PSS Development Research Articles

Single nucleotide polymorphisms of GEMIN3 modify the risk of primary Sjögren's syndrome in female patients

BackgroundMicroRNA (miRNA)-processing machinery may modify the risk of primary Sjögren's syndrome (pSS) by altering miRNA expression profiles. Inflammatory cytokines and reactive oxygen species (ROS) are also involved in pSS; however, the role of altered miRNAs expression in its pathogenesis is still unclear. We aimed to evaluate the relationship between single-nucleotide polymorphisms (SNPs) in miRNA processing machinery genes, including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348), and the risk of pSS in female patients. The potential associations of cytokines and ROS with pSS-susceptible SNPs were also evaluated. Materials and MethodsThe SNPs confirmed by polymerase chain reaction ligase detection reaction were genotyped in 74 female patients with pSS and 77 controls. The relationship was analyzed by Student's t-test, Wilcoxon rank-sum test, chi-square test, Pearson's correlation test, and binary logistic regression analysis. ResultsFor rs197412 of the GEMIN3 gene, the genotype TT carrier was associated with a 2.172-fold increased risk for pSS when compared with that of CT+CC carrier (odds ratio: 2.172, 95% CI, 1.133–4.166, p=0.019). Simultaneously, the pSS-susceptible TT carriers were associated with increased interferon-γ (IFN-γ) (P < 0.001) and tumor necrosis factor-α (TNF-α) (P = 0.003) levels when compared with that of CT+CC genotype carriers in female patients with pSS. The subsequent analysis also showed a weak positive correlation between IFN-γ and TNF-α levels (r=0.271, P = 0.019). ConclusionThe predictors of GEMIN3 SNPs might modify pSS development in females by mediating the expression of miRNAs and therefore regulate the levels of IFN-γ and TNF-α.

VNN2-expressing circulating monocytes exhibit unique functional characteristics and are decreased in patients with primary Sjögren's syndrome

ObjectiveThis study aims to elucidate the significance of VNN2 expression in peripheral blood monocytes and its clinical relevance in primary Sjögren's syndrome (pSS). MethodsWe investigated VNN2 expression by analyzing single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells. Flow cytometry was used to detect and compare VNN2 expression in total monocytes, classical monocytes (cMo), intermediate monocytes (iMo) and non-classical monocytes (ncMo). Additionally, we examined the expression of HLA, ICAM1, CD62L, ITGAM, S100A8, S100A9, CCR2, CCR6, CX3CR1 and CXCR3 in VNN2+ and VNN2- cells. We analyzed the correlation between VNN2 expression and clinical indicators and assessed the clinical utility of VNN2+ monocytes in pSS diagnosis using receiver operating characteristic curves. ResultsWe observed high VNN2 expression in monocytes, with significantly higher levels in CD14++ monocytes compared to ncMo. VNN2+ monocytes exhibited decreased expression of HLA and CD62L and increased expression of ICAM1, ITGAM, S100A8, S100A9, CCR2, CCR6, CX3CR1 and CXCR3 compared to VNN2- monocytes. Although scRNA-seq data showed that VNN2 mRNA was upregulated, cell surface expression of VNN2 was decreased in monocytes from pSS patients compared to healthy controls. The reduced levels of VNN2+ monocyte subpopulations in pSS patients were negatively correlated with anti-ribosome antibody levels and positively correlated with complement 4 levels. Detection of VNN2 expression in monocytes can aid in the auxiliary diagnosis of pSS. ConclusionMonocytes expressing cell surface VNN2 are significantly reduced in pSS patients. This suggests a potential role for VNN2 in pSS development and its potential use as a diagnostic marker for pSS.

The DHSmart model for smart product-service system (smart PSS): dynamic, data-driven, human-centred

AbstractDespite its transformative impact, a systematic approach to Smart PSS development remains elusive. Addressing this, the study introduces a dynamic conceptual model named DHSmart and its accompanying canvas, adaptable to various contexts and technological advancements. Notably, it offers a structured approach to designing ‘Smart’ in Smart PSS, capturing the interplay between data, humans, and smart systems while directing digitalisation that achieves competitive advantage. It also serves as a unifying framework, enabling meaningful interdisciplinary contributions in theory and practice.

Single nucleotide polymorphisms in cytokine genes and their association with primary Sjögren's syndrome in Saudi patients: A cross-sectional study.

To determine the allelic frequencies and effects of genotypic variations in cytokine gene polymorphisms in a Saudi Arabian population. This cross-sectional study involved 41 patients with Primary Sjögren's syndrome (pSS) and 71 healthy controls between October 2018 and May 2019. Single nucleotide polymorphisms genotyping was performed using the SEQUENOM MassARRAY® System, targeting nine polymorphisms in different cytokine genes. Chi-square tests were used to compare the patients and controls. The interleukin-1 beta (IL-1β) rs1143627 CT (control, 52.7%; patients, 21.2%) and TT + CT (p= 0.003; p=0.033) genotypes were less frequent in patients with pSS than in healthy controls. The C allele in rs10488631 in the interferon regulatory factor 5 (IRF5) gene and the A allele in rs12583006 in the B-cell activating factor (BAFF) gene were associated with an increased risk of pSS development in the patient group. The CT genotype at -31 (rs1143627) in the IL-1β gene was not associated with a high risk of pSS development in the Saudi population, in contrast to what has been verified in other ethnicities. However, the C allele in rs10488631 in IRF-5 and the A allele in rs12583006 in BAFF were associated.

Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease

Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2−/− mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.

Kano-FBS model: a data-driven innovative design approach for smart product-service system development

Smart product-service system (Smart PSS), as an emerging digital paradigm, should meet user expectations and optimize their experience with a higher degree of sustainability. As a complex solution bundle with digital technology, its innovative design method differs from the existing method for traditional products. For a reason that massive user-generated data can be collected in the usage stage, which can be utilized to obtain new user requirements and calculate the user satisfaction degree. According to the real-time user preference information, some modules can be upgraded or adjusted in order to extend the lifecycle of the sustainable Smart PSS. Nevertheless, few studies focus on conducting innovative design by concerning massive information collected in the usage stage in a sustainable Smart PSS environment, let alone a novel approach to support the information re-use in product development of other fields. Aiming to fill this gap, a new innovative design methodology is proposed by combining Function-Behavior-Structure (FBS) and Kano model to guide Smart PSS development. User requirements and behaviors are predicted and analysed by forecasting and collecting information from the perspective of information. As an illustrative case study, a self-service medicine vending system is described to explain the proposed approach. This research provides guidance for Smart PSS in the medical field.

A data-driven innovative design method for smart product-service systems to achieve mass personalization in rehabilitation

Smart product-service system (Smart PSS), as an emerging digital paradigm, offers users solution bundles to enhance the digitalization capability of the system by utilizing user-generated data. Massive information can be collected to investigate the dynamic changes of user requirements and assists the developers in designing personalized products and services. Meanwhile, key technologies (i.e. big data analysis and cloud computing) have enabled upgrading the rehabilitation equipment from the traditional physical training device to the personalized smart rehabilitation product-service system. However, few studies focus on gathering and utilizing user-generated physiological data to guide the innovative design of rehabilitation solutions in the Smart PSS environment. To fill this gap, an innovative design method is proposed to guide the Smart PSS development in the personalized rehabilitation field. The presented approach can be divided into three phases: the research phase, the development phase, and the usage phase. A personalized lower limb rehabilitation smart product-service system was described to explain the proposed approach.

A machine learning-based iterative design approach to automate user satisfaction degree prediction in smart product-service system

As an emerging digital servitization paradigm, smart product-service system (Smart PSS) leverages smart, connected products and their generated services to work as a solution bundle to improve individual user satisfaction. As a complex solution bundle at both system and product level, its iterative design differs from the existing ones mainly in two aspects. Firstly, massive in-context data during the usage stage can be leveraged to calculate the satisfaction degree of individual users intelligently. Secondly, Smart PSS, consisting of both digitalized service and physical components, can be changed in a more flexible way in a data-driven manner. An iterative design method for fast positioning and replacing the unsatisfied modules can improve the user experience and extend the Smart PSS usage life. Nevertheless, some studies made attempts, and it is still missing an iterative design method with automatic real-time user satisfaction prediction. Aiming to fill this gap, this work proposes a machine learning-based iterative design approach to automate user satisfaction prediction in the Smart PSS environment. Furthermore, an illustrative case study of a surgical robot for flexible ureteroscopy is demonstrated along with this proposed methodological framework, which overcomes the challenges of subjectivity and tedious assessment of the experts in the conventional approaches. This research can offer some valuable guidelines to today’s industrial companies in Smart PSS development.

Differences in clinical phenotypes of primary Sjögren's syndrome depending on early or late onset.

Previous research suggests that systemic involvement in primary Sjögren's syndrome (pSS) is a marker of disease prognosis. To evaluate pSS disease activity and the clinical phenotype of pSS patients depending on the age at diagnosis with long-term follow-up. The study group consisted of patients diagnosed with pSS based on the 2016 pSS classification criteria. The study group consisted of 46 patients with early-onset pSS (≤35 years of age) and 32 patients with late-onset pSS (≥65 years of age). The study group was identified from a total of 228 patients diagnosed with pSS. There were no differences regarding the frequency of eye and mouth dryness, focus score (FS) ≥1 or anti-SSA/SSB antibodies depending on age. Rheumatoid factor (RF) was more common among older patients (p > 0.05). In the overall assessment of disease activity using European League Against Rheumatism (EULAR) Sjögren Syndrome Disease Activity Index (ESSDAI), no differences related to age were observed on the first and last visit (after 36 months on average). Lymphadenopathy and changes in the hematology domain (p < 0.05) were more common in patients with the early-onset phenotype. Changes in the lungs and musculoskeletal system occurred regardless of age. Patients with early-onset pSS differ from those with late-onset pSS in terms of higher incidence of peripheral lymphadenopathy and cytopenia. The involvement of lung tissue and joints as well as dryness symptoms are common in pSS regardless of age. The RF plays a role in the pathomechanism of pSS development.

A bespoke PSS development roadmap for construction OEMs

A bespoke PSS development roadmap for construction OEMs

A context-aware concept evaluation approach based on user experiences for smart product-service systems design iteration

With the trend of ‘digitalization’ and ‘servitization’ in the manufacturing industry, numerous product-service systems fail to seize a market share and encounter an imbalance between digital investments and expected revenues. This phenomenon is probably caused by the insufficient evaluation on user experience and by the lag between user requirement changes and the offered solutions. Both limitations can be mitigated via automatic Smart PSS evaluation based on broader concerns on user experience information that was collected from either product-service bundles or user behavior. In this paper, a context-aware concept evaluation approach is proposed for Smart PSS design iteration, aiming to satisfy users in a more timely and automatic manner. Derived from the conventional information axiom method, the proposed approach introduces a context-aware evaluation indicator identification module and an automatic system range identification procedure based on natural language processing techniques, and eventually return the most robust concepts during the usage phase. With less human intervention in the design process, it relieves the lag between user requirement changes and the solutions, and reduces the prescriptive instructions in the conventional information axiom method. A case study of a 3D printer company’s design iteration is conducted, which proves the proposed approach’s feasibility. It is hoped that this work provides practical guidance for achieving a more context-aware Smart PSS development.

POS0177 POTENTIAL INVOLVEMENT OF IL-40 AND IL-40-PRODUCING CELLS IN PRIMARY SJOGREN’S SYNDROME (pSS) AND pSS-ASSOCIATED LYMPHOMA

Background:The pathogenesis of pSS relies on a complex interplay between both innate and adaptive immune responses in which B cells play a pivotal role. Their chronic aberrant hyperactivation may drive clonal escape and consequent lymphomagenesis [1]. In the last few years, B cells have emerged as potential effector cells, able to release a wide range of cytokines that actively contribute to shape the microenvironment they act in. Recently, IL-40, a novel B cell associated cytokine encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99) was described. Naïve B cells can express IL-40 at both tissue and peripheral level and the stimulation of B cells with IL-4 and TGF-β significantly increases IL-40 release. In addition, human B cells lymphomas are able to constitutively produce IL-40 [2]. Taking into account this emerging evidence and considering the well-known role of IL-4 and TGF-β in pSS pathogenesis, as well as the association with lymphomas, we decided to focus our attention on IL-40 in pSS patients.Objectives:The aim of the present study was to investigate IL-40 expression in the salivary glands of patients affected by pSS and pSS-associated non-Hodgkin’s lymphoma (NHL).Methods:Minor salivary gland biopsies were obtained from 22 patients with pSS and 12 patients with non-specific chronic sialoadenitis (nSCS), included as controls. Paraffine-embedded samples of parotid glands from patients with a previous diagnosis of pSS-associated NHL (n=10) were selected from the biopsy bank of the Pathology Unit of the Ospedale Cervello (Palermo, Italy). Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry (IHC) for IL-40, IL-4, TGF-β1 was performed on salivary glands from patients and controls. The cellular sources of IL-40 among infiltrating inflammatory cells were determined by fluorescence-activated cell sorting (FACS) analysis and immunofluorescence (IF). Serum IL-40 levels were measured by ELISA in both patients (n=10) and controls (n=9).Results:IL-40 was significantly increased at both protein and mRNA level in the inflamed salivary glands of patients with pSS where a positive strong correlation between the IL-40 mRNA levels and the focus score (FS) was evidenced. The expression of IL-40 in parotid glands of pSS-associated NHL was also markedly increased (Figure 1). IL-40 expression correlated with the presence of IL-4 and TGF-β; both cytokines were significantly increased in pSS at mRNA and protein level. Among infiltrating immune cells, CD19+ B cells resulted the major source of IL-40. However, we identified CD4+, CD8+ T cells and CD68+ macrophages as additional producers of IL-40 in both FACS and IF analysis. The ELISA test also showed a significant increase of serum IL-40 concentration in pSS patients (p value = 0.0190), compared to controls.Conclusion:Our preliminary results suggest that IL-40 may play a role in the pathogenesis of pSS and pSS-associated NHL. To the best of our knowledge, this is the first demonstration of the overexpression of this cytokine in salivary gland tissue and sera in pSS. Moreover, we demonstrated that IL-40 is produced by several cellular types, such as T cells and macrophages, and is not exclusively released by B cells. Further studies are necessary to clarify IL-40 pathways and functions in order to unravel IL-40 possible role in pSS development.

IL‐17 drives salivary gland dysfunction via inhibiting TRPC1‐mediated calcium movement in Sjögren’s syndrome

ObjectivesThis study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS).MethodsSalivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies.ResultsIncreased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice.ConclusionThese findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.

Knowledge transfer and engineering methods for smart-circular product service systems

Smart Product Service Systems (Smart PSS) have the potential to contribute to a Circular Economy (CE), but in the design of these systems engineering teams often lack information and knowledge on CE strategies and processes. Against this background, the authors propose a knowledge transfer system for the design of Smart-circular PSS. The system can be used in the concept phase of the Smart PSS development process and delivers information on CE strategies via a Smart-circular PSS Lifecycle Flowchart (SCPLF) and service archetypes. These strategies can be selected, supplemented and extended according to individual user requirements. The approach was validated using an intelligent street lighting system. This paper summarizes findings from the application and provides insights into potentials and limitations for the design of Smart-circular Smart PSS.

A data-driven reversible framework for achieving Sustainable Smart product-service systems

Higher sustainability with extended product lifecycle is a tireless pursuit in companies’ product design/development endeavours. In this regard, two prevailing concepts, namely the smart circular system and smart product-service system (Smart PSS), have been introduced, respectively. However, most existing studies only focus on the sustainability of physical materials and components, without considering the cyber-physical resources as a whole, let alone an integrated strategy towards the so-called Sustainable Smart PSS. To fill the gap, this paper discusses the key features in Sustainable Smart PSS development from a broadened scope of cyber-physical resources management. A data-driven reversible framework is hereby proposed to sustainably exploit high-value and context-dependent information/knowledge in the development of Sustainable Smart PSS. A four-step context-aware process in the framework, including requirement elicitation, solution recommendation, solution evaluation, and knowledge evolvement, is further introduced to support the decision-making and optimization along the extended or circular lifecycle. An illustrative example is depicted in the sustainable development of a smart 3D printer, which validates the feasibility and advantages of the proposed framework. As an explorative study, it is hoped that this work provides useful insights for Smart PSS development with sustainability concerns in a cyber-physical environment.

A holistic relook at engineering design methodologies for smart product-service systems development

The rapid development and implementation of smart, connected products have triggered a promising manufacturing paradigm of servitization, i.e. smart product-service systems (Smart PSS). Unlike existing product development or service design process, Smart PSS owns the unique design characteristics of IT-driven value co-creation, closed-loop design, and context-awareness enabled by the advanced information and communication technologies. Nevertheless, to the best of authors’ knowledge, there is scarcely any discussion on its design theories, which serves as the fundamental basis. To identify the limitations of current design approaches in supporting Smart PSS development and suggest some future research directions, this paper conducts a systematic literature review at existing engineering design methodologies to verify its appropriateness for the Smart PSS development. 9 typical design methods have been chosen based on the systematic review of 101 representative items published ever since the coin of PSS to date (04/05/2020) and 48 supplementary works. They are further compared and evaluated from three aspects, including “smart design” objects, enabling smart technologies and smart application fields. Not surprisingly, the investigation results indicate that none of the existing methodologies can fully meet the design characteristics of Smart PSS, while three research directions of Smart PSS design methodology are provided as the potential solution at last. It is hoped this paper can attract more open discussions and offer useful insights to both academics and industries in their development of Smart PSS.

Design entropy theory: A new design methodology for smart PSS development

Smart product-service systems (Smart PSS), as an emerging digital servitization paradigm, leverages smart, connected products and their generated services as a solution bundle to meet individual customer needs. Owing to the advanced information and communication technologies, Smart PSS development differs from the existing product and/or service design mainly in three aspects: (1) closed-loop design/redesign iteration; (2) value co-creation in the context; and (3) design with context-awareness. These unique characteristics bring up new design challenges, and to the authors' best knowledge, none of the existing design theories can address them well. Aiming to fill this gap, a novel design methodology for the Smart PSS development is proposed based on the information theory, where both the system and stakeholders can be regarded as the information containers. Hence, the closed-loop design/redesign iteration can be treated as the dynamic change of information and entropy in a balanced ecosystem. Meanwhile, the value co-creation process is considered as the exchange of accumulated information via the container. Lastly, the design context-awareness represents the process of reducing entropy. As a novel prescriptive design theory, it follows Shannon’s information theory to determine the best design/redesign solutions by considering the three characteristics integrally. It is hoped that the proposed design entropy theory can largely facilitate today's Smart PSS development with better performance and user satisfaction.

A Knowledge Graph-Aided Concept–Knowledge Approach for Evolutionary Smart Product–Service System Development

Abstract In order to meet user expectations and to optimize user experience with a higher degree of flexibility and sustainability, the Smart product–service system (Smart PSS), as a novel value proposition paradigm considering both online and offline smartness, was proposed. However, conventional manners for developing PSS require many professional consultations and still cannot meet with the new features of Smart PSS, such as user context-awareness and ever-evolving knowledge management. Therefore, aiming to assist Smart PSS development cost-effectively, this paper adopted the knowledge graph (KG) technique and concept–knowledge (C-K) model to propose an evolutionary design approach. Two knowledge graphs are firstly established with open-source knowledge, prototype specifications, and user-generated textual data. Then, triggered by personalized requirements, four KG-aided C-K operators are conducted based on graph-based query patterns and computational linguistics algorithms, thus generating innovative solutions for evolving Smart PSS. To validate the performance of the proposed approach, a case study of a smart nursing bed fulfilling multiple personalized requirements is conducted, and the evaluation result of its knowledge evolution is acceptable. It hopes that this work can offer insightful guidance to industrial organizations in their development of Smart PSS.

A META-MODEL FOR PRODUCT SERVICE SYSTEMS OF SYSTEMS

AbstractA Product Service System of Systems (PSSoS) is a set of products, services, infrastructure, and a network where its constituent elements exhibit operational and managerial independence. As such, a PSSoS shows PSS characteristics of heterogeneity and evolvability and SoS characteristics of emergence and diversity. Neither existing PSS nor SoS development approaches fully address these characteristics. Thus, PSSoS development raises new challenges. In this paper, we propose a PSSoS meta-model that integrates PSS and SoS key concepts, to provide a basis for future PSSoS development methods.