bluuebunny/crossref_metadata_2025 huggingface dataset:
Placing a workers’ resistance movement against factory closure
Authors: Sergot Bertrand , Saives Anne-Laure
Published: January 2023

À l’invitation à « penser spatialement » lancée par ce numéro spécial, nous répondons par la proposition de penser « placialement » les phénomènes organisationnels. En nous appuyant sur un courant émergent liant lieu (en anglais, place ) et résistance organisationnelle, nous voulons comprendre, à travers l’étude d’un cas révélateur – la longue lutte des ex-salariés de Fralib en France –, comment penser de manière lieuitaire un mouvement local de travailleurs ayant résisté à une fermeture d’usine. Le lieu est central dans ce cas car le mouvement de résistance étudié apparaît comme co-construit avec un sens renouvelé de l’usine en tant que lieu à la propriété collective. Notre objectif, dans cet article, est donc de participer à l’intégration du lieu dans le répertoire conceptuel du management et de l’étude des organisations en analysant de manière inductive la dimension lieuitaire d’un phénomène comme la résistance organisationnelle. L’article reflète l’approche empirique adoptée. Il retrace d’abord des fondements théoriques dans notre champ sur la résistance en organisation et sa dimension spatiale avant de définir le concept de lieu selon la perspective relationnelle adoptée dans cette étude. Une section méthodologique décrit ensuite nos matériaux textuels (l’intégralité du blog mis en ligne par les ouvriers résistants durant toute la lutte) et notre technique d’analyse du discours assistée par ordinateur. Après la présentation des 6 classes de discours obtenues, nous discutons notre double contribution : 1) la description de trois couples de pratiques organisationnelles lieuifiées de résistance ; et 2) un retour théorique sur deux principes descriptifs du lieu en organisation et management que sont l’unicité et la délimitation.
Intensifier les lieux du travail : Des temporalités de la scène au plateau
Authors: de Vaujany François-Xavier
Published: January 2023

Historiquement ou plus métaphysiquement, l’unité spatiale et temporelle des modes d’organisation est aujourd’hui largement questionnée. La digitalisation, la pandémie, la crise climatique, un management plus décentré ou encore de multiples ruptures géopolitiques ont radicalement métamorphosé l’espace-temps du travail et son organisation. En s’inscrivant dans le vocabulaire et la logique du théâtre, cet essai propose de décrire à la fois un glissement et une tension générative entre la scène et la salle, puis la scène et le plateau. Si la scène est un lieu au sens le plus habituel, un emplacement bien défini et clos dans l’espace plus large du monde, le plateau est tout entier événements saisis dans la même durée et producteurs de lieux éphémères selon leur propre topologie. Plus que jamais décentrés, événementialisés et enjeux de profondeur, les lieux du management doivent aujourd’hui être intensifiés, démultipliés et mis en conversation. Gérés comme des plateaux, ils sont désormais abordés comme des expériences. Aux « spect-acteurs » managers de construire activement les co-présences ou les intensités pouvant placer leurs équipes dans des lieux communs souvent transitoires. Dans un contexte de généralisation du télétravail, ces intensifications des lieux sont plus que jamais nécessaires.
“Ask, ‘When You Do This, How Much Pain Are You In?’”: Content Preferences for a Conversational Pain Self-Management Software Application
Authors: Shade Marcia Y. , Hama Rasila Soumana , Eisenhauer Christine , Khazanchi Deepak , Pozehl Bunny
Published: January 2023

The purpose of the current study was to examine older adults' preferences for conversational pain management content to incorporate in an interactive application (app) for pain self-management. Conversational statements and questions were written as a script to encourage evidence-based pain self-management behaviors. The content was converted from text to female chatbot speech and saved as four groups of MP3 files. A purposive sample of 22 older adults participated in a guided interaction through the MP3 files. One-on-one interviews were conducted to garner participants' conversational content preferences. Overall, participants want the conversational content to increase health care provider engagement in pain management communication. Older adults preferred the inclusion of conversational statements and questions for monitoring the multifaceted dimensions of pain, treatment accountability, guidance for alternative treatments, and undesirable effects from pain treatments. The design of mobile health apps must incorporate the needs and preferences of older adults. [Journal of Gerontological Nursing, 49(1), 11–17.]
Mental Health of Older Adults at the End of Life
Authors: Mayahara Masako , Paun Olimpia
Published: January 2023

With advanced age, older adults (aged ≥65 years) become increasingly aware of the finality of their lives and many accept death as an unavoidable universal event. Over the past few decades, end-of-life treatment preferences shifted in the United States toward hospice and palliative care over curative treatment, with the ultimate goal of facilitating a good death. In addition to physical comfort, emotional well-being is essential in older adults at the end of life. Despite high prevalence of depression, patients on hospice are rarely screened for depressive symptoms. Left untreated, depression increases the risk for complicated grief and suicide. Provider education and training are needed to facilitate early detection of symptoms and timely treatment for depression and grief at the end of life. Family caregivers should also be included in mental health support, as they care for their loved ones and beyond, including post-death bereavement support. [
Journal of Psychosocial Nursing and Mental Health Services, 61
(1), 12–15.]
Mast cells in severe respiratory virus infections: insights for treatment and vaccine administration
Authors: Mamontov Andrey , Polevshchikov Alexander , Desheva Yulia
Published: January 2023

Mast cells (MCs) are a part of the innate immune system and express receptors for microbial and viral pathogens characteristic of this system. The pathological role of MCs has been demonstrated for a number of highly virulent viral infections. The role of MCs and their Fc receptors for IgE in the immediate-type hypersensitivity reactions and in immunocomplex reactions is well-known, although the role of MCs and their Fc receptors for IgG (FcγR) in immunocomplex processes is much less studied. Antibody-dependent enhancement syndrome (ADE) has been observed in a number of viral infections and is associated with greater secondary infection. ADE is enhanced by virus-specific antibodies, which are not involved in the virus penetration into the cell but are capable of forming immune complexes. The role of MCs in ADE is well-established for dengue infection, RSV infection and coronavirus (CoV) infection. The involvement of IgG-mediated mast cell responses in other human viral infections including Coronavirus disease 2019 (COVID-19) is poorly understood. Recently discovered mast cell activation disease is considered one of the causes of severe post-infectious complications in COVID-19. If the role of MCs in the pathogenesis of severe viral infections, including ADE in recurrent viral infection is clarified, these cells and the products they release may serve as promising targets for such therapeutic agents as histamine receptor blockers or membrane stabilizers to prevent possible complications.
Use of beneficial bacterial endophytes: A practical strategy to achieve sustainable agriculture
Authors: Medison Rudoviko Galileya , Tan Litao , Medison Milca Banda , Chiwina Kenani Edward
Published: January 2023

Beneficial endophytic bacteria influence their host plant to grow and resist pathogens. Despite the advantages of endophytic bacteria to their host, their application in agriculture has been low. Furthermore, many plant growers improperly use synthetic chemicals due to having no or little knowledge of the role of endophytic bacteria in plant growth, the prevention and control of pathogens and poor access to endobacterial bioproducts. These synthetic chemicals have caused soil infertility, environmental contamination, disruption to ecological cycles and the emergence of resistant pests and pathogens. There is more that needs to be done to explore alternative ways of achieving sustainable plant production while maintaining environmental health. In recent years, the use of beneficial endophytic bacteria has been noted to be a promising tool in promoting plant growth and the biocontrol of pathogens. Therefore, this review discusses the roles of endophytic bacteria in plant growth and the biocontrol of plant pathogens. Several mechanisms that endophytic bacteria use to alleviate plant biotic and abiotic stresses by helping their host plants acquire nutrients, enhance plant growth and development and suppress pathogens are explained. The review also indicates that there is a gap between research and general field applications of endophytic bacteria and suggests a need for collaborative efforts between growers at all levels. Furthermore, the presence of scientific and regulatory frameworks that promote advanced biotechnological tools and bioinoculants represents major opportunities in the applications of endophytic bacteria. The review provides a basis for future research in areas related to understanding the interactions between plants and beneficial endophytic microorganisms, especially bacteria.
The Corporate Social Responsibility of the Family SMEs
Authors: Mighri Zouhayer , Ben Ghodbane Sana , Soufeljil Mohamed , Redouane Adel
Published: January 2023

The social responsibility of business is a topical theme, which is of interest to both the researchers and the leaders of the companies. This paper aims to respond to the following problem: if the family companies adopt CSR then what about the social dimensions to their counterparts among non-family members? The study that the authors conducted with 141 enterprises shows that the adoption of the social responsibility of the small business family is progressive and slow. The authors find that the family SME is characterized by societal choices that differ from those of the non-family business. Our results have a considerable professional contribution. In this paper the authors provide to the manager an analysis of the behavior of leaders in a family SME around their CSR commitments. This paper is organized as follows: first, there is presented an introduction and review of literature and research hypotheses. The third section describes the study's sample and methodology choice where the authors briefly describe the main methods or treatments applied. The fourth section presents the discussion of results, and the last section concludes the study.
Innovative Performance Management Practices for the Sustainable Development of Moroccan Construction SMEs
Authors: Ezziadi Abdelali , Lahouirich Mohamed Wadie , Chachdi Aziza
Published: January 2023

The construction industry plays a crucial role in the economic and social development of every country However, the construction sector uses 36% of total energy, 30% of raw materials, 39% of energy-related CO2 emissions, and 35% of solid waste production. In fact, the emergence of sustainable development has been accompanied by a profusion of research dealing with the impact of the integration of sustainability on managerial practices. In Morocco, the orientation to sustainable construction implies an evolution of construction project management practices to not only ensure that projects meet time, cost, and technical quality requirements, but also to guarantee that the construction project is sustainable. This paper aims to study the sustainable project management practices developed within Moroccan companies. For this purpose, the authors have used secondary data and activity reports from seven Moroccan companies in the construction sector. The results of this study show that the seven companies adopt very heterogeneous practices, ranging from continuous actions to specific actions
Assessing the Impact of Financial Performance on the Entrepreneurship Dynamic for Social and Economic Development in Businesses
Authors: Lahouirich Mohamed Wadie , Ezziadi Abdelali
Published: January 2023

Considering the weight of SMEs on an international scale, mainly in times of crisis, entrepreneurship becomes an important factor for achieving economic and social development that meets the demands of society. However, entrepreneurship requires motivations and implies objectives, and especially a financial performance, which will play the role of vector for entrepreneurship, and by extension for socio-economic development. In other words, it is about connecting 3 concepts: Financial performance, entrepreneurship, and socio-economic development. For that, this paper will first focus on the motivations and objectives of entrepreneurs, before developing in detail the concept of financial performance, its evolution to the sustainable development, as well as its importance in the entrepreneurial environment, as vector and objective.
Integrating Industry 4.0 Technologies Into Lean Thinking for the Development of Efficient, Low-Carbon Processes
Authors: Sartal Antonio , León-Mateos Fernando , Bellas Roberto
Published: January 2023

This chapter aims to explore how lean manufacturing (LM) can leverage Industry 4.0 resources to achieve better industrial performance while achieving cleaner processes. In today's environment, to remain competitive, companies need to incorporate new resources to respond to environmental concerns - especially in the fight against climate change - without compromising efficiency. The goal is not only to clarify and extend the literature on the relationship between LM and Industry 4.0, but also to do so by simultaneously studying the impact on throughput and CO2 emissions reduction. Moving away from the usual separate assessment, the authors propose a comprehensive analysis that allows us to evaluate how LM can establish the right conditions on the shop floor for the development of 4.0 technology-intensive environments, and how these technologies can subsequently be leveraged to enhance the contribution of lean practices to industrial performance and sustainability.
Industry 4.0
Authors: Rodrigues Marlene , Sousa Bruno Barbosa , Costa José Baptista , Braga Vítor
Published: January 2023

The supply chain has developed extensively in Portugal over the last ten years. There are three very important areas that integrate organizations; namely, the purchasing area, the production area, and the distribution area, which is commonly called the logistics area. Humans are moving towards a totally digital era, and so this study aims to understand how the concept of Industry 4.0 has impacted the Portuguese business fabric, focusing on the purchasing area. The transformation in the processes has led to the discovery of new forms of digital technologies in the products' processes to generate competitiveness in the market. New business models are a driving force for evolution and progress in the digital era. These models are based on the pillars of Industry 4.0, bringing sustainability to the industry, reducing waste, and forecasting more accurately the market.
An Overview of Available Deepfake Datasets in Neural Network-Based Soil and Weather Prediction Models for High Quality Crops
Authors: Sanjeetha A. Anisha , Sivaraj R. , Uma P.
Published: January 2023

Transportation, the environment, business, and agriculture are just a few areas where IoT and DL-based solutions are profoundly impacting. Soil nutrient insufficiency is a prevalent problem that can spread and harm plants if not addressed right away. An IoT-based system that monitors soil and weather conditions for nutrient deficiencies can help increase crop yields. One of the most crucial factors to include in existing deepfakes datasets is soil temperature when modelling terrestrial ecosystems. From January 1, 2010, through December 31, 2018, the Baker, Beach, Cando, Crary, and Fingal weather stations in North Dakota recorded daily weather and soil temperature readings. This study presents an enhanced convolutional neural network-based approach to soil and weather forecasting (CNN). In order to enhance the classification accuracy of the pre-trained CNN architecture, the slime mold algorithm is employed to optimise the model weight.
Data Storage, Data Forwarding, Data Retrieval With Big Data Deepfakes in Secure Cloud Storage
Authors: Vinitha K. , Thirumoorthy P. , Hemalatha S.
Published: January 2023

Deduplication technologies are extensively used in distributed storage management to lower the space and transfer rate needs of services by eliminating redundant information and storing only its single replica. Many clients redistributing comparable data to a shared repository is ideal for deduplication; however, this practise raises concerns about data ownership and confidentiality. Each data owner can confidently show a distributed storage server that they are the rightful owner of a piece of data via confirmation of holding plans. In contrast to state, many clients would encrypt data before re-appropriating it to distributed storage for added safety. Due to the unpredictable nature of encryption, this prevents data duplication. Some recent deduplication systems have been proposed to solve this issue by allowing multiple owners to share the same encryption key for identical data.
Improving Tuberculosis Medication Adherence: The Potential of Integrating Digital Technology and Health Belief Model
Authors: Sazali Mohd Fazeli , Rahim Syed Sharizman Syed Abdul , Mohammad Ahmad Hazim , Kadir Fairrul , Payus Alvin Oliver , Avoi Richard , Jeffree Mohammad Saffree , Omar Azizan , Ibrahim Mohd Yusof , Atil Azman , Tuah Nooralisa Mohd , Dapari Rahmat , Lansing Meryl Grace , Rahim Ahmad Asyraf Abdul , Azhar Zahir Izuan
Published: January 2023

Tuberculosis (TB) is a significant public health concern. Globally, TB is among the top 10 and the leading cause of death due to a single infectious agent. Providing standard anti-TB therapy for at least 6 months is recommended as one of the crucial strategies to control the TB epidemic. However, the long duration of TB treatment raised the issue of non-adherence. Non-adherence to TB therapy could negatively affect clinical and public health outcomes. Thus, directly observed therapy (DOT) has been introduced as a standard strategy to improve anti-TB medication adherence. Nonetheless, the DOT approach has been criticized due to inconvenience, stigma, reduced economic productivity, and reduced quality of life, which ultimately could complicate adherence issues. Apart from that, its effectiveness in improving anti-TB adherence is debatable. Therefore, digital technology could be an essential tool to enhance the implementation of DOT. Incorporating the health belief model (HBM) into digital technology can further increase its effectiveness in changing behavior and improving medication adherence. This article aimed to review the latest evidence regarding TB medication non-adherence, its associated factors, DOT’s efficacy and its alternatives, and the use of digital technology and HBM in improving medication adherence. This paper used the narrative review methodology to analyze related articles to address the study objectives. Conventional DOT has several disadvantages in TB management. Integrating HBM in digital technology development is potentially effective in improving medication adherence. Digital technology provides an opportunity to improve medication adherence to overcome various issues related to DOT implementation.
Immunometabolic Analysis of Synovial Fluid from Juvenile Idiopathic Arthritis Patients
Authors: Giacalone Vincent D , Cammarata-Mouchtouris Alexandre , Moncada-Giraldo Diego , Shenoy Sreekala P V , Ponder Lori A , Gergely Talia R , Kim Susan O , Chandler Joshua D , Vega-Fernandez Patricia , Manos Cynthia K , Flanagan Elaine R , Prahalad Sampath , Tirouvanziam Rabindra
Published: January 2023

Juvenile idiopathic arthritis (JIA) is an inflammatory rheumatic disorder. Polymorphonuclear neutrophils (PMNs) are present in JIA synovial fluid (SF), but with variable frequency. SF PMNs in JIA were previously shown to display high exocytic but low phagocytic and immunoregulatory activities. To further assess whether the degree of SF neutrophilia associated with altered immune responses in JIA, we collected SF and blood from 16 adolescent JIA patients. SF and blood leukocytes were analyzed by flow cytometry. SF and plasma were used for immune mediator quantification and metabolomics. Healthy donor blood T cells were cultured in SF to evaluate its immunoregulatory activities. PMN and T cell frequencies were bimodal in JIA SF, delineating PMN high/T cell low (PMNHigh) and PMN low/T cell high (PMNLow) samples. Proinflammatory mediators were increased in SF compared with plasma across patients, and pro- and anti-inflammatory mediators were further elevated in PMNHigh SF. Compared to blood, SF PMNs showed increased exocytosis and programmed death-1/programmed death ligand-1 expression, and SF PMNs and monocytes/macrophages had increased surface-bound arginase-1. SPADE analysis revealed SF monocyte/macrophage subpopulations coexpressing programmed death-1 and programmed death ligand-1, with higher expression in PMNHigh SF. Healthy donor T cells showed reduced coreceptor expression when stimulated in PMNHigh versus PMNLow SF. However, amino acid metabolites related to the arginase-1 and IDO-1 pathways did not differ between the two groups. Hence, PMN predominance in the SF of a subset of JIA patients is associated with elevated immune mediator concentration and may alter SF monocyte/macrophage phenotype and T cell activation, without altering immunoregulatory amino acids.
Inflammatory Chemokine Receptors Support Inflammatory Macrophage and Dendritic Cell Maturation
Authors: Bartolini Robin , Medina-Ruiz Laura , Hayes Alan J , Kelly Christopher J , Halawa Heba A , Graham Gerard J
Published: January 2023

Dendritic cells form clusters in vivo, but the mechanism behind this has not been determined. In this article, we demonstrate that monocytes from mice deficient in the chemokine receptors CCR1, CCR2, CCR3, and CCR5 display reduced clustering in vitro, which is associated with impaired dendritic cell and macrophage differentiation. We further show that the differentiating cells themselves produce ligands for these receptors that function, in a redundant manner, to regulate cell clustering. Deletion of, or pharmacological blockade of, more than one of these receptors is required to impair clustering and differentiation. Our data show that chemokines and their receptors support clustering by increasing expression of, and activating, cell-surface integrins, which are associated with cell–cell interactions and, in the context of monocyte differentiation, with reduced expression of Foxp1, a known transcriptional suppressor of monocyte differentiation. Our data therefore provide a mechanism whereby chemokines and their receptors typically found in inflammatory environments can interact to promote murine monocyte differentiation to macrophages and dendritic cells.
Current Status of Immunology Education in U.S. Medical Schools
Authors: Reynolds Austin B , Bhattacharjee Ritvik , Zhao Yuan
Published: January 2023

Immunology is an integral component of undergraduate medical education because of its critical role in many disease processes. Due to the complexity of the subject, the best practice of immunology education in the undergraduate medical curriculum has not been extensively discussed. This study intended to determine the current status of immunology education in U.S. medical schools with the hope of providing insight into curriculum design pertaining to this subject. Immunology curriculum information was collected from the curriculum Web pages of 199 U.S. medical schools, including multiple campuses. Data pertaining to the setting of immunology education such as subjects that are co-taught with immunology, timing of courses, credit hours, and integration level were recorded in Microsoft Excel for analysis. Of 199 U.S. medical schools studied, 174 posted curriculum information related to immunology online. For course settings, 59 (33.9%) offer immunology with microbiology, 42 (24.1%) offer immunology as part of a foundational sciences course, and 18 (10.3%) offer immunology as a stand-alone course. Ten programs (5.7%) have immunology fully integrated in system-based curriculum. Of 119 medical schools that provide information regarding timing, 94 (71.9%) provide immunology education in year 1 of the curriculum, 16 (9.2%) in year 2, and 9 (5.2%) in both years 1 and 2. Differences exist in allopathic versus osteopathic programs in the immunology curriculum setting. Credit hour data were not complete due to inconsistent availability. Our data suggest that immunology education in U.S. medical schools lacks consensus. Continued discussion on best practices of immunology education across U.S. medical schools is recommended.
Differential expression of complement receptors on human basophils and mast cells. Evidence for mast cell heterogeneity and CD88/C5aR expression on skin mast cells.
Authors: Füreder W , Agis H , Willheim M , Bankl H C , Maier U , Kishi K , Müller M R , Czerwenka K , Radaszkiewicz T , Butterfield J H , Klappacher G W , Sperr W R , Oppermann M , Lechner K , Valent P
Published: January 2023

Complement-dependent activation of immune cells is regulated by cell surface membrane receptors. In this study, expression of complement receptors (CR) on human blood basophils (n = 11), tissue mast cells (lung, n = 7; skin, n = 10; uterus, n = 4; tonsil, n = 3; heart, n = 10), and on respective human cell lines (basophil line KU-812, mast cell line HMC-1) was analyzed by the use of mAbs and indirect immunofluorescence. Normal blood basophils and KU-812 cells were found to express C5aR (CD88), membrane cofactor protein (CD46), decay-accelerating factor (CD55), and membrane attack complex inhibitory factor (CD59), as well as the previously recognized CR1 (CD35), CR3 alpha (CD11b), CR4 alpha (CD11c), and CR3/4 beta (CD18). Mast cells from all organs as well as HMC-1 cells expressed CD46, CD55, and CD59, but not CD11b, CD21, or CD35. The C5aR (CD88) was detectable on skin mast cells, a subset (5 to 15%) of cardiac mast cells, and on HMC-1 cells, but not on lung, uterus, or tonsillar mast cells (< 5%). Moreover, double immunoperoxidase staining (tryptase vs C5aR/CD88) revealed in situ expression of C5aR on skin, but not lung mast cells. Recombinant human (rh) C5a, at 10(-10) to 10(-7) M, induced secretion of histamine from basophils (rhC5a, 10(-8) M: 53.4 +/- 3.1% vs control < 5%) and from skin mast cells (rhC5a, 10(-8) M: 25.8 +/- 16.1% vs control < 10% histamine release), but not from other mast cells (rhC5a or control: < 10%, p > 0.05). The rhC5a-induced secretion of histamine from basophils and skin mast cells was inhibited by S5/1, a blocking Ab against CD88 (basophils: 37.2% to 75.1%; skin mast cells: 39.2% to 83.9% inhibition, p < 0.05). Together, this study shows that a) basophils and mast cells express a different profile of complement receptors, b) C5a-dependent mediator release in skin mast cells and basophils is mediated via CD88, and c) mast cells constitute a heterogeneous lineage in terms of expression of the C5a binding site CD88.
IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts.
Authors: Onoe Y , Miyaura C , Kaminakayashiki T , Nagai Y , Noguchi K , Chen Q R , Seo H , Ohta H , Nozawa S , Kudo I , Suda T
Published: January 2023

Activated T cells secrete the cytokine IL-13, which regulates inflammatory and immune responses. To explore the role of IL-13 in bone metabolism, we examined the effects of the cytokine on bone resorption and PG synthesis in osteoblasts. IL-13 suppressed the bone-resorbing activity stimulated by IL-1 alpha, which was determined by the release of 45Ca from prelabeled mouse long bones. Histologic examinations revealed that IL-1 alpha markedly stimulated bone resorption with increased osteoclast recruitment, and that the simultaneous addition of IL-13 considerably inhibited it. The gamma-chain of IL-2 receptors may be functionally involved in the signal transduction of not only IL-2, but also IL-4, IL-7, and IL-13. Of these cytokines, IL-4 similarly suppressed IL-1 alpha-induced bone resorption, but IL-2 and IL-7 did not. Both IL-13 and IL-4 inhibited PGE2 production stimulated by IL-1 alpha in long bone cultures. Suppression of IL-1 alpha-induced bone resorption by IL-13 and IL-4 was recovered by adding exogenous PGE2 to the long bone cultures. Neither IL-4 nor IL-13 further inhibited IL-1 alpha-induced bone resorption in the presence of indomethacin. To examine the effects of IL-13 on PG synthesis, we measured the mRNA levels of cytosolic phospholipase A2 (cPLA2), constitutively expressed cyclooxygenase (COX-1) and inducible COX (COX-2) in mouse osteoblast-like cells. IL-1 alpha markedly stimulated the mRNA expression of COX-2, but not that of COX-1. Both IL-13 and IL-4 dose-dependently suppressed the IL-1 alpha-induced stimulation of both COX-2 mRNA expression and PGE2 synthesis. A small increase (1.7-fold) in cPLA2 mRNA levels was detected in the cultures with IL-1 alpha, but the expression was not affected by IL-13 or IL-4. These results indicated that IL-13 and IL-4 inhibit bone resorption by suppressing COX-2-dependent PG synthesis in osteoblasts.
Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice.
Authors: Murphy W J , Tian Z G , Asai O , Funakoshi S , Rotter P , Henry M , Strieter R M , Kunkel S L , Longo D L , Taub D D
Published: January 2023

Previous studies from this laboratory have demonstrated that the chemokines RANTES (recombinant human regulated upon activation, normally T cell expressed and presumably secreted), macrophage chemotactic peptide-1, recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) IL-8, and IP-10 are capable of inducing human T cell infiltration into the injection site of severe combined immunodeficiency (SCID) mice reconstituted with human PBL. However, the ability of these chemokines to facilitate T cell homing into various lymphoid tissues has not been examined. Initial studies focused on the ability of rhMIP-1 beta to induce human T cell infiltration into injection sites in human PBL-SCID mice. SCID mice received s.c. injections of rhMIP-1 beta or PBS (1 microgram/injection) in the hindflank for 4 h or sequential injections for 3 days. Biopsies of the MIP-1 beta injection site revealed the presence of significant mononuclear cell accumulation 72 h after injection. Immunohistologic evaluation determined that significant numbers of human CD3+ T cells were recruited in response to MIP-1 beta injections, and this infiltration could be specifically blocked by co-administration of anti-MIP-1 beta antiserum. We subsequently examined these chemokine-injected mice for the effect of trafficking of human T cells to peripheral lymphoid organs. Flow cytometric analysis of the thymus in human PBL-SCID mice revealed that treatment with rhMIP-1 beta or rhRANTES, but not platelet factor-4, resulted in improved thymic homing of the human T cells after 72 h. This trafficking effect was shown to be direct, as pretreatment of the human T cells with the chemokines in vitro also improved peripheral lymphoid trafficking of the human cells. In addition, co-injection of rhMIP-1 beta with anti-1 beta antiserum abrogated the increase in T cell homing to the thymus. These data demonstrate that MIP-1 beta and RANTES directly augment human T cell trafficking to peripheral murine lymphoid tissues. Chemokines may, therefore, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation and homing, and may be of potential clinical use in promoting immune cell trafficking and function.
IL-15 promotes cytokine production of human T helper cells.
Authors: Mori A , Suko M , Kaminuma O , Inoue S , Ohmura T , Nishizaki Y , Nagahori T , Asakura Y , Hoshino A , Okumura Y , Sato G , Ito K , Okudaira H
Published: January 2023

IL-15 is a newly identified cytokine that has T cell and B cell growth factor activity similar to that of IL-2. In this study, a novel biologic function of IL-15 to promote cytokine production by human Th cells has been elucidated. Dermatophagoides farinae 11 (a major allergen of house dust mite)-specific human T cell clones produced IL-5 in response to recombinant human IL-15 as well as to either anti-CD3 or IL-2 stimulation. IL-5 mRNA became detectable 3 h after IL-15 stimulation and reached a maximum at 9 h. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was clearly transcribed in response to IL-15, indicating that the approximately 500-bp human IL-5 promoter/enhancer segment 5' upstream of the coding region sufficiently responded to IL-15. IL-15-induced IL-5 synthesis was completely inhibited by the tyrosine kinase inhibitor, herbimycin A, suggesting the involvement of tyrosine kinases in the signal transduction leading to IL-5 synthesis as well as to proliferation of T cells induced by IL-15. Whereas IL-5 production by human peripheral T cells was abolished by the addition of anti-IL-2-neutralizing Abs into the culture, IL-15 restored the IL-5 synthesis despite effective IL-2 neutralization. IL-15 produced at the site of allergic inflammation may play a role in the recruitment and activation of eosinophils by inducing IL-5 (a Th2 cytokine) production by T cells.
Induction of tolerance in murine autoimmune diabetes by transient blockade of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 pathway.
Authors: Moriyama H , Yokono K , Amano K , Nagata M , Hasegawa Y , Okamoto N , Tsukamoto K , Miki M , Yoneda R , Yagi N , Tominaga Y , Kikutani H , Hioki K , Okumura K , Yagita H , Kasuga M
Published: January 2023

The present study demonstrated that a short-term administration of mAbs against leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) at critical periods resulted in complete protection of autoimmune diabetes in non-obese diabetic (NOD) mice. When these mAbs were administered for only 6 days at 2 wk of age, neither diabetes nor insulitis was observed at 30 wk of age. It appears that the tolerance against beta cell Ag(s) was induced by this transient blockade of the LFA-1/ICAM-1 pathway. Protective suppressor activity was not enough to prevent diabetes because co-transfer of splenocytes from female NOD mice, which had received these mAbs at 2 wk of age, resulted in only a short delay of the diabetic onset caused by adoptive transfer of splenocytes from acutely diabetic NOD mice. Transfer of these splenocytes to young NOD mice could not also abrogate the spontaneous diabetes and insulitis. Furthermore, cyclophosphamide treatment could not abrogate the protection. When splenocytes from the treated NOD mice were transferred to NOD-SCID mice, none of the recipient mice developed significant insulitis and subsequent overt diabetes, suggesting the absence or the inactivation of diabetogenic effector T cells. However, splenic T cells from the insulitis-free NOD mice that had received the mAb treatment preserved proliferative responses to both islet cells and 65-kDa glutamic acid decarboxylase (GAD65) in vitro. These results suggest that a unique peripheral tolerance was induced by the transient blockade of the LFA-1/ICAM-1 pathway in an early age of NOD mice.
Expression of vascular cell adhesion molecule-1 by vascular endothelial cells in immune and nonimmune inflammatory reactions in the skin.
Authors: Harrison A A , Stocker C J , Chapman P T , Tsang Y T , Huehns T Y , Gundel R H , Peters A M , Davies K A , George A J , Robinson M K , Haskard D O
Published: January 2023

Expression of VCAM-1 was compared with that of E-selectin in cytokine-induced lesions and in delayed-type hypersensitivity reactions to tuberculin purified protein derivative (PPD) in pig skin. Lumenally expressed Ags were quantified by measuring localization in skin of i.v. injected (111)In-mAb 10.2C7 (anti-vascular cell adhesion molecule-1 (anti-VCAM-1), (125)I-mAb 1.2B6 (anti-E-selectin), and (99m)Tc-MOPC21 (control IgG1). Anti-VCAM-1 mAb uptake was greater following intradermal (i.d.) injection of TNF-alpha than following injection of IL-1, while the two cytokines induced similar uptake of anti-E-selectin. In immunologically naive pigs there was no detectable increase in anti-VCAM-1 after i.d. injection of PPD, although anti-E-selectin uptake was increased at 3 and 6 h. In contrast, i.d. injection of PPD in sensitized pigs led to increased uptake of both anti-VCAM-1 and anti-E-selectin at 6, 8, 24, and 48 h, each of which was significantly greater than the uptake of control IgG1 into the same lesions (each p < 0.01). Anti-TNF-alpha mAb abolished the increased uptake of anti-VCAM-1 3 and 8 h following i.d. injection of PPD in sensitized pigs and significantly inhibited uptake at 24 h (p = 0.0025), but did not significantly reduce uptake of anti-E-selectin. We conclude that in this delayed-type hypersensitivity model 1) E-selectin expression by endothelial cells follows sequential Ag nonspecific and immune-specific phases, 2) increased VCAM-1 expression by endothelial cells is only seen in sensitized animals, and 3) expression of VCAM-1 appears to be relatively more dependent on TNF-alpha than E-selectin. Differential expression of E-selectin and VCAM-1 may influence the leukocytic infiltrate during the course of nonspecific and immune-specific inflammatory reactions.
mTOR regulates protection against lethal H5N1 influenza infection by modulating the antibody response (VAC2P.926)
Authors: McGargill Maureen , Keating Rachael , Hertz Tomer , Wehenkel Marie , Harris Tarsha , Edwards Benjamin , McClaren Jennifer , Brown Scott , Surman Sherri , Wilson Zachary , Bradley Philip , Hurwitz Julia , Chi Hongbo , Doherty Peter , Thomas Paul
Published: January 2023

Highly pathogenic H5N1 avian influenza viruses pose a continuing global threat. Current vaccines will not protect against novel pandemic viruses. Creating “universal” vaccines has been unsuccessful because the immunological mechanisms promoting heterosubtypic immunity are incompletely defined. We show that rapamycin, an immunosuppressive drug that inhibits mTOR, promotes cross-strain protection against a lethal H5N1 infection when administered during H3N2 virus immunization. Rapamycin reduced germinal center formation and inhibited B cell class-switching, yielding a unique repertoire of antibodies that mediated heterosubtypic protection. Our data establish a requirement for mTORC1 in B cell class-switching and demonstrate that rapamycin skews the antibody response away from high affinity variant epitopes, targeting more conserved elements of hemagglutinin. Our current data indicate that a primary intranasal infection with FluMist enhances heterosubtypic immunity even more, which can be further enhanced with rapamycin. In this model the CD8 T cells contribute to enhanced protection providing us a model to study the synergy between cross-reactive antibodies and CD8 T cells. These findings have intriguing implications for influenza vaccine design.
Gene-associated retinoid-interferon-induced mortality 19 (GRIM-19) attenuates autoimmune arthritis by regulation of Th17 and Treg cells (VAC3P.957)
Authors: Moon Young-Mee , Lee Jennifer , Lee Seon-Yeong , Kim Eun-Kyoung , Son Hea-Jin , Seo Hyeon Beom , Kwok Seung-Ki , Ju Ji Hyeon , Yang Chul-Woo , Park Sung-Hwan , Cho Mi-La
Published: January 2023

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional factor in interleukin (IL)-6-mediated Th17 differentiation. Because Th17 is believed to be a central player in rheumatoid arthritis (RA), we hypothesized that an endogenous STAT3 inhibitor, genes associated with retinoid-interferon-induced mortality 19 (GRIM-19), could attenuate collagen-induced arthritis (CIA) by suppressing Th17 and reciprocally increasing Treg. The numbers of CD4+/IL-17+ cells and CD4+ phosphorylated (p)-STAT3+ cells were decreased, while the numbers of CD4+/CD25+/Foxp3+ cells and CD4+/pSTAT5+ cells were increased in both GRIM-19 overexpression vector-administered and GRIM-19 Tg mice. Administration of GRIM-19 overexpression vector into CIA mice markedly suppressed the clinical and histological signs of arthritic joints. Similarly, when CIA was induced in GRIM-19 Tg mice, the arthritic phenotype was markedly attenuated and the expressions of inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-α, and IL-17) in arthritic joints were also significantly reduced. Moreover, bone marrow-derived monocytes/macrophages obtained from GRIM-19 Tg mice showed attenuated receptor activator of nuclear factor kappa-B ligand-induced osteoclastogenesis in vitro. GRIM-19 improved the clinical and histologic features of CIA and also inhibited osteoclast formation. These data suggest that GRIM-19 may be a novel treatment agent for RA.
PD-1 and Tim-3 regulate the expansion of vaccine-induced tumor antigen-specific CD8+ T cells in patients with advanced melanoma (VAC3P.944)
Authors: Fourcade Julien , Sun Zhaojun , Pagliano Ornella , Chauvin Joe-Marc , Wang Hong , Sander Cindy , Janjic Bratislav , Tarhini Ahmad , Tawbi Hussein , Kirkwood John , Moschos Stergios , Guillaume Philippe , Luescher Immanuel , Krieg Arthur , Anderson Ana , Kuchroo Vijay , Zarour Hassane
Published: January 2023

Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we have evaluated vaccine-induced CD8+ T cells for frequency, function and expression of the inhibitory receptors PD-1 and Tim-3 in patients with metastatic melanoma immunized with incomplete Freund’s adjuvant, CpG-oligodeoxynucleotide, and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V either alone, or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 whereas a minority also upregulated Tim-3 and the levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration inversely correlated with their expansion in vivo. PD-1 and Tim-3 blockades further enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades in addition to cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.
Endogenous anti-β-glucan antibodies, a potential predictive biomarker for the efficacy of soluble yeast β-1,3/1,6 glucan (Imprime PGG®) immunotherapy in cancer patients (VAC3P.947)
Authors: Antonysamy Mary , Bose Nandita , Chan Anissa , Ertelt Katie , Gorden Keith , Grossman William , Huhn Richard , Jonas Adria , Leonardo Steven , Lowe Jamie , Mattson Paulette , McMurray Diane , Nelson Mariana , Ottoson Nadine , Patchen Myra , Qiu Xiaohong , Rathman Blaine , Walsh Richard , Wurst Lindsay , Yokoyama Yumi
Published: January 2023

The innate immune response to Imprime PGG® (Imprime PGG) is being leveraged to develop a novel cancer immunotherapy in conjunction with anti-tumor monoclonal antibodies. Previous research has demonstrated the presence of endogenous anti-β-glucan antibodies (ABA) as a necessary prerequisite for the binding and functional activity of Imprime PGG in innate immune cells. In this study, healthy donors with varying levels of ABA were evaluated to determine the threshold of ABA above which binding and modulation of functions were observed. Donors who had ABA levels above the threshold showed Imprime PGG binding (> 5%) to their neutrophils and monocytes with significant modulation of functions, including, a) activation of complement (C5a), b) increased surface expression of complement receptor 3, c) modulation of activation markers (CD62L), and d) production of selective chemokines (IL-8). The potential of the ABA level being a clinical biomarker was then evaluated in a non-small cell lung cancer trial by segregating patients into biomarker (BM) positive or negative populations based on the established ABA threshold. The BM positive patients showed a significantly increased objective response rate and marked survival benefit not seen in the BM negative patients. These results demonstrate a successful translation of biomarker discovery in healthy donors to clinical utility in cancer patients. ABA is a potential predictive biomarker for efficacy of Imprime PGG immunotherapy.
Regulation of Inflammatory Bowel Disorder by ST8Sia6
Authors: Crotts Sydney B , Antonetti Regina , Shapiro Michael J , Rajcula Matthew , Theodore Keith , Lee Hyun Se Kim , Shapiro Virginia
Published: January 2023

Inflammatory bowel disorders (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) affect between 1–3 million people in the United States with prevalence on the rise. Patients present with symptoms including diarrhea, abdominal cramps, and weight loss. Many factors are implicated in pathogenesis, including host immune response. Identification of molecules that regulate IBD is critical in understanding pathogenesis. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 knockout (KO) mice exhibit increased spontaneous small bowel lamina propria CD4 TH1 polarization, increased inflammatory cytokine production, and decreased IgA class switching of Peyer’s patch B cells, indicative of inflammation. Additionally, adult ST8Sia6 KO mice have shortened small bowels, likely due to baseline inflammation. These mice do not exhibit obvious baseline symptoms, but ST8Sia6 KO mice exhibit increased weight loss and decreased survival when challenged with dextran sodium sulfate (DSS)-induced colitis, which was also enhanced when co-housed with wildtype (WT) mice and after antibiotic treatment. These DSS-challenged ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the gut as compared to WT controls. The accelerated DSS-colitis is also observed when ST8Sia6-deficient bone marrow is transplanted into WT recipients, indicating that the effect is mediated specifically by immune cells. This data demonstrates a role for ST8Sia6 in regulating the host immune response to inflammatory bowel disorders, and further elucidating this role will aid in developing a mechanistic understanding of IBD pathogenesis.

Supported by grants from NIH R01 CA243545