Miracle-dz/UniFAR-FTUs huggingface dataset:
Virtualise manufacturing capabilities in the cloud: requirements, architecture and implementation

In recent years, cloud manufacturing concept has been proposed by taking advantage of cloud computing to enhance the performance of manufacturing industry. Cloud manufacturing can be perceived as two types, i.e., manufacturing version of computing cloud, and a distributed environment that is networked around manufacturing cloud. This paper discusses manufacturing resources, abilities and relevant essentials from the service-oriented perspective. The functional requirements of a cloud manufacturing environment are also discussed, along with an interoperable manufacturing system framework. Cloud resource integration methods have been developed based on the function block and software agent technologies. It is possible to achieve a collaborative, intelligent, and distributed environment via cloud manufacturing technologies.
IFN Regulatory Factor 8 Regulates MDM2 in Germinal Center B Cells1

IFN regulatory factor 8 (IRF8) is a transcription factor that affects the differentiation and function of myeloid, dendritic, and B cells. Herein we report that IRF8 regulates the expression of Mdm2, a suppressor of p53-dependent and -independent apoptosis pathways, in germinal center (GC) B cells. In GC B cells of IRF8-deficient mice, Mdm2 transcripts were greatly down-regulated, and MDM2 protein was poorly expressed in GC of Irf8−/− mice. Small interfering RNA-induced repression of IRF8 in a GC-derived B cell line resulted in decreased expression of MDM2 at the protein level but increased expression of p53 and p21. We found that IRF8 binds to the Mdm2 P2 promoter, and that cotransfection of an IRF8 expression vector with an Mdm2 reporter construct stimulated significant increases in reporter activity. Additionally, transcripts of the p53 target Pmaip1 (Noxa) were significantly increased in IRF8-deficient GC B cells as well as in the IRF8 knockdown B cell line. Finally, cells deficient in IRF8 exhibited growth suppression and increased sensitivity to apoptosis induced by etoposide or IL-21. These results suggest that by regulating MDM2, IRF8 might allow GC B cells to tolerate physiological DNA breaks that otherwise would trigger apoptosis.
Experimental Autoimmune Encephalomyelitis in Lewis rats: IFN-β Acts As a Tolerogenic Adjuvant for Induction of Neuroantigen-Dependent Tolerance1

Cytokine-Ag fusion proteins represent a novel approach for induction of Ag-specific tolerance and may constitute an efficient therapy for autoimmune disease. This study addressed whether a fusion protein containing rat IFN-β and the encephalitogenic 73–87 determinant of myelin basic protein (i.e., the neuroantigen, or NAg) could prevent or treat experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The optimal structure of the fusion protein was comprised of the rat IFN-β cytokine as the N-terminal domain with an enterokinase (EK) linker to the NAg domain. Both cytokine and NAg domains had full biological activity. Subcutaneous administration of 1 nmol of IFNβ-NAg fusion protein in saline on days −21, −14, and −7 before encephalitogenic challenge on day 0 resulted in a substantial attenuation of EAE. In contrast, administration of IFN-β or NAg alone did not affect susceptibility to EAE. The covalent attachment of IFN-β and NAg was not necessary, because separate injections of IFN-β and NAg at adjacent sites were as effective as injection of IFNβ-NAg for prevention of disease. When treatment was initiated after disease onset, the rank order of inhibitory activity was as follows: the IFNβ-NAg fusion protein ≥ a mixture of IFN-β plus NAg > IFN-β > NAg. The novel finding that IFN-β acts as a tolerogenic adjuvant as well as a tolerogenic fusion partner may have significance for development of tolerogenic vaccines.
Locally Administered TLR7 Agonists Drive Systemic Antitumor Immune Responses That Are Enhanced by Anti-CD40 Immunotherapy1

Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers. However, for therapy to be effective against a broad range of solid tumor types, it must promote a strong systemic antitumor response that targets metastases in addition to primary tumor. We therefore investigated the potential of locally delivered imiquimod to stimulate an effective systemic antitumor response in a murine model of malignant mesothelioma (AB1-HA) with primary and distal tumors (dual tumor). Persistent delivery of imiquimod into primary tumor significantly retarded tumor growth in all treated mice compared with vehicle control. This local antitumor immune response required both CD8 T cells and NK cells, but not CD4 T cells, and was reliant on type I IFN induction. In vivo CTL studies and Ly6A/E staining of lymphocytes suggested that local imiquimod treatment had indeed induced a systemic, Ag-specific CD8 response. However, notably this response was not sufficient to retard the growth of an untreated distal tumor. Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor. These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
Oncothermia Application for Various Malignant Diseases

Oncothermia was introduced to our hospital in 2010. Our objective is to report results of 277 patients treated by oncothermia during 20 months. We present some characteristic cases and statistical study of the overall results. We concluded by stating the feasibility of oncothermia to treat high variety of malignant diseases also in their very advanced (T4N3M1) stages.
Protective effect of anakinra on audiovestibular function in a murine model of endolymphatic hydrops

Introduction Ménière’s disease (MD), a common disease in the inner ear, is characterized by an increase in endolymph in the cochlear duct and vestibular labyrinth. The pathophysiology of the condition appears to be the immune response. Studies have shown that basal levels of the IL-1β increased in some MD patients. Methods Here, we used a murine model of endolymphatic hydrops (EH) to study the effect of anakinra on auditory and vestibular function. Mice were intraperitoneal injected with anakinra or saline before LPS by postauricular injection. Weight and disease severity were measured, histologic changes in auditory were assessed, and inflammation state was evaluated. Results We found that anakinra therapy reduced LPS-induced EH, alleviated LPS-induced hearing loss and vestibular dysfunction, and inhibited the expression of the inflammatory cytokines and macrophage infiltration in the cochlea of mice. We further demonstrated that anakinra ameliorated the disorganization and degeneration of myelin sheath, and reduced the neuron damage in cochlea of EH mice. Discussion Consequently, anakinra contributes to a promising therapeutic approach to MD, by restricting EH, alleviating auditory and vestibular function, inhibiting inflammation of the inner ear and protecting the cochlear nerve. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with MD.
Flexibility, trade-offs and learning in manufacturing system design

Three independent case-based research projects are examined, using similar methodologies, so as to understand the relationships between the nature of each manufacturing system's redesign, their strategic context, the assessment of each system's flexibility, their managers' perceptions of the trade-offs involved in the design and the degree of organisational learning. A model is proposed which suggests an interplay between three related sets of activities. These are a "structuring" activity, a "suppositional" activity and an "assimilation" activity. Parallels are drawn between these studies and other work on learning and technological competence.
Plasma thiol status is altered in children with mitochondrial diseases

Abstract Objective. This study was undertaken to investigate thiol metabolism as a marker of oxidative stress and antioxidative defence capacity in a cohort of children with biochemically and/or genetically confirmed mitochondrial disease. Previous studies suggest that lower glutathione levels, which have been shown to further compromise mitochondrial function, may occur in these diseases. Better understanding of the pathogenesis of mitochondrial diseases is important in order to improve their treatment. Methods. We studied plasma and erythrocyte glutathione and cysteine levels, the activities of erythrocyte glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase G6PDH) and glutathione S-transferase (GST), as well as the levels of erythrocyte thiobarbituric acid-reactive species (TBA-RS) and protein carbonyls in 10 children with a biochemical and/or genetic diagnosis of mitochondrial disease and six controls. Results. Levels of reduced cysteine (CYSH) as well as reduced to oxidised cysteine ratio were lower in plasma of patients with mitochondrial diseases (p = 0.008 and p = 0.02, respectively). Plasma levels of reduced glutathione (GSH) were low in patients with mitochondrial diseases, mostly below the detection limit. We did not detect significant differences in erythrocyte thiols or glutathione-related enzyme activities. Conclusion. Plasma thiols and their redox state are altered in patients with mitochondrial diseases, suggesting an increase in oxidative stress and depletion of antioxidant supplies. If confirmed in further studies, this relative thiol deficiency could be an important factor in the pathophysiology of mitochondrial diseases.
Wiskott-Aldrich Syndrome Protein Is Required for Homeostasis and Function of Invariant NKT Cells1

NKT cells comprise a separate T lineage expressing semi-invariant T cell receptors. Canonical invariant NKT (iNKT) cells specifically recognize lipid Ags presented by CD1d, a MHC class I-like molecule. iNKT cells function, in part, as initial responders to bacterial infection and play a role in immune surveillance and tumor rejection. The Wiskott-Aldrich Syndrome protein (WASp) serves as a crucial link between cellular stimuli and cytoskeletal rearrangements. Although we and others have identified a key role for WASp in homeostasis of T-regulatory and marginal zone B cells, little data exist regarding the role for WASp within the iNKT lineage. Analysis of WASp-expressing cell populations in heterozygous female WASp mice revealed a substantial selective advantage for WASp+ vs WASp− iNKT cells. Although adult WASp-deficient (WASp−/−) mice had normal thymic and bone marrow iNKT numbers, we observed 2- to 3-fold reduction in the numbers of iNKT cells in the spleen and liver. This peripheral iNKT deficit is manifested, in part, due to defective iNKT homeostasis. WASp−/− iNKT cells exhibited reduced levels of integrin surface expression and decreased homing and/or retention within peripheral tissues in a competitive repopulation model. In addition, analysis of young mice showed that WASp is important for both maturation and egress of thymic iNKT cells. WASp−/− iNKT cells also exhibited a marked reduction in Ag-induced proliferation and cytokine production. Our findings highlight the crucial role for WASp in iNKT development, homeostasis, and activation, and identify iNKT dysfunction as an additional factor likely to contribute to the clinical features observed in WAS patients.
Fluid Flow Regulates Stromal Cell Organization and CCL21 Expression in a Tissue-Engineered Lymph Node Microenvironment1

In the paracortex of the lymph node (LN), T zone fibroblastic reticular cells (TRCs) orchestrate an immune response by guiding lymphocyte migration both physically, by creating three-dimensional (3D) cell networks, and chemically, by secreting the chemokines CCL19 and CCL21 that direct interactions between CCR7-expressing cells, including mature dendritic cells and naive T cells. TRCs also enwrap matrix-based conduits that transport fluid from the subcapsular sinus to high endothelial venules, and fluid flow through the draining LN rapidly increases upon tissue injury or inflammation. To determine whether fluid flow affects TRC organization or function within a 3D network, we regenerated the 3D LN T zone stromal network by culturing murine TRC clones within a macroporous polyurethane scaffold containing type I collagen and Matrigel and applying slow interstitial flow (1–23 μm/min). We show that the 3D environment and slow interstitial flow are important regulators of TRC morphology, organization, and CCL21 secretion. Without flow, CCL21 expression could not be detected. Furthermore, when flow through the LN was blocked in mice in vivo, CCL21 gene expression was down-regulated within 2 h. These results highlight the importance of lymph flow as a homeostatic regulator of constitutive TRC activity and introduce the concept that increased lymph flow may act as an early inflammatory cue to enhance CCL21 expression by TRCs, thereby ensuring efficient immune cell trafficking, lymph sampling, and immune response induction.
In Vivo Imaging of an Inducible Oncogenic Tumor Antigen Visualizes Tumor Progression and Predicts CTL Tolerance

Visualizing oncogene/tumor Ag expression by noninvasive imaging is of great interest for understanding processes of tumor development and therapy. We established transgenic (Tg) mice conditionally expressing a fusion protein of the SV40 large T Ag and luciferase (TagLuc) that allows monitoring of oncogene/tumor Ag expression by bioluminescent imaging upon Cre recombinase-mediated activation. Independent of Cre-mediated recombination, the TagLuc gene was expressed at low levels in different tissues, probably due to the leakiness of the stop cassette. The level of spontaneous TagLuc expression, detected by bioluminescent imaging, varied between the different Tg lines, depended on the nature of the Tg expression cassette, and correlated with Tag-specific CTL tolerance. Following liver-specific Cre-loxP site-mediated excision of the stop cassette that separated the promoter from the TagLuc fusion gene, hepatocellular carcinoma development was visualized. The ubiquitous low level TagLuc expression caused the failure of transferred effector T cells to reject Tag-expressing tumors rather than causing graft-versus-host disease. This model may be useful to study different levels of tolerance, monitor tumor development at an early stage, and rapidly visualize the efficacy of therapeutic intervention versus potential side effects of low-level Ag expression in normal tissues.
Th17 Cells Are the Dominant T Cell Subtype Primed by Shigella flexneri Mediating Protective Immunity

The T cell response to Shigella, the causative agent of bacillary dysentery, remains poorly understood. Using a murine model of infection, we report that Shigella flexneri primes predominately IL-17A– and IL-22–producing Th17 cells. Shigella-specific Th1 cells are only significantly induced on secondary infection, whereas specific Th2 and CD8+ T cells are undetectable. Apart from Th17 cells that are primed in a MHC class II- and IL-6–dependent, but IL12/23p40-independent manner, we identified γδ T cells as an additional but minor source of IL-17A. Priming of IL-17A+ γδ T cells is dependent on IL12/23p40, but independent of MHC-class II and IL-6. Th17 cells have emerged as important players in inflammatory, autoimmune, and infectious diseases. Among the yet unresolved questions is their role in long-term immunity to pathogens. In this study, we show that the elicited S. flexneri-specific Th17 pool gives rise to an enhanced recall response up to 12 mo after priming, suggesting the presence of a long-term memory state. The clearance of primary infection is impaired in the absence of T cells, but independently of IL-17A. However, after reinfection, IL-17A produced by S. flexneri-specific Th17 cells becomes important to ultimately restrict bacterial growth. These findings bring new insights into the adaptive immune response to Shigella infection and highlight the importance of pathogen-specific Th17 cell immunity for secondary immune protection.
A rare cause of complete atrioventricular block: Lyme carditis

Lyme disease is a tick-borne spirochete infection that may affect the heart. Cardiac manifestations include conduction disturbances and other pathologies of the heart. Disturbance of atrioventricular (AV) node conduction is the most common cardiac manifestation of Lyme disease. We report a 61-year old female, who was admitted to the emergency de- partment with the complaints of syncope, dizziness and generalized fatigue. Physical examination revealed normal findings. The patient's electrocardiogram on admission revealed a newly diagnosed bradycardia due to third degree of AV block with40/min ventricular rate. The patient was admitted to the coronary care unit and was placed a transvenous pacemaker. Lyme serology and Western blot were positive for Borrelia antibodies. The symptoms and AV block resolved completely after doxycycline therapy.
Hypofractionated helical intensity-modulated radiotherapy (75 Gy at 2.5 Gy/fraction) for intermediate- and high-risk prostate cancer: Assessment of toxicity

Abstract Purpose: To evaluate the toxicity of hypofractionated helical intensity-modulated radiotherapy (IMRT) for men with intermediate- and high-risk prostate cancer. Methods and Materials: A retrospective toxicity analysis was performed in 22 patients treated definitively with hypofractionated helical IMRT. The helical IMRT were designed to deliver 75 Gy in 2.5 Gy/fraction to the prostate gland, 63 Gy in 2.1 Gy/fraction to seminal vesicle, and 54 Gy in 1.8 Gy/fraction to pelvic lymph nodes. No patient received hormonal therapy. Toxicity was graded by the Radiation Therapy Oncology Group (RTOG) scales. Results: All patients tolerated the treatment well without treatment interruption, and there was no Grade 3 or more acute toxicity. With a median follow-up of 24.5 months, there was no Grade 3 or more late toxicity. The late Grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity for total 22 patients were 9.1% and 18.2%, respectively, and the late Grade 1 GI and GU toxicity were 18.2% and 50%, respectively. Late GU toxicity was associated with greater bladder volume irradiated ≥70 Gy. Late GI toxicity did not correlate with any of the dosimetric parameters. Conclusions: This study demonstrate that hypofractionated helical IMRT with high biologic effective dose (BED) is well tolerated with favourable toxicity rate. If longer follow-up periods and larger cohorts confirm the favourable biochemical control rate and our favourable toxicity assessment results, the hypofractionated IMRT (total 75 Gy, 2.5 Gy/fraction) might be implemented in clinical field for treatment of prostate cancer.
MyD88 Adaptor-Like D96N Is a Naturally Occurring Loss-of-Function Variant of TIRAP

Signals elicited by TLRs following the detection of microbes are integrated and diversified by a group of four cytoplasmic adaptor molecules featuring an evolutionarily conserved Toll/IL-1R signaling domain. Single nucleotide polymorphisms (SNPs) in TLRs and their adaptor molecules have been shown to influence susceptibility to a range of infectious and other diseases. The adaptor MyD88 adaptor-like (Mal)/Toll/IL-1R–containing adaptor protein is involved in TLR2 and 4 signal transduction by recruiting another adaptor molecule, MyD88, to the plasma membrane. In this study, we used naturally occurring variants of Mal as tools to study the molecular biology of Mal in more detail in cellular model systems and to thereby identify functionally interesting variants whose corresponding nonsynonymous SNPs might be of further epidemiological interest. Of seven reported variants for Mal, we found Mal D96N associated with reduced NF-κB signaling and cytokine production after overexpression in HEK293 and Huh-7 cells. The D96N mutation prevented Mal from recruiting its signaling partner MyD88 to the plasma membrane and altered posttranslational modification of Mal. These findings led us to investigate the frequency of heterozygosity for the corresponding SNP rs8177400 in a Caucasian case-control study on the etiology of lymphoma, a disease in which TLRs have been implicated. Although rs8177400 did not modify lymphoma risk in general, its frequency of heterozygosity was accurately determined to 0.97%. Our data add rs8177400 (D96N) to the list of functionally important variants of Mal and warrant further research into its immunological, epidemiological, and diagnostic relevance.
The Impact of Dietary Intake and Sun Exposure on Vitamin D Deficiency among Couples

Result: Three hundred and twenty five couples were included in the study. The mean dietary intake of vitamin D was low, but not significantly different between men and women. Vitamin D level was <50 nmol/L in 209 (64.3%) men and 292 (89.8%) women. The mean 25(OH)D level in males (46.06 ± 12.97 nmol/L) was significantly higher than females (33.12 ± 13.48 nmol/L). There was a significant association between dietary intake and 25(OH)D levels in both men and women. Sun exposure was also found to be significantly associated with 25(OH)D level in males but not in females which is attributed to the use of veil.
Effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, with a focus on atherosclerosis

Atherosclerosis is a lipid-driven chronic inflammatory disease that is widespread in the walls of large and medium-sized arteries. Its pathogenesis is not fully understood. The currently known pathogenesis includes activation of pro-inflammatory signaling pathways in the body, increased oxidative stress, and increased expression of cytokines/chemokines. In the innate immune response, inflammatory vesicles are an important component with the ability to promote the expression and maturation of inflammatory factors, release large amounts of inflammatory cytokines, trigger a cascade of inflammatory responses, and clear pathogens and damaged cells. Studies in the last few years have demonstrated that NLRP3 inflammatory vesicles play a crucial role in the development of atherosclerosis as well as its complications. Several studies have shown that NLRP3 binding to ligands promotes inflammasome formation, activates caspase-1, and ultimately promotes its maturation and the maturation and production of IL-1β and IL-18. IL-1β and IL-18 are considered to be the two most prominent inflammatory cytokines in the inflammasome that promote the development of atherosclerosis. SGLT2 inhibitors are novel hypoglycemic agents that also have significant antiatherosclerotic effects. However, their exact mechanism is not yet clear. This article is a review of the literature on the effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, focusing on their role in antiatherosclerosis.