Human B cell stimulatory factor 2 (originally designated BSF2) was initially characterized and isolated as a T cell‐derived factor that caused the terminal maturation of activated B cells to immunoglobulin producing cells. Molecular cloning of the cDNA has revealed that BSF2 is identical with 26 kD protein, interferon β2, plasmacytoma growth factor and hepatocyte stimulating factor and the designation “IL‐6” has been proposed for this molecule. It is now known that BSF2/IL‐6 has a wide variety of biological functions and that (...) abnormal regulation of BSF2/IL‐6 expression may be related to the pathogenesis of certain autoimmune diseases such as rheumatoid arthritis and multiple myeloma. (shrink)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign (...) was conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

Social organization in microcosm : anomalies and ritual concentrate conflict -- Comparing on a grand scale : elementary forms do the organizing -- Building fundamental explanations : rituals do the institutionalizing, and institutions make change -- Analytic method is also ritual peacemaking : thinking in circles helps to defuse conflict -- Douglas's contribution to understanding human thought and conflict.

Thirty-eight individuals (mean age: 34.8 years old) participating in a 3-month yoga and meditation retreat were assessed before and after the intervention for psychometric measures, brain derived neurotrophic factor (BDNF), circadian salivary cortisol levels, and pro- and anti-inflammatory cytokines. Participation in the retreat was found to be associated with decreases in self-reported anxiety and depression as well as increases in mindfulness. As hypothesized, increases in the plasma levels of BDNF and increases in the magnitude of the cortisol awakening response (CAR) (...) were also observed. The normalized change in BDNF levels was inversely correlated with BSI-18 anxiety scores at both the pre-retreat (r = 0.40, p < 0.05) and post-retreat (r = 0.52, p < 0.005) such that those with greater anxiety scores tended to exhibit smaller pre- to post-retreat increases in plasma BDNF levels. In line with a hypothesized decrease in inflammatory processes resulting from the yoga and meditation practices, we found that the plasma level of the anti-inflammatory cytokine Interleukin-10 was increased and the pro-inflammatory cytokine Interleukin-12 was reduced after the retreat. Contrary to our initial hypotheses, plasma levels of other pro-inflammatory cytokines, including Interferon Gamma (IFN-γ), Tumor Necrosis Factor (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) were increased after the retreat. Given evidence from previous studies of the positive effects of meditative practices on mental fitness, autonomic homeostasis and inflammatory status, we hypothesize that these findings are related to the meditative practices throughout the retreat; however, some of the observed changes may also be related to other aspects of the retreat such as physical exercise-related components of the yoga practice and diet. We hypothesize that the patterns of change observed here reflect mind-body integration and well-being. The increased BDNF levels observed is a potential mediator between meditative practices and brain health, the increased CAR is likely a reflection of increased dynamic physiological arousal, and the relationship of the dual enhancement of pro- and anti-inflammatory cytokine changes to healthy immunologic functioning is discussed. (shrink)

The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human disease. (...) Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin‐6 and c‐FOS production, possibly via the transcription factor NF‐kB. (shrink)

Frailty is a complex geriatric syndrome with multifactorial associated mechanisms that need to be examined more deeply to help reverse the adverse health-related outcomes. Specific inflammatory and physical health markers have been associated with the onset of frailty, but the associations between these factors and psycho-social health outcomes seem less studied. This systematic review aimed to identify, in the same study design, the potential associations between frailty and markers of inflammation, and physical or psycho-social health. A literature search was performed (...) from inception until March 2021 using Medline, Psycinfo, and EMBASE. Three raters evaluated the articles and selected 22 studies, using inclusion and exclusion criteria. Regarding biomarkers, 95% of the included studies showed significant links between inflammation [especially the higher levels of C-reactive protein and interleukin-6 ], and frailty status. Approximately 86% of the included studies showed strong links between physical health decline, and frailty status. At most, 13 studies among the 22 included ones evaluated psycho-social variables and mixed results were observed regarding the relationships with frailty. Results are discussed in terms of questioning the medical perception of global health, centering mostly on the physical dimension. Therefore, the development of future research studies involving a more exhaustive view of frailty and global health is strongly encouraged. (shrink)

ObjectiveThe scarcity of research on associations between inflammatory markers and symptoms of depression and anxiety during adolescence has yielded inconsistent results. Further, not all studies have controlled for potential confounders. We explored the associations between baseline inflammatory markers and psychological distress including moderators at follow-up in a Norwegian adolescent population sample.MethodsData was derived from 373 girls and 294 boys aged 15–18 years at baseline, in the Fit Futures Study, a large-scale 2-year follow-up study on adolescent health. Baseline data was gathered (...) from 2010 to 2011 and follow-up data from 2012 to 2013. Psychological distress was measured with Hopkins Symptom Checklist. Serum levels of the following inflammatory markers were measured: C-reactive protein, Interleukin 6, Transforming growth factor alpha, Tumor necrosis factor alpha variant 1, and variant 2. Independent associations between baseline inflammatory markers and HSCL-10 at follow-up were explored by linear regressions, in sex-stratified analyses.ResultsIn girls, analyses showed positive associations between all inflammatory markers and HSCL-10, except for TRANCE. However, all associations were non-significant in crude as well as in adjusted analyses. In boys, CRP and TGF-α showed significant associations with HSCL-10, that remained significant after adjustment. Additionally, moderators were found. In boys, CRP was associated with HSCL-10 in those with high body fat and those being physical inactive, and the association between TWEAK and HSCL-10 was dependent upon sleep duration.ConclusionThere were significant prospective associations between CRP, TFG-α, and HSCL-10 in boys aged 15–18 years at baseline. (shrink)

Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a crucial signaling molecule regulating a diverse array of physiological processes, including adaptive immunity, innate immunity, bone metabolism and the development of several tissues including lymph nodes, mammary glands, skin and the central nervous system. It is a member of a group of six closely related TRAF proteins, which serve as adapter molecules, coupling the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 is unique in (...) that, in addition to mediating TNFR family signaling, it is also essential for signaling downstream of an unrelated family of receptors, the interleukin‐1 (IL‐1) receptor/Toll‐like receptor (IL‐1R/TLR) superfamily. Gene targeting experiments have identified several indispensable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action. By virtue of its many signaling roles, TRAF6 represents an important target in the regulation of many disease processes, including immunity, inflammation and osteoporosis. BioEssays 25:1096–1105, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Two types of interleukin 1 (IL‐1α and IL‐1β) have been defined by purifying the molecules from activated human peripheral blood cells, followed by cloning and expressing the molecules in Escherichia coli. Both types of IL‐1 stimulate proliferation and differentiation of T‐ and B‐lymphocytes and induce cartilage proteoglycan degradation but differ in other properties. For example, demineralization and appears to be a major mediator in the pathogenesis of joint erosion in rheumatoid arthritis. Synthetic adjuvants elicit the production of IL‐1 separate (...) from endogenous pyrogen, and this property is required for the new generation of vaccines based on antigens produced by recombinant DNA technology. (shrink)

Interleukin‐15 (IL‐15) is a pleiotropic cytokine of the 4 α‐helix bundle family, which binds to a receptor complex that displays common elements with the IL‐2 receptor and a unique high‐affinity α chain. This review focuses on juxtacrine and reverse signaling levels in the IL‐15/IL‐15R system. Specifically, we discuss how agonistic stimulation of membrane‐bound IL‐15 induces phosphorylation of members of the MAP kinase family and of focal adhesion kinase (FAK), thereby upregulating processes including cytokine secretion, cell adhesion and migration. In (...) addition, we explore IL‐15 trans‐presentation and intracellular signaling, and define promising molecular targets for future pharmacological intervention in infectious diseases and immunological disorders. These frontiers in IL‐15/IL‐15Rα research serve as highly instructive examples for key concepts, unsolved problems and therapeutic opportunities in juxtacrine and reverse signaling in general. BioEssays 28: 362–377, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. (...) The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

Cytokines, also referred to as interleukins, are the major orchestrators of host defence processes, and, as such, are involved in insults, repair and restoration of tissue homeostasis. This review summarises recent findings on and emerging models of the biological roles of the double-edged sword interleukin-13 (IL-13), which have been principally obtained from studies in mice that are deficient for IL-13, or its components. IL-13-mediated functions not only contribute to the susceptible phenotype in Leishmania major infection but also seem to (...) play a protective role in chronic leishmaniasis. Moreover, IL-13 plays a key protective role in the expulsion of helminths from the gut while also actively contributing to the pathology in schistosomiasis. In allergic asthma, IL-13 has also been found to be a key factor. Therapeutic administration of an IL-13 inhibitor in mice successfully prevents both the allergic disease phenotype and schistosoma egg-induced lung pathology. If this scenario holds true in humans, we soon may have an efficient drug for treatment of IL-13-mediated diseases. BioEssays 22:646–656, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

This chapter presents findings on a study of neuropsychological aspects of visual hallucinations with a focus on hallucinations in Parkinson's disease. The results of the study suggest that VHs in PD are a complex multifactor effect of different risk factors, primarily the dysfunctions of the visual system and the system that regulates rapid eye movement sleep and arousal. The study reported here also investigated whether the same risk factors are implicated in proneness to VHs as they are in VHs in (...) PD. The results suggest that the predisposition to VHs in the healthy young population is a multifactor effect of strikingly similar risk factors to those found in PD. However, in addition to the dysfunctions of the visual and arousal system, proneness to hallucinations in the normal population is also predicted by a specific personality profile. (shrink)

"Aptavani 6" is the sixth in a series of spiritual books titled "Aptavani". In this series, Gnani Purush (embodiment of Self knowledge) Dada Bhagwan addresses age-old unanswered questions of spiritual seekers. Dadashri offers in-depth answers to the urgent questions of: "What is the cause of life problems?", "I experience so much internal struggle while facing problems -- teach me how to get inner peace?", "What is peace of mind, and how can I attain it?", "I have so many problems in (...) everyday life, my life feels like the very definition of injustice -- help me understand how to live?!"Dadashri explains that, from understanding "Who am I?" and attaining knowledge of Self, a foundation of spirituality opens up within. From this spiritual awakening, a newfound ability to face life problems arises. One begins to experience inner equanimity and peace of mind -- regardless of any problems in everyday life. (shrink)

Frontmatter -- Also sprach Zarathustra. Erster Theil -- Also sprach Zarathustra. Zweiter Theil -- Also sprach Zarathustra. Dritter Theil -- Also sprach Zarathustra. Vierter und letzter Theil.

The effects of non-standard Philosophy on Epistemelogy.

English summary: This Arabic edition and French translation of Avicennas commentary on Aristotles Lambda offers a clear opportunity to better understand the Greek philosophers influence on medieval Arabic philosophy, especially concerning the hierarchy of the universe. French description: Ce texte d'Avicenne est l'un des seuls commentaires sur Aristote laisses par le philosophe persan. Il s'attaque au noyau theologique de la Metaphysique du Stagirite, les chapitres 6 a 10 du livre Lambda. Avicenne depend d'une tradition greco-arabe (Alexandre d'Aphrodise, Themistius, l'ecole "peripateticienne" (...) de Bagdad). La tradition arabe a aussi attribue a Aristote plusieurs oeuvres d'origine neoplatonicienne, notamment une Theologie adaptee de Plotin, et un Livre du Bien pur, adaptation des Elements de Theologie de Proclus. Le Dieu d'Aristote est ainsi pour Avicenne la Cause premiere efficiente de l'etre. La structure hierarchique de l'univers resulte de l'emanation produite par l'autointelligence du premier Principe. Il ne fait pas de doute, pour Avicenne, que ces doctrines aient ete celles du Stagirite. (shrink)

The study examines the multifaceted nature of legitimacy in the context of international law, elucidating its paramount importance for the law's authority and its pervasive influence on the applicability of legal norms globally. The pressing relevance of this inquiry emerges from the challenges posed by the application of international law in complex scenarios such as military interventions and global governance, which necessitate a refined comprehension of legitimacy's contours. The research's objective is to dissect the essence, theoretical frameworks, and practical dimensions (...) of legitimacy, thereby elucidating its pivotal role and manifestations within the international legal order. The principal findings underscore that legitimacy in international law transcends mere legal validity, embedding itself within a broader ethical and communicative framework that demands consideration of justice, human rights, and international peace and security. Legitimacy is found to be inherently dynamic, shaped significantly by the interactive processes among global actors and the consensus within the international interpretative community on ethical and legal standards. The study highlights the crucial role of narrative and argumentation in legitimizing or delegitimizing actions under international law, illustrating how perceptions of legitimacy can evolve and influence international legal practices and decisions. The nuanced understanding of legitimacy gleaned from this research contributes to a more precise conceptualization of its role, emphasizing its indispensable function in guiding the application of international law, enhancing global governance, and promoting a more equitable and just international order. (shrink)