurrent HSK. However, the presence of CXCL1 is required for recurrent HSK as evidenced by the lack of corneal disease in mice treated with anti-CXCL1 Ab. This was confirmed using mice lacking the primary receptor for CXCL1, CXCR2. Corneal disease in this strain was significantly reduced compared with wild-type C57BL/6 controls. Unexpectedly, lack of disease occurs even though CXCL1 knockout mice display increased viral shedding at the cornea. The primary mechanism that CXCL1 plays during disease is its ability to stimulate neutrophils to infiltrate the cornea following reactivation. This paper provides further evidence that primary HSK and recurrent HSK possess overlapping yet distinct disease mechanisms.
Spectrum of high-resolution computed tomography imaging in occupational lung disease
Authors: Satija Bhawna , Kumar Sanyal , Ojha Umesh Chandra , Gothi Dipti 
Published: January 2014

AbstractDamage to the lungs caused by dusts or fumes or noxious substances inhaled by workers in certain specific occupation is known as occupational lung disease. Recognition of occupational lung disease is especially important not only for the primary worker, but also because of the implications with regard to primary and secondary disease prevention in the exposed co-workers. Although many of the disorders can be detected on chest radiography, high-resolution computed tomography (HRCT) is superior in delineating the lung architecture and depicting pathology. The characteristic radiological features suggest the correct diagnosis in some, whereas a combination of clinical features, occupational history, and radiological findings is essential in establishing the diagnosis in others. In the presence of a history of exposure and consistent clinical features, the diagnosis of even an uncommon occupational lung disease can be suggested by the characteristic described HRCT findings. In this article, we briefly review the HRCT appearance of a wide spectrum of occupational lung diseases.
Horse-shoe lung-rediscovered via volume rendered images
Authors: Bharati Alpa , Merchant Suleman A , Garekar Swati , Patel Tapan 
Published: January 2014

AbstractHorseshoe lung, usually associated with pulmonary venolobar syndrome, is a rare congenital anomaly involving the fusion of the postero-basal segments of the right and left lungs across the midline. The fused segment or the isthmus lies posterior to the pericardium and anterior to the aorta.The associated pulmonary venolobar syndrome involves anomalous systemic arterial supply and anomlaous systemic venous drainage of the right lung. With the advent of MDCT imaging, we can diagnose this rare condition as well all its associated anomalies non-invasively. Volume-rendered techniques greatly simplify the complex anatomy and provide easy understanding of the same.
Occupational Changes in Caregivers for Spouses with Stroke and Aphasia
Authors: Kniepmann Kathy , Cupler Molly Harlacker 
Published: January 2014

Introduction: Stroke is a leading cause of disability worldwide. While health services focus on the needs of diagnosed persons, families provide extensive informal care with diverse effects on daily life and health. Understanding caregivers' experience is critical to support their health and sustained contributions. This exploratory study examined how caring for partners with stroke and aphasia impacts caregivers' activities, identifying possible differences according to race/ethnicity through the lens of occupation. Method: Mixed methods identified the occupational impact of caring for a partner with stroke and aphasia. Twelve participants completed the Carer Communication Outcome After Stroke, Occupational Gaps Questionnaire, Activity Card Sort, and a semi-structured interview. Findings: The impact of aphasia on caregivers varied greatly. The Occupational Gaps Questionnaire revealed gaps in cultural activities. On the Activity Card Sort, caregivers experienced occupational loss, primarily in low-demand leisure and social activities. Six themes emerged from the interviews: personal factors, finding new equilibrium, participation barriers, compensations for aphasia, uncertainty, and obligations. Trends differed somewhat by race/ethnicity. Conclusion: Findings have implications for health professionals working with individuals with stroke and aphasia. The caregivers' experience deserves attention to support their quality of life and wellbeing, which can promote sustained assistance for their relatives with stroke.
Occupational Therapists' Attitudes, Knowledge, and Implementation of Evidence-Based Practice: A Systematic Review of Published Research
Authors: Upton Dominic , Stephens Danielle , Williams Briony , Scurlock-Evans Laura 
Published: January 2014

Introduction: Evidence-based practice is the procedure whereby clinicians incorporate best research evidence, clinical expertise, and patient values to provide best patient care. Recently, there has been a significant push towards occupational therapists' adoption of evidence-based practice. This systematic review aimed to determine occupational therapists' attitudes, knowledge, and utilization of evidence-based practice. Method: A search of literature published between 2000–12 was conducted in relation to occupational therapists' practice. Academic Search Complete, Cumulative Index of Nursing and Allied Health Literature Plus, PsycARTICLES, Ingenta, Medline, Science Direct, and Journal Storage were systematically searched using MeSH and free-text keywords. Google Scholar and reference lists were also searched. Findings: Thirty-two papers were selected for review: 23 were quantitative, 8 were qualitative, and 1 used a mixed methods design. Studies demonstrated that occupational therapists hold positive attitudes towards evidence-based practice. However, these attitudes do not translate into practice, with research indicating a lack of evidence-based practice utilization. Occupational therapists perceive a number of barriers to evidence-based practice, including lack of time, lack of availability and accessibility of research, and having limited research skills. Conclusion: It is essential that educational and training initiatives provide therapists with the tools and support they need to engage fully with research evidence and its application within clinical care.
Three-Year Outcomes of Cultured Limbal Epithelial Allografts in Aniridia and Stevens-Johnson Syndrome Evaluated Using the Clinical Outcome Assessment in Surgical Trials Assessment Tool
Authors: Shortt Alex J. , Bunce Catey , Levis Hannah J. , Blows Peter , Doré Caroline J. , Vernon Amanda , Secker Genevieve A. , Tuft Stephen J. , Daniels Julie T. 
Published: January 2014

Abstract
Limbal stem cell deficiency (LSCD) is an eye disorder in which the stem cells responsible for forming the surface skin of the cornea are destroyed by disease. This results in pain, loss of vision, and a cosmetically unpleasant appearance. Many new treatments, including stem cell therapies, are emerging for the treatment of this condition, but assessment of these new technologies is severely hampered by the lack of biomarkers for this disease or validated tools for assessing its severity. The aims of this study were to design and test the reliability of a tool for grading LSCD, to define a set of core outcome measures for use in evaluating treatments for this condition, and to demonstrate their utility. This was achieved by using our defined outcome set (which included the Clinical Outcome Assessment in Surgical Trials of Limbal stem cell deficiency [COASTL] tool) to evaluate the 3-year outcomes for allogeneic ex vivo cultivated limbal epithelial transplantation (allo-CLET) in patients who had bilateral total LSCD secondary to aniridia or Stevens-Johnson syndrome. The results demonstrate that our new grading tool for LSCD, the COASTL tool, is reliable and repeatable, and that improvements in the biomarkers used in this tool correlate positively with improvements in visual acuity. The COASTL tool showed that following allo-CLET there was a decrease in LSCD severity and an increase in visual acuity up to 12 months post-treatment, but thereafter LSCD severity and visual acuity progressively deteriorated.
Concise Review: Parthenote Stem Cells for Regenerative Medicine: Genetic, Epigenetic, and Developmental Features
Authors: Daughtry Brittany , Mitalipov Shoukhrat 
Published: January 2014

Abstract
Embryonic stem cells (ESCs) have the potential to provide unlimited cells and tissues for regenerative medicine. ESCs derived from fertilized embryos, however, will most likely be rejected by a patient's immune system unless appropriately immunomatched. Pluripotent stem cells (PSCs) genetically identical to a patient can now be established by reprogramming of somatic cells. However, practical applications of PSCs for personalized therapies are projected to be unfeasible because of the enormous cost and time required to produce clinical-grade cells for each patient. ESCs derived from parthenogenetic embryos (pESCs) that are homozygous for human leukocyte antigens may serve as an attractive alternative for immunomatched therapies for a large population of patients. In this study, we describe the biology and genetic nature of mammalian parthenogenesis and review potential advantages and limitations of pESCs for cell-based therapies.