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Abstract Background DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes. Methods EAE was induced in C57BL6/J mice by immunization with MOG35-55 peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR. Results MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)-specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination. Conclusions These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms.

Abstract Gene expression analysis has proven to be a very useful tool to gain knowledge of the factors involved in the pathogenesis of diseases, particularly in the initial or preclinical stages. With the aim of finding new data on the events occurring in the Central Nervous System in animals affected with Bovine Spongiform Encephalopathy, a comprehensive genome wide gene expression study was conducted at different time points of the disease on mice genetically modified to model the bovine species brain in terms of cellular prion protein. An accurate analysis of the information generated by microarray technique was the key point to assess the biological relevance of the data obtained in terms of Transmissible Spongiform Encephalopathy pathogenesis. Validation of the microarray technique was achieved by RT-PCR confirming the RNA change and immunohistochemistry techniques that verified that expression changes were translated into variable levels of protein for selected genes. Our study reveals changes in the expression of genes, some of them not previously associated with prion diseases, at early stages of the disease previous to the detection of the pathological prion protein, that might have a role in neuronal degeneration and several transcriptional changes showing an important imbalance in the Central Nervous System homeostasis in advanced stages of the disease. Genes whose expression is altered at early stages of the disease should be considered as possible therapeutic targets and potential disease markers in preclinical diagnostic tool development. Genes non-previously related to prion diseases should be taken into consideration for further investigations.

Technology Enhanced Learning (TEL) is a new pedagogical domain aiming to study the usage of information and communication technologies to support teaching and learning. The following study investigated how this domain is used to increase technical skills in Computer Science (CS). A Delphi method was applied, using three-rounds of online survey questions, given to 17 TEL experts from different European countries. The results showed that these experts consider TEL an effective and interesting support to acquire CS skills. Furthermore, the findings revealed the five best tools in TEL to acquire necessary CS knowledge. Future research can provide a guideline to implement effective TEL tools in CS studies. This manuscript investigates Technology Enhanced Learning (TEL) tools and its applications to learn specific skills in CS. As general content the results of a Delphi study that identifies the benefits of TEL while teaching are highlighted.

This paper reviews methodological approaches to the design (or redesign) of the supply chain (SC), including comprehensive approaches (proposals concerning the entire process of designing the SC) and those that deal with four specific aspects of the process (definition of the SC objectives, reverse SC, finance, and generation and use of scenarios) that have a decisive influence on the whole design of the SC. The comprehensive approaches include those based on typologies of products, markets and SCs and those that propose a succession of the stages to follow through the design process. The discussion shows that the use of typologies is not adequate to face SC design and that the methods proposing a succession of stages may suit, provided that they are developed and presented in a manner appropriate to their use for practitioners. The discussion leads also to suggest several research lines. [ABSTRACT FROM AUTHOR]

Primary progressive multiple sclerosis is a poorly understood disease entity with no specific prognostic biomarkers and scarce therapeutic options. We aimed to identify disease activity biomarkers in multiple sclerosis by performing an RNA sequencing approach in peripheral blood mononuclear cells from a discovery cohort of 44 untreated patients with multiple sclerosis belonging to different clinical forms and activity phases of the disease, and 12 healthy control subjects. A validation cohort of 58 patients with multiple sclerosis and 26 healthy control subjects was included in the study to replicate the RNA sequencing findings. The RNA sequencing revealed an interleukin 1 beta (IL1B) signature in patients with primary progressive multiple sclerosis. Subsequent immunophenotyping pointed to blood monocytes as responsible for the IL1B signature observed in this group of patients. Functional experiments at baseline measuring apoptosis-associated speck-like protein containing a CARD (ASC) speck formation showed that the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome was overactive in monocytes from patients with primary progressive multiple sclerosis, and canonical NLRP3 inflammasome activation with a combination of ATP plus lipopolysaccharide was associated with increased IL1B production in this group of patients. Primary progressive multiple sclerosis patients with high IL1B gene expression levels in peripheral blood mononuclear cells progressed significantly faster compared to patients with low IL1B levels based on the time to reach an EDSS of 6.0 and the Multiple Sclerosis Severity Score. In agreement with peripheral blood findings, both NLRP3 and IL1B expression in brain tissue from patients with primary progressive multiple sclerosis was mainly restricted to cells of myeloid lineage. Treatment of mice with a specific NLRP3 inflammasome inhibitor attenuated established experimental autoimmune encephalomyelitis disease severity and improved CNS histopathology. NLRP3 inflammasome-specific inhibition was also effective in reducing axonal damage in a model of lipopolysaccharide-neuroinflammation using organotypic cerebellar cultures. Altogether, these results point to a role of IL1B and the NLRP3 inflammasome as prognostic biomarker and potential therapeutic target, respectively, in patients with primary progressive multiple sclerosis. [ABSTRACT FROM AUTHOR]

Many authors consider that production and marketing decisions should be integrated. In this paper, we discuss an aggregate planning problem that includes production, selling price, cash management and flexible capacity (by means of hiring and firing and with the possibility of unlimited production subcontracting). The demand is considered to be a nonlinear function of the product selling price. The problem, which is modelled as a mixed integer linear program, can be solved using standard optimisation software. The results of a computational experiment and a numerical example are shown to illustrate the performance of the proposed model and obtain some managerial insights. [ABSTRACT FROM PUBLISHER]

Purpose: The aim of this study is to analyse the prevalence of the staffing policies associated with the characteristics of the two basic types of organisational configurations identified by Institutional theory (Professional Partnership and Managed Professional Business), or conversely, if they have been evolving as a consequence of contextual factors and trends. Design/methodology: Exploratory research was performed through the case study method. Six case studies were conducted in Spanish affiliates of leading multinational management consulting firms. Findings: Our analysis revealed that the staffing policies and practices of the companies differ significantly. It was further deduced that the origin of companies and the practice of activities other than business consulting could influence their staffing policies. It is concluded that mixed models do exist nowadays and that the origin of companies largely determines their policies. Research limitations/implications: Cultural factors among countries could influence HRM policies and practices. Furthermore, the size of companies could determine (or limit) the implementation of certain staffing policies. The study could be extended to a sample of consulting companies of various sizes and countries to enrich the results. Practical implications: For HR managers, knowing the staffing policies at these major companies is a benchmark of HRM effectiveness to be applied to their own companies. In particular, these cases are relevant for other knowledge intensive organizations. Originality/value: The paper provides current empirical evidence on the HRM staffing policies of leading consulting firms and their evolution. [ABSTRACT FROM AUTHOR]

The aim of the article is threefold: analyzing (1) the antecedents of satisfaction of online travel agencies (OTAs)' customers, and the mediating role of loyalty, and word of mouth; (2) the different customers' profiles attending to these antecedents; and (3) how antecedents affect satisfaction according to the customer profile. An exploratory factor analysis (EFA) and a structural equation modeling (SEM) were used on a sample of 264 OTAs' Spanish customers. A non-hierarchical cluster analysis was performed forcing two clusters, and they were identified the most important factors that explain satisfaction for each cluster. EFA results provide five antecedents of satisfaction. However, SEM analysis results show that only "information" (efficiency of the website and quality of information provided) and "utility" for using the platforms are significant antecedents of satisfaction. The relation between satisfaction, loyalty, and word-of-mouth are also significant. The quality of the information provided in the websites is the main antecedent for the cluster of satisfied customers. In contrast, utility is the most important for the cluster of unsatisfied customers. [ABSTRACT FROM AUTHOR]

Previous work by our group showed that transferring bone marrow cells transduced with a self-antigen induced immune tolerance and ameliorated experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We also found that following retroviral transduction of murine bone marrow (BM) cells, the majority of cells generated and transduced were myeloid-derived suppressor cells (MDSCs). Here, we aimed to determine whether purified antigen-expressing MDSCs have similar therapeutic effects than those of unfractionated BM, and to investigate their potential mechanisms. We performed phenotypic and functional analyses in these cells using the same animal model, and we used purified antigen-expressing MDSCs in preventive and therapeutic approaches. These cells exerted therapeutic effects similar to those of BM cells, which depended upon self-antigen expression. The majority of monocytic (M)-MDSCs expressed the immunosuppressive molecule programmed death ligand-1 (PD-L1), CD80, CD86 and MHC class II molecules. Additionally, the animals infused with antigen-expressing cells exhibited lower percentages of activated T cells and higher percentages of B cells with a regulatory phenotype (B220 + CD1d high CD5 + ) in the spleen than their respective controls. MDSCs expressing self-antigens, alloantigens or therapeutic transgenes are tolerogenic and can be exploited therapeutically in autoimmune diseases, transplantation and in gene therapy, respectively. [ABSTRACT FROM AUTHOR]

Heat shock protein (Hsp)70 is one of the most important stress-inducible proteins. Intracellular Hsp70 not only mediates chaperone-cytoprotective functions but can also block multiple steps in the apoptosis pathway. In addition, Hsp70 is actively released into the extracellular milieu, thereby promoting innate and adaptive immune responses. Thus, Hsp70 may be a critical molecule in multiple sclerosis (MS) pathogenesis and a potential target in this disease due to its immunological and cytoprotective functions. To investigate the role of Hsp70 in MS pathogenesis, we examined its immune and cytoprotective roles using both in vitro and in vivo experimental procedures. We found that Hsp70.1-deficient mice were more resistant to developing experimental autoimmune encephalomyelitis (EAE) compared with their wild-type (WT) littermates, suggesting that Hsp70.1 plays a critical role in promoting an effective myelin oligodendrocyte glycoprotein (MOG)-specific T cell response. Conversely, Hsp70.1-deficient mice that developed EAE showed an increased level of autoreactive T cells to achieve the same production of cytokines compared with the WT mice. Although a neuroprotective role of HSP70 has been suggested, Hsp70.1-deficient mice that developed EAE did not exhibit increased demyelination compared with the control mice. Accordingly, Hsp70 deficiency did not influence the vulnerability to apoptosis of oligodendrocyte precursor cells (OPCs) in culture. Thus, the immunological role of Hsp70 may be relevant in EAE, and specific therapies down-regulating Hsp70 expression may be a promising approach to reduce the early autoimmune response in MS patients. [ABSTRACT FROM AUTHOR]

Purpose: The main objective of this article is to present an up-to-date review of new product forecasting techniques. Design/methodology/approach: A systematic review of forecasting journals was carried out using the ISI-Web of Knowledge database. Several articles were retrieved and examined, and forecasting techniques relevant to this study were selected and assessed. Findings: The strengths, weaknesses and applications of the main forecasting models are discussed to examine trends and set future challenges. Research limitations/implications: A theoretical reference framework for forecasting techniques classified into judgmental, consumer/market research, cause-effect and artificial intelligence is proposed. Future research can assess these models qualitatively. Practical implications: Companies are currently motivated to launch new products and thus attract new customers to expand their market share. In order to reduce uncertainty and risk, many companies go to extra lengths to forecast sales accurately using several techniques. Originality/value: This article outlines new lines of research on the improvement of new product performance which will aid managers in decision making and allow companies to sustain their competitive advantages in this challenging world. [ABSTRACT FROM AUTHOR]

Knowledge management (KM) and critical success factors (CSFs) are interesting issues in the current business world. Knowledge is an important driving force for business success and competiveness, especially in the consulting industry whose core business is to sell knowledge itself. Previous works suggested a positive relation between the CSF and the success of a KM project, but only few of them related it in a quantitative way. This paper aims to identify the CSF in a consulting firm (strategic, cultural and technological factors) and to build a success model for designing KM projects based on these CSF identified. This model was tested using structured equation model. With this study we contribute to recognising the importance of these success factors in a KM project in the consulting industry to achieve the maximum success. [ABSTRACT FROM AUTHOR]

Purpose – The purpose of this paper is to identify the values that make up a knowledge-friendly culture in the consulting industry, in which the implementation of in-house knowledge management (KM) projects has positive performance outcomes. Design/methodology/approach – An exploratory analysis and a structural equation model were used on a sample of 100 knowledge workers (managers and internal KM project managers) in the consulting sector. Findings – The results of this study indicate that the values identified (trust, transparency, flexibility, collaboration, commitment, honesty and professionalism) bear a close positive relation to the success of the KM project implementation (innovation, employee satisfaction, capabilities, quality and productivity). These values are divided into three groups. Research limitations/implications – This research focuses on the consulting industry in Catalonia, Spain; further research will be required in order to apply the findings to other countries in the world. Practical implications – The study provides a better understanding of the cultural success factor in knowledge management initiatives. It offers a significant and practical advance in terms of systematizing KM in organizations. Originality/value – Knowledge management plays a crucial role in consulting companies, so it is necessary to determine the factors that contribute to its success, and particularly the factor of knowledge culture. However, few empirical studies have analyzed these values. The paper's main contribution is therefore identification of the core values of a knowledge-friendly culture and their impact on performance. [ABSTRACT FROM AUTHOR]

Background: DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes. Methods: EAE was induced in C57BL6/J mice by immunization with MOG35-55 peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR. Results: MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)- specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination. Conclusions: These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Aquaporins (AQP) are a family of transmembrane proteins that act as water selective channels. AQP1 and AQP4 are widely expressed in the central nervous system where they play several roles. Overexpression of AQP has been reported in some human and animal transmissible spongiform encephalopathies, but information is scanty about their distribution in the central nervous system in bovine spongiform encephalopathy (BSE). Double immunohistochemistry for AQP1, AQP4 and GFAP was developed in a transgenic mouse line overexpressing the bovine cellular prion protein (BoTg110), intracerebrally infected with cattle BSE. Western blot for AQP1 and AQP4, and immunohistochemistry for both AQP and GFAP were carried out in cases of BSE-diagnosed cattle as part of surveillance plan in Catalonia (Spain). A marked increase in AQP1 and AQP4 was observed in mice at the terminal stage of the disease, when they had a wide range of clinical signs, whereas no increase could be observed in the early stage before the onset of the clinical signs. In cattle which did not show evidence of clinical signs, both AQP already showed a great increase. The AQP overexpression correlated with GFAP-immunoreactive astrocytes and PrPres deposition in both cases. The results of this study suggest that AQP overexpression in glial cells could lead to an imbalance in water and ion homeostasis which could contribute to triggering the typical histopathological changes of BSE. [Copyright &y& Elsevier]

Abstract: The extracellular matrix (ECM) of the central nervous system (CNS) is found dispersed in the neuropil or forming aggregates around the neurons called perineuronal nets (PNNs). The ECM mainly contains chondroitin sulphate proteoglycans (CSPG), hyaluronic acid (HA) and tenascin-R. Heparan sulphate proteoglycans (HSPG) can also be secreted in the ECM or be part of the cell membrane. The ECM has a heterogeneous distribution which has been linked to several functions, such as specific regional maintenance of hydrodynamic properties in the CNS, in which aquaporins (AQP) play an important role. AQP are a family of membrane proteins which acts as a water channel and AQP4 is the most abundant isoform in the brain. Nevertheless the importance of these proteins, their distribution and correlation in the whole CNS of mice is only partially known. In the present study, the histochemical and immunohistochemical distribution of PNNs, using Wisteria floribunda agglutinin (WFA), aggrecan, HA, HSPGs and AQP4 is described, and their perineuronal and neuropil staining has been semi-quantitatively evaluated in the whole CNS of mice. The results showed that the aggrecan, HA and HSPGs perineuronal distribution coincided partially and this could be related to ECM functional properties. AQP4 showed a heterogeneous distribution throughout the CNS. In some areas, an inverse correlation between AQP4 and ECM components has been observed, suggesting a complementary role for both in the maintenance of water homeostasis. A common location for AQP4 and HSPGs has also been observed in CNS neuropil. [Copyright &y& Elsevier]

Supply chains (SC) aim to provide products to the final customer at a certain service level. However, unforeseen events occur that impede supply chain objectives. SC Risk has been studied in the literature, providing frameworks and methodologies to manage SC failures. Nevertheless, more efforts are needed to prevent hazardous and disruptive risks and their consequences. These risks must be considered during the process of designing a supply chain. Some methodological contributions concerning risk in the supply chain network design (SCND) are conceptual frameworks for mitigating SC disruptions, which suggest strategies and measures for designing robust and resilient SCs. Although such contributions are valuable, they do not indicate how to cope with risk when designing a SC. The main objective of this research is to describe a methodology aimed at including risk considerations into the SCND. Our proposal aims to be, on the one hand, a comprehensive approach that includes a risk identification and assessment procedure in each of the stages of the SCND process and, on the other hand, a tool for decision-making in SC design or redesign processes when SC risks need to be considered. The methodology proposed is an extension of a SCND methodology including risk considerations in order to improve the performance of the supply chains. A case study illustrates how the proposed methodological works, achieving the identification of SC risks already observed in previous works. [ABSTRACT FROM AUTHOR]

Abstract: Notch is a family of receptors involved in the differentiation of several tissues, including the central nervous system and the immune system. One of the Notch ligands, delta-like 4 (Dll4), has been implicated in the differentiation of Th1 cells and the development of Th17 responses, which are involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Our results show that a single administration of an anti-Dll4 antibody is not enough to avoid the development of EAE or to ameliorate the already established clinical signs, despite the treatment reduces the proliferative T cell responses and decreases Th1/Th17 immune responses. [Copyright &y& Elsevier]

Objective: To identify biomarkers associated with progressive phases of MS and with neuroprotective potential., Methods: Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs)., Results: Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01)., Conclusion: These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD)., Methods: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1)., Results: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples., Conclusions: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)