Tolerance To Conditions Research Articles

Immunological Consequences of In Utero Exposure to Foreign Antigens.

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen’s observation of blood cell sharing in twin calves. Owen’s conceptual framework subsequently constituted the backbone of Medawar’s “actively acquired tolerance” as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as “self” so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of “actively acquired tolerance” might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.

To Explore the Issue of Religion and The Development of Tolerance Among Religious Communities, Especially the Youth in Indonesia

This article examines the issue of religion and the development of tolerance among religious communities, especially the youth in Indonesia. Starting from the condition of Indonesia as a nation with diversity, every group and individual is formed naturally with different views and opinions which at any time can get out of control. This study uses a descriptive qualitative approach with the focus of the study on the current state of religious tolerance in Indonesia as well as showing the government's efforts to build religious tolerance. The practice of religious intolerance in Indonesia is shown in the practice of prohibiting the establishment of places of worship, violence experienced by the ulama, cases of rejection of certain identities, and so on. In fact, after the reformation there are three parties that should play a role and be responsible according to their capacity in maintaining religious harmony and tolerance, namely individuals, local governments, and the central government. A number of facts in the field show that in its development, the regulations that are expressly stated as guidelines for the duties of regional governments have not been observed and implemented optimally by a number of local governments. Particularly related to work facilitation and support for FKUB, many local governments have not paid enough attention to FKUB which is a forum for the community to build, maintain and empower religious communities for harmony and prosperity in the life of society, nation and state.

Hepatic Dendritic Cells in the Development and Progression of Metabolic Steatohepatitis.

Metabolic Associated Fatty liver disease (MAFLD) is a global health problem and represents the most common cause of chronic liver disease in the world. MAFLD spectrum goes from simple steatosis to cirrhosis, in between metabolic steatohepatitis with progressive fibrosis, which pathogenesis is not completely understood. Hence, the role of the immune system has become an important fact in the trigger of inflammatory cascades in metabolic steatohepatitis and in the activation of hepatic stellate cells (HSCs). Among, the more studied immune cells in the pathogenesis of MAFLD are macrophages, T cells, natural killer and dendritic cells. In particular, hepatic dendritic cells had recently attracted a special attention, with a dual role in the pathogenesis of MAFLD. These cells have the capacity to switch from a tolerant state to active state inducing an inflammatory cascade. Furthermore, these cells play a role in the lipid storage within the liver, having, thus providing a crucial nexus between inflammation and lipid metabolism. In this review, we will discuss the current knowledge on the dual role of dendritic cells in lipid accumulation, as wells as in the triggering of hepatic inflammation and hepatocytes cell death in metabolic steatohepatitis.

The Role of Risk or Contributory Death Factors in Methadone-Related Fatalities: A Review and Pooled Analysis.

Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association among pre-existing and external conditions and diseases and the resultant methadone death capacity have been investigated. Beside a systematic literature review, a retrospective case-control study was done, dividing cases in which methadone was the only cause of death (controls), and those with associated clinical-circumstantial (naive/non-tolerant state), pathological (pulmonary or cardiovascular diseases) or toxicological (other drugs detected) conditions. Methadone concentrations were compared between the two groups and the association with conditions/diseases was assessed by multiple linear and binomial logistic regressions. Literature cases were 139, in house 35, consisting of 22 controls and 152 cases with associated conditions/diseases. Mean methadone concentrations were 2122 ng/mL and 715 ng/mL in controls and cases respectively, with a statistically significant difference (p < 0.05). Lower methadone concentrations (by 24, 19 and 33% respectively) were detected in association with naive/non-tolerant state, pulmonary diseases and presence of other drugs, and low levels of methadone (<600 ng/mL) might lead to death in the presence of the above conditions/diseases.

Regulatory B Cells in Autoimmune Diabetes.

Since they were discovered almost three decades ago, a subset of B cells denoted as regulatory B cells (Bregs) have elicited interest throughout the immunology community. Many investigators have sought to characterize their phenotype and to understand their function and immunosuppressive mechanisms. Indeed, studies in murine models have demonstrated that Bregs possess varied phenotypic markers and could be classified into different subsets whose action and pivotal role depend on the pathological condition or stimuli. Similar conclusions were drawn in clinical settings delineating an analogous Breg population phenotypically resembling the murine Bregs that ultimately may be associated with a state of tolerance. Recent studies suggested that Bregs may play a role in the onset of autoimmune diabetes. This review will focus on deciphering the different subclasses of Bregs, their emerging role in autoimmune diabetes, and their potential use as a cell-based therapeutic.

T cell-depleting nanoparticles ameliorate bone loss by reducing activated T cells and regulating the Treg/Th17 balance

Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women. Under chronic inflammatory conditions caused by estrogen deficiency, activated T cells contribute to elevated levels of proinflammatory cytokines, impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells (BMMSCs), and disturbed regulatory T cell (Treg)/Th17 cell balance. However, therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed. Here, we produced T cell-depleting nanoparticles (TDNs) that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized (OVX) mice. TDNs consist of monocyte chemotactic protein-1 (MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand (FasL) as the corona. We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo. Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state, further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype. Mechanistically, we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles (ApoEVs), which promoted macrophage transformation towards the M2 phenotype. These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.

Feeding Pattern Followed by Hospitals for Patients with Dengue Fever: An Observational Study

Background: Dengue is an acute viral infection and occurs in three different conditions- Dengue fever (DF),dengue hemorrhagic fever (DHF) and dengue shock syndrome. Supportive and symptomatic treatment isindicated during infection, however less is known about feeding care obligatory in its management.Objective: it was aimed to study feeding care offered to DF patients admitted to hospitals.Materials and Method: An observational study was conducted on 48 patients (16 children and 32 adults)diagnosed for dengue fever and admitted to hospital (3 -government and 2-private hospitals were included)during the months of January to May. Details regarding medical symptoms, body temperature, state ofconsciousness, food tolerance and food intake from day 1 to day 5 was obtained. Oral intake of water andIV infused were recorded.Results: Relationship existed between symptoms, state of consciousness and tolerance to food and water;accordingly patients were classified as seriously sick, moderately sick and mildly sick. Patients with bodytemperature ?102°F, abdomen pain, hepatomegaly and dehydration was associated with food intolerance andnon-responsiveness (seriously sick), they took significantly longer time to develop food tolerance comparedto their counterpart with less serious conditions (p ? 0.0001). Severity of sickness affected hospital stay,severely sick patients stayed longer as compared to the mildly sick (children 4.67±0.94 vs 4±0; adults6.43±3.16 vs 3.67± 1.11 days).Majority of adults (71.9%) and children (56.3%) received normal diet. Energy and protein intake of patients(adults and children) in all the three groups were markedly lower than the RDA. Energy intake increasedsignificantly from 1st to 5th day in all three groups. Differences in energy intake (adults-5.0±2.6 Kcals to18.0±6.5 and children 10.0±3.8 - 29.0±6.8 Kcal/kg/day) was extremely significant (p? 0.001) among severelysick compared to the moderately (adults 11.0±1.6- 17.0±4.9 and children 20.0±2.9- 23.0±6.9 Kcal/kg/day)and mildly sick patients (adults 17.0±2.1- 21.0±3.8 and children 38.0±7.8- 39.0±5.7 Kcal/kg/day). Proteinintake among both adults and children was very low. All patients regardless of the conditions received IVfluids at time of hospital admission. Severely sick received higher volumes of IV infusions and less quantityof oral fluids compared to the moderate and mildly sick. With improvement in conditions, it crisscrossedwith reduced IV infusions and increased oral intakes. Each patient had different fluid needs and varied eachday.Conclusion: Presently, diet management ofDF patient is less judicious. In view of poortolerance and unconsciousness that prevail,food selection should be carefully managed.Easily digestible and nutritious drinks suchas fruits juices and soups should be included to complement for improving electrolytedisturbance and dehydration. Data base shouldbe developed about feeding requirements forDF patients.

The COVID-19 Burden or Tryptophan Syndrome: Autoimmunity, Immunoparalysis and Tolerance in a Tumorigenic Environment

SARS-CoV-2, a new virus, which has been causing the catastrophic pandemic in the world in 2020, triggers numerous physiologic changes in humans, with potentially fatal evolution due to COVID-19. COVID-19 can trigger immunoparalysis with deep and silent immunosuppression and a state of tolerance that may elicit opportunities for neoplastic transformation or latent infectious diseases. In addition, all neurologic or psychiatric symptoms have been observed - as clinically present in usual diseases, but behind these phenomena, there is often the chronic phase of COVID-19 as a background, mediated by intense platelet activation.

Manifestation of lipopolysaccharide-induced tolerance in neuro-glial primary cultures of the rat afferent somatosensory system

ObjectiveBacterial lipopolysaccharide (LPS) may contribute to the manifestation of inflammatory pain within structures of the afferent somatosensory system. LPS can induce a state of refractoriness to its own effects termed LPS tolerance. We employed primary neuro-glial cultures from rat dorsal root ganglia (DRG) and the superficial dorsal horn (SDH) of the spinal cord, mainly including the substantia gelatinosa to establish and characterize a model of LPS tolerance within these structures.MethodsTolerance was induced by pre-treatment of both cultures with 1 µg/ml LPS for 18 h, followed by a short-term stimulation with a higher LPS dose (10 µg/ml for 2 h). Cultures treated with solvent were used as controls. Cells from DRG or SDH were investigated by means of RT-PCR (expression of inflammatory genes) and immunocytochemistry (translocation of inflammatory transcription factors into nuclei of cells from both cultures). Supernatants from both cultures were assayed for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by highly sensitive bioassays.ResultsAt the mRNA-level, pre-treatment with 1 µg/ml LPS caused reduced expression of TNF-α and enhanced IL-10/TNF-α expression ratios in both cultures upon subsequent stimulation with 10 µg/ml LPS, i.e. LPS tolerance. SDH cultures further showed reduced release of TNF-α into the supernatants and attenuated TNF-α immunoreactivity in microglial cells. In the state of LPS tolerance macrophages from DRG and microglial cells from SDH showed reduced LPS-induced nuclear translocation of the inflammatory transcription factors NFκB and NF-IL6. Nuclear immunoreactivity of the IL-6-activated transcription factor STAT3 was further reduced in neurons from DRG and astrocytes from SDH in LPS tolerant cultures.ConclusionA state of LPS tolerance can be induced in primary cultures from the afferent somatosensory system, which is characterized by a down-regulation of pro-inflammatory mediators. Thus, this model can be applied to study the effects of LPS tolerance at the cellular level, for example possible modifications of neuronal reactivity patterns upon inflammatory stimulation.

Synergistic efficacy of combined EGFR and HDAC inhibitors overcomes tolerance to EGFR monotherapy in salivary mucoepidermoid carcinoma

ObjectivesMucoepidermoid carcinoma (MEC) is the most common type of salivary gland malignancy. Advanced or high-grade MECs are refractory to chemotherapy, often leading to tumor recurrence/metastasis and abysmal ~35% 5-year survival. Causal links have been established between Epithelial Growth Factor Receptor (EGFR) activation and poor outcome. Herein we investigated the therapeutic efficacy of EGFR inhibition against MEC using in vitro pre-clinical models. Materials and MethodsFive human MEC cell lines were used in cell viability, cytotoxicity, apoptosis, cell cycle, 2D-clonogenicity, and 3D-spheroid formation assays following treatment with Erlotinib (EGFR inhibitor), SAHA (Histone Deacetylase inhibitor; HDAC) and CUDC-101 (dual EGFR-HDAC inhibitor). Effects on MEC cancer stem cells were evaluated using flow cytometry. Gene expression and pathway regulation were evaluated via qPCR and Western blot, respectively. ResultsMEC cells enter a quiescent, non-proliferative yet rapidly reversible drug tolerant state upon EGFR inhibition. Despite robust suppression of MEC cell proliferation, no discernable apoptosis is detected. Combination of EGFR and HDAC inhibitors exhibits synergistic effects, exerting ~5-fold more potent cell cytotoxicity compared to HDAC or EGFR monotherapy. CUDC-101, a single molecule with dual EGFR-HDAC inhibitor moieties, exerts irreversible and potent cytotoxic activity against MEC cells and blunts MEC cancer stem-cell tumorigenicity. ConclusionMEC cells are intrinsically tolerant to EGFR inhibition. Combining EGFR and HDAC inhibitors exerts synergistic and potent cytotoxic effects, suggesting that EGFR inhibitors still hold significant promise against MEC. Future studies are needed to assess the applicability and efficacy of dual EGFR-HDAC inhibitors for the clinical management of MEC.

LPS Tolerance Inhibits Cellular Respiration and Induces Global Changes in the Macrophage Secretome

Inflammatory response plays an essential role in the resolution of infections. However, inflammation can be detrimental to an organism and cause irreparable damage. For example, during sepsis, a cytokine storm can lead to multiple organ failures and often results in death. One of the strongest triggers of the inflammatory response is bacterial lipopolysaccharides (LPS), acting mostly through Toll-like receptor 4 (TLR4). Paradoxically, while exposure to LPS triggers a robust inflammatory response, repeated or prolonged exposure to LPS can induce a state of endotoxin tolerance, a phenomenon where macrophages and monocytes do not respond to new endotoxin challenges, and it is often associated with secondary infections and negative outcomes. The cellular mechanisms regulating this phenomenon remain elusive. We used metabolic measurements to confirm differences in the cellular metabolism of naïve macrophages and that of macrophages responding to LPS stimulation or those in the LPS-tolerant state. In parallel, we performed an unbiased secretome survey using quantitative mass spectrometry during the induction of LPS tolerance, creating the first comprehensive secretome profile of endotoxin-tolerant cells. The secretome changes confirmed that LPS-tolerant macrophages have significantly decreased cellular metabolism and that the proteins secreted by LPS-tolerant macrophages have a strong association with cell survival, protein metabolism, and the metabolism of reactive oxygen species.

Taiwan’s Covenantal Pluralism

Despite its diplomatic isolation, Taiwan shines in East Asia as a beacon for pluralism. This is a rare example of a progressive and liberal society where both deep religious diversity and a tolerant secular state co-exist. Taiwan’s liminality between world empires, and its unique position in the global economy partly explain its openness to a diversity of worldviews, but also exposes it to greater challenges to achieve covenantal pluralism. Taiwan’s hard-won democracy has entrenched positive trends, but three issues threaten to undermine it: the political pressure of a domineering China that limits its own religious diversity and that wants to annex Taiwan; the rise in influence of a rather intransigent and divisive religious minority that demonizes its opponents; and the increasing labor immigration addressing the challenges of an aging society.

Применение кверцетина в липосомальной форме для оптимизации метаболической терапии ишемической болезни сердца

The study of the clinical efficacy and safety of the dietary supplement L-Quercet as part of the complex therapy of patients with coronary artery disease with stable angina of II functional class, taking into account their effect on the clinical course of the disease, exercise tolerance and functional state of the endothelium. It has been shown that the inclusion of L-Quercet in the complex therapy in patients with stable angina leads to an improvement in the clinical course of angina pectoris, allows to significantly increase exercise tolerance and the quality of life of patients. The use of L-Quercet improves the indicators of endothelial function according to the results of the cuff test, which is one of the main factors in the prevention of the development and progression of atherosclerosis and coronary artery disease, and also causes an increase in the effectiveness of antianginal pharmacotherapy

Fault-tolerant estimation of satellite orbital states

This paper is devoted to global positioning system (GPS)-based fault-tolerant satellite orbital states estimation which is used for the pseudo-ranging model. GPS is widely used by many researchers to determine the orbit state vectors of satellites, but errors in GPS measurements can cause major errors in satellite location detection. Therefore, there is a need for an architecture that will resist possible measurement errors and GPS malfunctions. This study aims to present the novel approaches to tolerate the errors that may take place in GPS measurements. The satellite localisation has been detected via a pseudo-ranging model between four GPS satellites and the target satellite. The Keplerian equations and orbit elements are used for the satellite dynamic model with orbital J2 perturbation which is due to the flattened shape of the earth is taken into account via the extended Kalman filter (EKF) algorithms. The reconfigurable and the adaptive version of fault-tolerant localisation architecture eliminate the GPS measurement errors during estimating satellite position vectors. The comparison of the prediction architectures of the fault tolerant satellite state vectors originally proposed. At the same time, it is possible to use fault tolerant architectures designed to detect whether GPS satellites are malfunctioning or not.

The Pursuit of Regulatory T Cells in the Induction of Transplant Tolerance.

Organ transplantation is a preferred treatment option for patients with end-stage organ failure. However, transplant induces a robust rejection response that necessitates life-long immunosuppression, which often leads to a plethora of comorbidities. Thus, the goal of transplantation is to achieve a state of tolerance wherein the host permanently accepts the transplanted organ while maintaining normal immune responses to other antigens. Regulatory T cells (Tregs) play an important role in realizing this goal and are being explored in both animal models and human clinical trials. In this chapter, we discuss the key principles of transplant rejection and Treg biology, as well as the status of human clinical trials utilizing Tregs as cellular therapy. We discuss how the current immunosuppressive drugs are utilized in transplantation in favoring an increased Treg to T effector cell ratio, different approaches in generation of therapeutic Tregs, and various facets in Treg trial designs in the clinic. Such clinical trials provided many opportunities to leverage our understanding of Tregs in transplantation. They also demonstrated Tregs as a safe cellular therapy for human use, but the efficacy of this treatment has yet to be fully realized.

Finite-Time Fault-Tolerant State Estimation for Markovian Jumping Neural Networks With Two Delay Components

This paper focuses on the finite time fault tolerant state estimation of Markovian jumping neural networks with two delay components. Firstly, the mathematical expression of the state estimator is defined when the system components have faults and the system output has external disturbances. Then, an augmented Lyapunov-Krasovslii functional including additive delay information, state information and activation function information is used to derive stochastic finite time stability conditions for error state systems. In addition, some advanced reciprocally convex inequalities are used to obtain linear matrix inequality (LMI) conditions that are easy to solve. Finally, numerical simulation is carried out to verify the effectiveness of the proposed method. Numerical results show that the proposed state estimator can still guarantee the estimation performance in the finite time stability framework even if there are component faults.

A Robust Method for Generating, Quantifying, and Testing Large Numbers of Escherichia coli Persisters.

Bacteria can exhibit phenotypes that render them tolerant against antibiotics. However, often only a few cells of a bacterial population show the so-called persister phenotype, which makes it difficult to study this health-threatening phenotype. We recently found that certain abrupt nutrient shifts generate Escherichia coli populations that consist almost entirely of antibiotic-tolerant cells. These nearly homogeneous persister cell populations enable assessment with population-averaging experimental methods, such as high-throughput methods. In this chapter, we provide a detailed protocol for generating a large fraction of tolerant cells using the nutrient-switch approach. Furthermore, we describe how to determine the fraction of cells that enter the tolerant state upon a sudden nutrient shift and we provide a new way to assess antibiotic tolerance using flow cytometry. We envision that these methods will facilitate research into the important and exciting phenotype of bacterial persister cells.

A Justiça e o problema da obediência a uma lei injusta – uma análise comparativa das teorias de Rawls e Dworkin

A possibilidade de se tolerar um desobediente civil é parte integrante, para muitos autores, do próprio conceito de Estado Democrático de Direito. Porém, a fundamentação e os limites da referida desobediência é matéria controversa, mormente quanto à possibilidade de infringir uma lei com fulcro na objeção de consciência. A discussão central, portanto, permeia a incorporação ou não da objeção de consciência como um fundamento válido para a desobediência civil. Percebe-se, a partir deste debate, que questões morais e legais poderão entrar em conflito e os limites da desobediência dependerão da fundamentação e da justificação tanto filosófica quanto jurídica. Frente à vasta e complexa gama de autores que trabalham o tema, optou-se, no presente ensaio, pela análise crítica e comparativa das teorias de John Rawls e Ronald Dworkin, que divergem exatamente no ponto acima descrito. O primeiro, alicerçado em sua teoria da justiça&#x0D; como equidade, promove o entendimento procedimental da desobediência civil fundamentada em princípios políticos publicamente aceitos, excluindo questões morais. O segundo, por seu turno, entende que em toda regra há um conteúdo moral, passível, portanto, de desobediência com fulcro na objeção de consciência. Tendo em vista a referida dicotomia entre princípios morais e princípios políticos, busca-se verificar se a teoria de Rawls impõe um caráter exageradamente restritivo ou se a compreensão de Dworkin traduz comportamentos estatais excessivamente tolerantes. O presente artigo se justifica pela influência decisiva que ambos os autores têm desempenhado no que se refere à fundamentação da desobediência civil, principalmente no debate em relação às doutrinas liberais de justiça.

Tolerance Protocols in Large Animal VCA Models—Comprehensive Review

The clinical application of vascularized composite allografts (VCA) has continue to expand each year as new transplants are performed. However, chronic rejection and the many side effects from chronic immunosuppression continue to inhibit widespread application of VCA. Immune tolerance to VCA would address these two issues and shift the risk-benefit ratio to allow for the more widespread application of these transplants. Future development of clinical tolerance protocols will be generated from pre-clinical experiments performed in large animal models. This article reviews the current state of large animal tolerance protocols published for VCA. The most successful tolerance protocols thus far include the use of hematopoietic stem cell transplant with non-myeloablative preconditioning and establishment of donor cell chimerism. In addition to this strategy, several groups have examined the inclusion of mesenchymal and adipose-derived stem cells to address the complications related to the use of hematopoietic stem cell transplant (such as graft versus host disease). These large animal models are critical to development of a viable pre-clinical model for tolerance in vascularized composite allografts that can deliver a tolerant state with minimal harm to the recipient of these non-life-saving transplants.

Transient Fault Tolerant State Assignment for Stochastic Computing Based on Linear Finite State Machines

Transient Fault Tolerant State Assignment for Stochastic Computing Based on Linear Finite State Machines