Miracle-dz/UniFAR-FTUs huggingface dataset:
IRF6 Regulates the Expression of IL-36γ by Human Oral Epithelial Cells in Response to Porphyromonas gingivalis

IFN regulatory factors (IRFs) help to shape the immune response to pathogens by imparting signaling specificity to individual TLRs. We recently demonstrated that IRF6 provides specificity to TLR2 signaling in oral epithelial cells. TLR2 plays an important role in eliciting inflammation to Porphyromonas gingivalis, a keystone pathogen in periodontitis. Therefore, we investigated a role for IRF6 in mediating the inflammatory cytokine response of oral epithelial cells to P. gingivalis. IRF6 expression was strongly upregulated when human oral epithelial cells were challenged with P. gingivalis. Moreover, gene silencing and gene promoter experiments indicated that IRF6 acts downstream of IL-1R–associated kinase 1 to stimulate the expression of the IL-1 family cytokine IL-36γ in response to P. gingivalis. IRF6 and IL-1R–associated kinase 1 also regulated the stimulation of IL-36γ expression by a TLR2 agonist. IL-36γ was shown to elicit inflammatory responses by human monocyte-derived dendritic cells and macrophages, including the expression of the neutrophil chemokines IL-8 and CXCL1, as well as the Th17 chemokine CCL20. IL-36γ similarly stimulated their expression by human oral epithelial cells. Significantly, the Th17 cytokine IL-17 not only stimulated the expression of important regulators of neutrophil recruitment and survival by oral epithelial cells, but IL-17 also stimulated them to express IL-36γ. Thus, our findings suggest that IRF6 is likely to promote inflammation to P. gingivalis through its regulation of IL-36γ.
Association of GSTM1 polymorphism with susceptibility to hepatocellular carcinoma (HCC) in Chinese population: A meta-analysis

This study was performed to study the association of GSTM1 polymorphism with susceptibility to hepatocellular carcinoma in Chinese population. Medicinal databases and review articles were screened with pre-specified criteria for case control design trials that reported the association of GSTM1 polymorphism with susceptibility to hepatocellular carcinoma (HCC) in Chinese population. The quality of included studies was critically evaluated. A total of 1252 articles were found and 22 articles were finally included. The GSTM1 null genotypes were associated with increased risk of HCC in Chinese population (OR = 1.52, 95% CI: 1.24 to 1.87, P < 0.0001). The evidence currently available shows that GSTM1 null genotypes are associated with increased risk of HCC in Chinese population.
Home-Delivered Mental Health Services for Aged Rural Home Health Care Recipients

Home health care programs are generally able to meet a wide variety of older persons’ medical care needs, but are often unable to provide for the specialized needs of those patients who are experiencing emotional problems. This situation is most problematic in rural communities where services to meet the mental health needs of homebound elders are often not available. This article reports the results of a study that tested the efficacy of providing home-delivered psychotherapy to 78 elderly patients of a rural home health care agency. Patients who completed the brief, task-centered psychotherapeutic intervention reported improvements in their emotional well-being and indicated significant reduction of the problems associated with the target complaints that were the focus of the interventive activities. These results suggest that home-delivered psychotherapeutic interventions may have an important role to play in treating the mental health problems of older, rural, home health care recipients.
Electronic Structure Calculation of Adsorbate Gas Molecules on an Armchair Graphene Nanoribbon

By using the first-principle methods, we have investigated the adsorption of the CO, CO2, NO, and NH3 molecules on an armchair graphene nanoribbon (AGNR). The optimal adsorption positions and orientations of these molecules on AGNR are determined. The adsorption energies, the charge transfer, and the density of states (DOS) are obtained. The NO, CO, and CO2 adsorbed molecules act as an acceptor, and the NH3 adsorbed molecule acts as a donor. The NO and CO molecules contributed with localized states in the center of the original band gap. But the system exhibits -type or -type semiconductor after NH3 or CO2 adsorption.
Work in progress report-Thoracic non-oncologic Appropriate set-up of the da Vinci Surgical System in relation to the location of anterior and middle mediastinal tumors

The da Vinci Surgical System (dV) and its later version wda Vinci S Surgical System (dVS)x have been used only in very few cases in selected thoracic surgical areas in Japan. Recently, we used the dV and dVS for various types of anterior and middle mediastinal tumors in clinical practice. We report our experience, and review the settings which depended on tumor location. Six patients gave written informed consent to undergo robotic surgery using the dV or dVS. We evaluated the feasibility, safety and appropriate settings of this system for the surgical treatment of mediastinal tumors. Tumor dissection was performed by two specialists in thoracic surgery certified to use the dV and dVS, and another specialist who acted as an assistant. We were able to access difficult-to-reach areas like the mediastinum. All the resected tumors were classified as benign tumors histologically. Crucial to the success of these operations was the set-up of the dV, which varied according to the location of mediastinal tumors. Robotic surgery enables various types of mediastinal tumor dissection more safely and easily than conventional video-assisted thoracoscopic surgery (VATS). The dV requires the appropriate set-up configuration, which varies according to the location of the mediastinal tumor. 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines

It has been known since the discovery of DNA vaccines >20 y ago that DNA vaccines can function as adjuvants. Our recent study reported the involvement of Aim2 as the sensor of DNA vaccines in eliciting Ag-specific Ab responses. Our findings indicated the presence of previously unrecognized innate immune response pathways in addition to the TLR9 pathway, which is mainly activated by the CpG motifs of DNA vaccines. Our data further demonstrated the requirement of type I IFN in DNA vaccine–induced immune responses via the Aim2 pathway, but the exact downstream molecular mechanism was not characterized. In the present study, we investigated the roles of the putative DNA sensor cyclic GMP–AMP synthase (cGas), as well as the downstream IFN regulatory factors (IRF) 3 and 7 in type I IFN induction and Ag-specific immune responses elicited by DNA vaccination. Our results showed that DNA vaccine–induced, Irf7-dependent signaling, as part of the Sting pathway, was critical for generation of both innate cytokine signaling and Ag-specific B and T cell responses. In contrast, Irf3 was not as critical as expected in this pathway and, more surprisingly, immune responses elicited by DNA vaccines were not cGas-dependent in vivo. Data from this study provide more details on the innate immune mechanisms involved in DNA vaccination and further enrich our understanding on the potential utility of DNA vaccines in generating Ag-specific immune responses.
Clonality studies in myelodysplasia and acute myeloid leukemia

textabstractIn adult humans, the production of blood cells or hematopoiesis is mainly restricted to the bone marrow. A small number of pluripotent stem cells, which are capable of selfrenewal, can generate committed progenitor cells. The latter are ineversibly committed to the granulocytic, monocytic, erythroid, megakaryocytic or the lymphoid cell lineage. After proliferation and differentiation, the mature blood cells entcr the circulation. The granulocytic and monocytic cells may be designated as myeloid cells; the erythroid cells are sometimes also included in this group. The blood cell formation is regulated by hematopoietic growth factors and cellular interactions e.g. with bone marrow stromal cells. Malignant transformation of hematopoietic cells results in ineffective hematopoiesis. Progenitor and/or precursor cells may accumulate due to a maturation arrest. Depending on the cell lineage involved, these disorders are refelTed to as myeIodysplastic syndrome, acute myeloid or lymphoblastic leukemia, myeloproliferative or lymphoproIiferative disease. The myelodyspIastic syndrome and acute myeloid leukemia are the subjects of investigation of this thesis.
RBP-J–Regulated miR-182 Promotes TNF-α–Induced Osteoclastogenesis

Increased osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α–induced osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow–derived macrophages/osteoclast precursors during inflammatory osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced osteoclastogenesis program induced by TNF-α in RBP-J–deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte–induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α–mediated osteoclastogenesis. Thus, RBP-J–regulated miR-182 promotes TNF-α–induced osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α–induced osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits osteoclastogenesis and suggest that targeting of the newly described RBP-J–miR-182–Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone resorption.
The CD4 and CD3δε Cytosolic Juxtamembrane Regions Are Proximal within a Compact TCR–CD3–pMHC–CD4 Macrocomplex

TCRs relay information about peptides embedded within MHC molecules (pMHC) to the ITAMs of the associated CD3γε, CD3δε, and CD3ζζ signaling modules. CD4 then recruits the Src kinase p56Lck (Lck) to the TCR–CD3 complex to phosphorylate the ITAMs, initiate intracellular signaling, and drive CD4+ T cell fate decisions. Whereas the six ITAMs of CD3ζζ are key determinants of T cell development, activation, and the execution of effector functions, multiple models predict that CD4 recruits Lck proximal to the four ITAMs of the CD3 heterodimers. We tested these models by placing FRET probes at the cytosolic juxtamembrane regions of CD4 and the CD3 subunits to evaluate their relationship upon pMHC engagement in mouse cell lines. The data are consistent with a compact assembly in which CD4 is proximal to CD3δε, CD3ζζ resides behind the TCR, and CD3γε is offset from CD3δε. These results advance our understanding of the architecture of the TCR–CD3–pMHC–CD4 macrocomplex and point to regions of high CD4–Lck + ITAM concentrations therein. The findings thus have implications for TCR signaling, as phosphorylation of the CD3 ITAMs by CD4-associated Lck is important for CD4+ T cell fate decisions.
Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1–dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell–APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4+ thymocytes was detected in the medulla of mice with T cell lineage–specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69+ double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.
Changes in Gene Expression during G-CSF–Induced Emergency Granulopoiesis in Humans

Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for G-CSF as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been investigated in humans. In this work, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy individuals after 5 d of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNA was subjected to microarray analysis. mRNA levels were compared with previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. One thousand one hundred and ten mRNAs were differentially expressed >2-fold throughout terminal granulopoiesis. Major changes were seen in pathways involved in apoptosis, cytokine signaling, and TLR pathways. In addition, G-CSF treatment reduced the levels of four of five measured granule proteins in mature neutrophils, including the proantibacterial protein hCAP-18, which was completely deficient in neutrophils from G-CSF–treated donors. These results indicate that multiple biological processes are altered to satisfy the increased demand for neutrophils during G-CSF–induced emergency granulopoiesis in humans.
ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

The development of therapies for multiple sclerosis targeting pathogenic T cell responses remains imperative. Previous studies have shown that estrogen receptor (ER) β ligands could inhibit experimental autoimmune encephalomyelitis. However, the effects of ERβ-specific ligands on human or murine pathogenic immune cells, such as Th17, were not investigated. In this article, we show that the synthetic ERβ-specific ligand 4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol (PHTPP) reversed established paralysis and CNS inflammation, characterized by a dramatic suppression of pathogenic Th responses as well as induction of IL-10–producing regulatory CD4+ T cell subsets in vivo. Moreover, administration of PHTPP in symptomatic mice induced regulatory CD4+ T cells that were suppressive in vivo. PHTPP-mediated experimental autoimmune encephalomyelitis amelioration was canceled in mice with ERβ-deficient CD4+ T cells only, indicating that expression of ERβ by these cells is crucial for the observed therapeutic effect. Importantly, synthetic ERβ-specific ligands acting directly on CD4+ T cells suppressed human and mouse Th17 cells, downregulating Th17 cell signature gene expression and expanding IL-10–producing T cells among them. TGF-β1 and aryl hydrocarbon receptor activation enhanced the ERβ ligand-mediated expansion of IL-10–producing T cells among Th17 cells. In addition, these ERβ-specific ligands promoted the induction and maintenance of Foxp3+ T regulatory cells, as well as their in vitro suppressive function. Thus, ERβ-specific ligands targeting pathogenic Th17 cells and inducing functional regulatory cells represent a promising subset of therapeutic agents for multiple sclerosis.
Computer access, skills and training among consultants and psychiatric trainees in Northern Ireland

AIMS AND METHOD Computers and information technology (IT) play an increasingly important role in the working lives of psychiatrists. Previous studies have shown that computer access and skills among psychiatric trainees were inadequate. This survey aimed to assess the level of access to, and skill in, different IT applications among consultants and trainees in Northern Ireland, as well as what training is offered and needed. RESULTS Most doctors (91%) had access to the more basic applications, such as word processing, and most felt at least adequately skilled. However, access to and knowledge of statistical software was particularly poor. A minority of doctors were offered training in IT (39%), even though most employers provided this facility. CLINICAL IMPLICATIONS Psychiatrists need greater access to IT, and need to make greater use of available training. This is especially relevant in light of future policy directions and the trend for evidence-based practice.
Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation

Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. In this study, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow–derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wild-type mice survived infection with minimal morbidity, 50% of Mmp10−/− mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were ∼3-fold greater in infected Mmp10−/− lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10−/− recipients to wild-type levels, demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, whereas M2 markers were reduced in Mmp10−/− tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10−/− BMDM long after they were downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages.
Symmetric dimethylarginine (SDMA) is raised in women with polycystic ovary syndrome: A pilot study

Summary Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction, which may be caused by elevated levels of asymmetric dimethylarginine (ADMA). ADMA reduces nitric oxide production in diabetes mellitus, hypertension and renal failure. Symmetric dimethylarginine (SDMA) is a stereoisomer produced alongside ADMA, and has recently been described as a risk factor for cardiovascular events. In this cross-sectional study based in a teaching hospital, 16 women with PCOS were recruited alongside 15 healthy controls, and fasting venous blood samples were obtained. Renal function was measured, and ADMA and SDMA were analysed using a high-performance liquid chromatography method. After controlling for BMI, mean ADMA and SDMA levels in women with PCOS were higher than in controls (p = 0.036 and p = 0.030, respectively). Renal function was not different between the two groups (p = 0.152). Women with PCOS have raised levels of SDMA, a molecule implicated in endothelial dysfunction and long-term cardiovascular risk.
Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

The serine/threonine kinase IL-1R–associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.
Spirometry use among older adults with chronic obstructive pulmonary disease: 1999-2008.

RATIONALE Clinical practice guidelines recommend spirometry to diagnose chronic obstructive pulmonary disease (COPD) and facilitate management. National trends in spirometry use in older adults with newly diagnosed COPD are not known. OBJECTIVES To examine the rate and beneficiary characteristics associated with spirometry use in subjects with newly diagnosed COPD between 1999 and 2008. METHODS We examined newly diagnosed beneficiaries with COPD using a 5% Medicare population from 1999 to 2008. A new COPD diagnosis required two outpatient visits or one hospitalization with primary International Classification of Diseases, 9th edition code 491.xx, 492.xx, or 496 occurring at least 30 days apart with none in the prior 12 months. The primary measurement was spirometry performed within 365 days (±) of the first claim with a COPD diagnosis. MEASUREMENTS AND MAIN RESULTS Between 1999 and 2008, 64,985 subjects were newly diagnosed with COPD. Of these, 35,739 (55%) had spirometry performed within 1 year before or after the initial diagnosis of COPD. Spirometry use increased from 51.3% in 1999 to 58.3% in 2008 (P < 0.001). Subjects with younger age, men, whites, those with higher socioeconomic status, and those with a greater number of comorbidities were more likely to have spirometry. In a multivariable analysis, compared with 1999, subjects diagnosed in 2008 had 10% higher odds (odds ratio, 1.10; 95% confidence interval, 1.06-1.13) of having spirometry performed. CONCLUSIONS Despite an increase in the use of spirometry over time in newly diagnosed older adults with COPD, spirometry use remains low. Clinical practice guidelines and educational efforts should focus on increasing the use of spirometry to diagnose and manage COPD.