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The integration of digital technologies into political processes represents a pivotal shift in the operational dynamics of political parties, highlighting an evolution from traditional to digital platforms. This transformation offers greater member engagement and decision-making transparency while also introducing new challenges in terms of security and control. This study presents an analytical overview of the Helios voting system as implemented by the Czech Pirate Party, used not only for primary elections, offering a critical examination of its operational framework, security measures, verification processes, and implications for intra-party democracy and member engagement. The Czech Pirate Party's engagement with Helios exemplifies a broader trend toward digitalization within political organizations, reflecting both the potential benefits and inherent challenges of such technological adoption. Drawing on theoretical insights from the literature on political party transformation in the digital age, this article assesses how i-voting systems like Helios can potentially enhance or detract from internal democracy. The discourse around digital platforms is nuanced, revealing opportunities for increased democratic engagement alongside risks of enhanced centralization and control. Empirical data from a survey of the Czech Pirate Party's membership base provides insights into perceptions of the Helios system's usability, security, and its impact on democratic processes within the party. The study further investigates Helios's technical aspects, focusing on its security protocols, verification mechanisms, and governance structures related to data and platform ownership, to understand its implications for electoral integrity and party governance. The research aims to contribute to the dialogue on e-voting platforms, highlighting the need for a careful balance between embracing technological advancements and upholding democratic principles.

This paper presents the first application of an Integrated Three-Dimensional aeromechanical analysis—defined as the coupled solution of three-dimensional finite element-based structural dynamics with a three-dimensional Reynolds-Averaged Navier-Stokes-based fluid dynamics—to predict the stresses on a modern coaxial rotor. The coupling was carried out with the University of Maryland's structural dynamic solver X3D and the U.S. Army's CREATETM–AV Helios suite of fluid dynamic solvers. A modern four-bladed hingeless coaxial rotor model—inspired by the gross dimensions of the Sikorsky S-97 Raider but generic and open source otherwise—is developed as a demonstration test case. The new structural solver is driven by parallel and scalable solvers and advanced high performance computing. It is enabled by high-order three-dimensional brick finite elements unified with multibody dynamics, integrated aerodynamics, and a special 3D-to-1D fluid-structure interfaces refines the power of delta-coupling procedure while retaining the advantages of existing CFD mesh motion schemes. The analysis predicts the three-dimensional stresses on the rotor blades and hub, together with the deformations, airloads, and wake, in an integrated manner. Two flight conditions are studied: a low-speed flight at 37 knots and a high-speed flight at 150 knots. Interesting three-dimensional unsteady stress patterns are revealed all across the blade but particularly inboard of 50% rotor radius—patterns that change from flight to flight and have remained invisible until now—since they could neither be predicted nor measured in flight. The maximum axial stresses exhibited 3/rev variation at low speed, and 2/rev variation at high speed flight. The lower rotor carried higher oscillatory stress burden at low speed, whereas both the rotors shared the same stress burden at high speed flight. The key conclusion is that such analysis is now indeed possible, and the stress patterns they reveal provide deeper insights into the dynamics of advanced rotors, and these might provide a path toward mitigating them in the future. [ABSTRACT FROM AUTHOR]

The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDAapproved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (Tregs), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of Tregs has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating Tregs correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing Treg-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit Treg-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of Treg-targeted immunotherapies for PDAC. [ABSTRACT FROM AUTHOR]

This study sought to compare the behavior of Treg subsets displaying different coexpression patterns of Neuropilin‐1 (Nrp1) and Helios, under the influence of gut stress unrelated to hematopoietic stem cell transplantation, pretransplantation conditioning, and posttransplant gastrointestinal acute graft versus host disease (GI‐aGvHD). Host CD4+/CD25hi/Foxp3+ Treg cells, identified by flow cytometry, were isolated from various tissues of mice affected by these stressors. Expression of CD25, CTLA‐4, CD39, OX40, integrin‐β7, LAG3, TGFβ/LAP, granzyme‐A, ‐B, and interleukin‐10 was compared in four Treg subsets displaying Helios or Nrp1 only, both or none. Fluorescence‐activated cell sorter–sorted Treg subsets, displaying markers affected in a conditioning‐ and GI‐aGVHD‐restricted manner, were further investigated by transcriptome profiling and T‐cell suppression assays. We found that conditioning by irradiation greatly diminished the relative frequency of Helios+/Nrp1+ Treg, shifting the balance toward Helios−/Nrp1− Treg in the host. Upregulation of integrin‐β7 and OX40 occurred in GI‐aGvHD‐dependent manner in Helios+/Nrp1+ cells but not in Helios−/Nrp1− Treg. Sorted Treg subsets, confirmed to overexpress Nrp1, Helios, OX40, or integrin‐β7, displayed superior immunosuppressive activity and enrichment in activation‐related messenger RNA transcripts. Our data suggest that conditioning‐induced shrinkage of the Nrp1+/Helios+ Treg subset may contribute to the development of GI‐GvHD by impairing gut homing and decreasing the efficiency of Treg‐mediated immunosuppression. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are critical immunosuppressive cells that are frequently present in the tumor microenvironment of solid cancers and enable progression of tumors toward metastasis. The cells expand in response to tumor-associated antigens and are actively involved in bypassing immunotherapy with immune checkpoint inhibitors through integrating numerous environmental signals. A point here is that Tregs are clonally distinct in peripheral blood from tumor area. Currently, an effective and novel task in cancer immunotherapy is to selectively destabilize or deplete intra-tumoral Tregs in order to avoid systemic inflammatory events. Helios is a transcription factor expressed selectively by Tregs and promotes their stabilization, and Trps1 is a master regulator of intra-tumoral Tregs. Anti-CCR8 and the IL-2Rβγ agonist Bempegaldesleukin selectively target intra-tumoral Treg population, with the former approved to not elicit autoimmunity. Disarming Treg-related immunosuppression in tumors through diverting their reprogramming or promoting naïve T cell differentiation into cells with effector immune activating profile is another promising area of research in cancer immunotherapy. Blimp-1 inhibitors and glucocorticoid-induced TNFR-related protein agonists are example approaches that can be used for diverting Treg differentiation into Th1-like CD4+ T cells, thereby powering immunogenicity against cancer. Finally, selective target of intra-tumoral Tregs and their reprogramming into effector T cells is applicable using low-dose chemotherapy, and high-salt and high-tryptophan diet. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127lowFoxP3hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database. [ABSTRACT FROM AUTHOR]

Introduction: The transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIO+ CD8 T cells is limited and conflicting. Methods: In this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS+ CD8 T cells. Results: These T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOST-BEThigh CD8 T cells that displayed robust effector functions, the memory HELIOS+ T-BEThigh CD8 T cells produce lower amounts of IFN-g and TNF-a and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS+ cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS+ CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS+ CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying TC17 cells. These CD8 T cells express TH17/TC17-related genes encoding RORgt, RORa, PLZF, and CCL20. Discussion: Our findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood. [ABSTRACT FROM AUTHOR]

The Helios protein (encoded by the IKZF2 gene) is a member of the Ikaros transcription family and it has recently been proposed as a promising biomarker for systemic lupus erythematosus (SLE) disease progression in both mouse models and patients. Helios is beginning to be studied extensively for its influence on the T regulatory (Treg) compartment, both CD4+ Tregs and KIR+/Ly49+ CD8+ Tregs, with alterations to the number and function of these cells correlated to the autoimmune phenomenon. This review analyzes the most recent research on Helios expression in relation to the main immune cell populations and its role in SLE immune homeostasis, specifically focusing on the interaction between T cells and tolerogenic dendritic cells (tolDCs). This information could be potentially useful in the design of new therapies, with a particular focus on transfer therapies using immunosuppressive cells. Finally, we will discuss the possibility of using nanotechnology for magnetic targeting to overcome some of the obstacles related to these therapeutic approaches. [ABSTRACT FROM AUTHOR]

The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (Tregs), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of Tregs has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating Tregs correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing Treg-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit Treg-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of Treg-targeted immunotherapies for PDAC.

IntroductionThe transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIOS+ CD8 T cells is limited and conflicting. MethodsIn this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS+ CD8 T cells.ResultsThese T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOS- T-BEThigh CD8 T cells that displayed robust effector functions, the memory HELIOS+ T-BEThigh CD8 T cells produce lower amounts of IFN-γ and TNF-α and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS+ cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS+ CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS+ CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying TC17 cells. These CD8 T cells express TH17/TC17-related genes encoding RORgt, RORa, PLZF, and CCL20. DiscussionOur findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood.

Foxp3 is regarded as the major transcription factor for T regulatory (Treg) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4+ T conventional (Tconv) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a Treg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3+ Treg cells and can potentially serve as a marker of human Treg. Here, we confirm that Foxp3 expression is readily upregulated by Tconv upon TCR stimulation in vitro, while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hTconv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4+ T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon Tconv cell activation in vivo and that Foxp3 expression alone can be used to quantitate Treg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of Treg in humans. [ABSTRACT FROM AUTHOR]

Greek and Roman mythology, which is its follower in many ways, show similar characteristics from the beginning. Roman mythology, which enriches it by taking the basic elements of Greek mythology and mythology, also reflects similarities in the deification of natural forces. It is seen that the forces that have always existed between the two cultures related to the sky from the beginning also have an important place in religion and mythology. Among these, the changes between the sun, the moon and the stars, and the day and night in the sky were regarded as related and sanctified. In particular, it is observed that the changes of the Olympian god lineage related to the sky were effective on people in different periods. This basic way of thinking has been reflected in the works of many artists as a source of inspiration. [ABSTRACT FROM AUTHOR]

How does a novelist from Emesa represent through two characters, one Egyptian, the other Ethiopian, the emblematic sanctuary of Hellenism, the « navel » of the world ? Is this representation fictional or factual ? Is it built on intertextuality or does it correspond to something seen ? It is difficult to decide, especially since the dating of the work is uncertain. The description, in the form of ekphrasis, lays emphasis on religious ceremonies where the love of the protagonists is born. Delphi and Apollo play a central role in the plot, even if, outside Greece, their fame and their primacy are questioned, even ignored. Begun in the Delphic sanctuary, the love affair finds its consecration in Ethiopia, in Meroe, where Helios supplants Apollo.

Foxp3 is regarded as the major transcription factor for T regulatory (Treg) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4+ T conventional (Tconv) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a Treg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3+ Treg cells and can potentially serve as a marker of human Treg. Here, we confirm that Foxp3 expression is readily upregulated by Tconv upon TCR stimulation in vitro, while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hTconv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4+ T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon Tconv cell activation in vivo and that Foxp3 expression alone can be used to quantitate Treg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of Treg in humans.

The Emperor Julian and Heliodorus, the author of the Aethiopica, both claimed descent from Helios, the supreme god of Neoplatonic philosophy in Late Antiquity, to whom many of Julian's ancestors, most notably Constantius Chlorus, also professed devotion. In his Hymn to King Helios, the emperor claimed to have private proofs of this that he did not wish to make public, but which appear to have had nothing to do with the taboo on divulging the mysteries of Mithras. There is a wide range of suggestive evidence in the historical record, from the hostile post-mortem testimony of Gregory of Nazianzus, to the anonymous slurs of the people of Antioch, the adulation of his own uneducated troops, and the coinage issued during his reign, that points to some genetic abnormality in his physical nature, most probably a form of albinism (an unknown condition at the time), which the emperor took as proof of the supernatural guidance of Helios in his life. [ABSTRACT FROM AUTHOR]

Abstract There are different subsets of T regulatory cells (Tregs), orchestrating critical roles in the regulation of anti-tumor immunity in colorectal cancer (CRC). In this study, we report that a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer disease-free survival (DFS), while their higher frequencies in tumor-infiltrating CD4+ Tregs was associated with better DFS. We further investigated such associations with four Tregs/T cells expressing or lacking FoxP3 and Helios (FoxP3±Helios±). For the first time, we report that a high frequency of circulating CD4+FoxP3+Helios+ Tregs was associated with poorer DFS, while a high frequency of tumor-infiltrating CD4+FoxP3−Helios− T cells was associated with poorer DFS. In the four FoxP3±Helios± T cell subsets expressing any of the immune checkpoints (ICs) investigated, we found that a high frequency of CD4+FoxP3+Helios−PD-1+ Tregs in circulation was associated with worse DFS. We also found that high frequencies of FoxP3+Helios+CTLA-4+ Tregs, FoxP3+Helios−CTLA-4+ Tregs, and FoxP3−Helios+CTLA-4+ CD4+ T cells in circulation were associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3−Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Our data show that certain CD4+ Treg/T cell subsets could serve as independent predictive biomarkers in CRC patients. Identification of the exact subpopulations contributing to clinical outcomes is critical for prognoses and therapeutic targeting.

Abstract Background Human immunodeficiency virus type 1 (HIV-1) causes impairment of T and B cell responses, which begins during the acute phase of infection and is not completely restored by antiretroviral treatment. Regulatory T cell (Tregs) can improve overall disease outcome by controlling chronic inflammation but may also suppress beneficial HIV-1 specific immune responses. We aimed to analyze the profile of Tregs and their correlation with the status of T cells activation, the expression of IL-2 and IFNγ and the profile of HIV-1 specific antibodies response in Mozambican people living chronically with HIV-1 (PLWH-C). Results In PLWH-C, the proportion of total Tregs was positively correlated with the proportion of IL-2+CD4 T cells (r = 0.647; p = 0.032) and IL-2+IFNγ+CD8 T cells (r = 0.551; p = 0.014), while the proportions of Helios+Tregs correlated inversely with levels of IL-2+CD8 T cells (r = − 0.541; p = 0.017). Overall, PLWH-C, with (82%) or without virologic suppression (64%), were seronegative for at least HIV-1 p31, gp160 or p24, and the breadth of antibody responses was positively correlated with proportions of CD38+HLA-DR+CD8 T cells (r = 0.620; p = 0.012), viral load (r = 0.452; p = 0.040) and inversely with absolute CD4 T cells count (r = − 0.481; p = 0.027). Analysis of all individuals living HIV-1 showed that the breadth of HIV-1 antibody responses was inversely correlated with the proportion of Helios+Tregs (r = − 0.45; p = 0.02). Conclusion Among Mozambican people living with HIV-1, seronegativity to some HIV-1 proteins is common, particularly in virologically suppressed individuals. Furthermore, lower diversity of HIV-specific antibodies is correlated to lower immune activation, lower viral replication and higher CD4 counts, in PLWH-C. Elevation in the proportion of Helios+Tregs is related to a reduction of CD8 T expressing intracellular IL-2, in PLWH-C, but may contribute to impairment of B cell function.

During the IVth century A. D., Asclepius, both celestial and terrestrial, is seen to have taken on the powerful features of Christ for the pagan revival of Julian to stem the spread of Christianity. The fact remains that in the Helios-King and Against the Galilaeans, Asclepius does not play a prominent role. In the first book, the latter is only mentioned in two passages. Among the panegyrists of Julian, Libanios, Himerius and Eunapius, the emperor became the worthy successor of Asclepius present on earth and the son of Helios having for attribute the term σωτήρ, attribute which he himself had granted to the god of medicine. Yet convinced that he had been predestined by Helios and Asclepius and that he had been invested with a mission of a healer, Julian did not inspire to become the savior of souls described in the Gospel of John.

The existence of various T regulatory cell (Treg) subsets in colorectal cancer (CRC) could play a variety of functions in the regulation of anti-cancer immunity. We studied correlations between CD4+ Treg subsets with the expression of immunological checkpoints on CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 in CRC patients with early and advanced TNM staging. Strong positive correlations were found between frequencies of FoxP3+ Tregs and FoxP3+Helios+ Tregs with frequencies of various immune checkpoint-expressing CD4+ T cells in the tumor microenvironment (TME). However, there were strong negative correlations between frequencies of FoxP3−Helios− T cells and these immune checkpoint-expressing CD4+ T cells. Specifically, in the TME, we found that the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, FoxP3+Helios− Tregs, and FoxP3−Helios− T cells with CD4+LAG-3+ T cells and CD4+CTLA-4+ T cells were higher in patients with early stages, suggesting the potential of these highly immunosuppressive cells in inhibiting inflammatory responses in the TME. However, the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, and FoxP3−Helios− T cells with CD4+TIM-3+ T cells were higher in patients with advanced stages. This is the first study to explore correlations of Treg subpopulations with immune checkpoint-expressing CD4+ T cells in CRC based on clinicopathological features of CRC patients. The findings of our study provide a justification for focusing on these cells that possess highly immunosuppressive features. Understanding the correlations between different immune checkpoints and Treg subsets in CRC patients has the potential to enhance our understanding of core mechanisms of Treg-mediated immunosuppression in cancer. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells play an important role in immune tolerance and contribute to the prevention of autoimmune diseases, including rheumatoid arthritis (RA). The differentiation, function and stability of Treg cells is controlled by members of the Ikaros zinc finger transcription factor family. In this study, we aimed to reveal how the expression of Ikaros transcription factors is affected by disease activity in RA. Therefore, we analyzed the ex vivo expression of Ikaros, Helios, Aiolos and Eos in Treg cells, Th17 cells and Th1 cells from RA patients by flow cytometry. We found significantly reduced expression of Helios, Aiolos and Eos in Treg cells from RA patients as compared to healthy controls. Moreover, Helios and Aiolos levels correlated with disease activity, as assessed by DAS28-CRP. In addition, Ikaros, Helios and Aiolos were significantly downregulated in Th1 cells from RA patients, while no difference between healthy individuals and RA was observed in Th17 cells. In summary, Helios and Aiolos expression in Treg cells correlates with disease activity and the expression levels of Ikaros transcription factors are diminished in Treg cells from RA patients. This observation could explain the reduced stability of Treg cells in RA. [ABSTRACT FROM AUTHOR]

The tumour microenvironment reshapes the specific gene expression of regulatory T cells (Tregs). A better definition of Treg subpopulations in the non-small-cell lung cancer (NSCLC) milieu is expected to clarify the identity and functional mode of Tregs and lead to the identification of better therapeutic targets. A total of 53 peripheral blood (PB) samples from 36 NSCLC patients and 17 control subjects and 42 matched bronchoalveolar lavage fluid (BALF) samples from 31 NSCLC patients and 11 control subjects were obtained to examine the frequencies of Treg subgroups through flow cytometry. Fifteen PB samples from healthy individuals were collected to explore the differential functions of Treg subsets. The PB samples of 5 patients after chemotherapy were obtained to evaluate the effect of chemotherapy on Treg subsets. Serum CYFRA 21-1 levels in NSCLC patients were determined using an electrochemiluminescence immunoassay. The proportions of CD4+CD25+FoxP3+ Tregs in both PB and BALF were increased in NSCLC patients compared to controls. In BALF, the TIGIT+, Helios+, and TIGIT+Helios+ Treg subset levels were significantly elevated; the levels of the last two subsets were associated with NSCLC development, while the level of TIGIT-Helios- Tregs was decreased. The proportions of overall Tregs and TIGIT+, Helios+, and Helios+TIGIT+ Tregs were positively correlated with the serum CYFRA 21-1 levels in all patients. Functional differences were observed between Helios+TIGIT+ and Helios-TIGIT- Tregs. After chemotherapy, regardless of the reduction in serum CYFRA 21-1 levels, the proportions of Tregs and Treg subsets did not change. Elevated TIGIT+Helios+ and Helios+ Treg levels may play a role in NSCLC tumour progression, and targeting TIGIT and Helios on Tregs may be an effective treatment for NSCLC. • It is the first time to unveil the function of different Treg subsets in BALF of NSCLC patients. • In NSCLC patients, the changes in Treg subsets in BALF are different from those in PB. • Targeting upregulated TIGIT+ and Helios+ Tregs may be an effective treatment for NSCLC. [ABSTRACT FROM AUTHOR]

Today, an increase in the real potential of grain crops, including spring barley, is a necessary condition for elements of crop cultivation technologies. Therefore, given the limited resource potential of spring barley crops, their fastidiousness to the soil, considerable attention should be paid to the photosynthetic potential of plants and the standardised application of mineral fertilisers. The aim of the study was to improve the elements of the technology of growing promising varieties of spring barley by establishing the mineral nutrition effect on the photosynthetic activity of plants in the conditions of the Luhanska Oblast. This study provides examples of improving some technologies for growing promising varieties of spring barley and determines the optimal norms for applying mineral nutrition to ensure the high photosynthetic potential of these plants in the climatic conditions of the steppe zone of Ukraine. It was found that the use of ammonium nitrate had a positive effect on the leaf area, increasing it by 1-2.2 thousand m2/ha compared to the control for all varieties studied. The combined use of diammonium phosphate and ammonium nitrate contributed to an increase in the leaf area by 2-4. 4 thousand m2/ha compared to the control variant. Simultaneous application of ActiBION increased the total leaf area for all samples studied by 3.8-6.4 thousand m2/ha. The best indicators among the studied varieties were observed on the six-row variety Helios and the double-row variety Stalker. The six-row variety Vakula and the two-row variety Adapt showed slightly lower results. Further research implies the study of the influence of photosynthetic activity of promising varieties of spring barley on crop productivity in the steppe zone of Ukraine. The findings can be recommended for production as one of the elements in the technology of growing spring barley in the climatic conditions of the Luhanska Oblast.

• Closing relations for basic geometries used in HYDRA-IBRAE/LM code are presented. • Simulation results on HELIOS, TALL, TALL-3D facilities are performed. • Correct determination of local resistance coefficients is important for simulation. • Simulation results showed a good agreement with experimental data. [ABSTRACT FROM AUTHOR]

T-cell–mediated autoimmunity reflects an imbalance in this compartment that is not restored by tolerogenic immune cells, e.g., regulatory T cells or tolerogenic dendritic cells (tolDCs). Although studies into T-cell equilibrium have mainly focused on regulatory CD4+FoxP3+ T cells (CD4+ Tregs), recent findings on the lesser known CD8+ Tregs (CD44+CD122+Ly49+) have highlighted their non-redundant role in regulating lupus-like disease and their regulatory phenotype facilitated by the transcription factor Helios in mice and humans. However, there are still remaining questions about Helios regulation and dynamics in different autoimmune contexts. Here, we show the absence of CD8+ Tregs in two lupus-prone murine models: MRL/MPJ and MRL/lpr, in comparison with a non-prone mouse strain like C57BL/6. We observed that all MRL animals showed a dramatically reduced population of CD8+ Tregs and a greater Helios downregulation on diseased mice. Helios induction was detected preferentially on CD8+ T cells from OT-I mice co-cultured with tolDCs from C57BL/6 but not in MRL animals. Furthermore, the Helios profile was also altered in other relevant T-cell populations implicated in lupus, such as CD4+ Tregs, conventional CD4+, and double-negative T cells. Together, these findings could make Helios a versatile maker across the T-cell repertoire that is capable of differentiating lupus disease states. [ABSTRACT FROM AUTHOR]

There are different subsets of T regulatory cells (Tregs), orchestrating critical roles in the regulation of anti-tumor immunity in colorectal cancer (CRC). In this study, we report that a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer disease-free survival (DFS), while their higher frequencies in tumor-infiltrating CD4+ Tregs was associated with better DFS. We further investigated such associations with four Tregs/T cells expressing or lacking FoxP3 and Helios (FoxP3±Helios±). For the first time, we report that a high frequency of circulating CD4+FoxP3+Helios+ Tregs was associated with poorer DFS, while a high frequency of tumor-infiltrating CD4+FoxP3-Helios- T cells was associated with poorer DFS. In the four FoxP3±Helios± T cell subsets expressing any of the immune checkpoints (ICs) investigated, we found that a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. We also found that high frequencies of FoxP3+Helios+CTLA-4+ Tregs, FoxP3+Helios-CTLA-4+ Tregs, and FoxP3-Helios+CTLA-4+ CD4+ T cells in circulation were associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Our data show that certain CD4+ Treg/T cell subsets could serve as independent predictive biomarkers in CRC patients. Identification of the exact subpopulations contributing to clinical outcomes is critical for prognoses and therapeutic targeting. [ABSTRACT FROM AUTHOR]

Aging leads to alterations in the immune system that result in ineffective responsiveness against pathogens. Features of this process, collectively known as immunosenescence, accumulate in CD8+ T cells with age and have been ascribed to differentiation of these cells during the course of life. Here we aimed to identify novel markers in CD8+ T cells associated with immunosenescence. Furthermore, we assessed how these markers relate to the aging-related accumulation of highly differentiated CD27-CD28- cells. We found that co-expression of the transcription factor Helios and the aging-related marker TIGIT identifies CD8+ T cells that fail to proliferate and show impaired induction of activation markers CD69 and CD25 in response to stimulation in vitro. Despite this, in blood of older adults we found TIGIT+Helios+ T cells to become highly activated during an influenza-A virus infection, but these higher frequencies of activated TIGIT+Helios+ T cells associate with longer duration of coughing. Moreover, in healthy individuals, we found that TIGIT+Helios+ CD8+ T cells accumulate with age in the highly differentiated CD27-CD28- population. Interestingly, TIGIT+Helios+ CD8+ T cells also accumulate with age among the less differentiated CD27+CD28- T cells before their transit into the highly differentiated CD27-CD28- stage. This finding suggests that T cells with immunosenescent features become prominent at old age also within the earlier differentiation states of these cells. Our findings show that co-expression of TIGIT and Helios refines the definition of immunosenescent CD8+ T cells and challenge the current dogma of late differentiation stage as proxy for T-cell immunosenescence. [ABSTRACT FROM AUTHOR]

The neutronics software, HELIOS, was validated in 2015 for performing core reload design and safety analysis of the Advanced Test Reactor. However, when HELIOS was benchmarked against historic fission-wire measurements (i.e., zero-power full-core measurements), a statistically resolved calculation-to-measurement bias was discovered. The azimuthal power along each fuel plate computed by HELIOS has consistently shown to underpredict measurements made by fission wires in historic zero-power tests near the fuel element side plates. It was hypothesized during the HELIOS software validation work that this bias is attributable to local moderation in coolant vents in the side plates axially just above and below the fission wires on the fuel plate edges. This work used detailed MCNP and MC21 models of the side plate vents to test this hypothesis. By comparing the average azimuthal biases between HELIOS and two-dimensional and three-dimensional (3-D) MCNP models and a 3-D MC21 model, it was found that the HELIOS azimuthal bias is not due to the measurement. [ABSTRACT FROM AUTHOR]

T regulatory cells (Tregs) play different roles in the regulation of anti-tumor immunity in colorectal cancer (CRC), depending on the presence of different Treg subsets. We investigated correlations between different CD4+ Treg/T cell subsets in CRC patients with immune checkpoint-expressing CD4+ T cells. Positive correlations were observed between levels of different immune checkpoint-expressing CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 with FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios− Tregs in the tumor microenvironment (TME). However, negative correlations were observed between levels of these immune checkpoint-expressing CD4+ T with FoxP3−Helios− T cells in the TME. These correlations in the TME highlight the role of cancer cells in the upregulation of IC-expressing Tregs. Additionally, positive correlations were observed between levels of FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios− Tregs and levels of CD4+CTLA-4+ T cells and CD4+PD-1+ T cells in peripheral blood mononuclear cells (PBMCs) and normal tissue-infiltrating lymphocytes (NILs). These observations suggest that CTLA-4 and PD-1 expressions on CD4+ T cell subsets are not induced only by the TME. This is the first study to investigate the correlations of different FoxP3+/−Helios+/− T cell subsets with immune checkpoint-expressing CD4+ T cells in CRC patients. Our data demonstrated strong correlations between FoxP3+/Helios+/− Tregs but not FoxP3−Helios+/− non-Tregs and multiple immune checkpoints, especially in the TME, providing a rationale for targeting these cells with highly immunosuppressive characteristics. Understanding the correlations between different immune checkpoints and Treg/T cell subsets in cancer patients could improve our knowledge of the underlying mechanisms of Treg-mediated immunosuppression in cancer. [ABSTRACT FROM AUTHOR]

T-cell–mediated autoimmunity reflects an imbalance in this compartment that is not restored by tolerogenic immune cells, e.g., regulatory T cells or tolerogenic dendritic cells (tolDCs). Although studies into T-cell equilibrium have mainly focused on regulatory CD4+FoxP3+ T cells (CD4+ Tregs), recent findings on the lesser known CD8+ Tregs (CD44+CD122+Ly49+) have highlighted their non-redundant role in regulating lupus-like disease and their regulatory phenotype facilitated by the transcription factor Helios in mice and humans. However, there are still remaining questions about Helios regulation and dynamics in different autoimmune contexts. Here, we show the absence of CD8+ Tregs in two lupus-prone murine models: MRL/MPJ and MRL/lpr, in comparison with a non-prone mouse strain like C57BL/6. We observed that all MRL animals showed a dramatically reduced population of CD8+ Tregs and a greater Helios downregulation on diseased mice. Helios induction was detected preferentially on CD8+ T cells from OT-I mice co-cultured with tolDCs from C57BL/6 but not in MRL animals. Furthermore, the Helios profile was also altered in other relevant T-cell populations implicated in lupus, such as CD4+ Tregs, conventional CD4+, and double-negative T cells. Together, these findings could make Helios a versatile maker across the T-cell repertoire that is capable of differentiating lupus disease states.

Aging leads to alterations in the immune system that result in ineffective responsiveness against pathogens. Features of this process, collectively known as immunosenescence, accumulate in CD8+ T cells with age and have been ascribed to differentiation of these cells during the course of life. Here we aimed to identify novel markers in CD8+ T cells associated with immunosenescence. Furthermore, we assessed how these markers relate to the aging-related accumulation of highly differentiated CD27-CD28- cells. We found that co-expression of the transcription factor Helios and the aging-related marker TIGIT identifies CD8+ T cells that fail to proliferate and show impaired induction of activation markers CD69 and CD25 in response to stimulation in vitro. Despite this, in blood of older adults we found TIGIT+Helios+ T cells to become highly activated during an influenza-A virus infection, but these higher frequencies of activated TIGIT+Helios+ T cells associate with longer duration of coughing. Moreover, in healthy individuals, we found that TIGIT+Helios+ CD8+ T cells accumulate with age in the highly differentiated CD27-CD28- population. Interestingly, TIGIT+Helios+ CD8+ T cells also accumulate with age among the less differentiated CD27+CD28- T cells before their transit into the highly differentiated CD27-CD28- stage. This finding suggests that T cells with immunosenescent features become prominent at old age also within the earlier differentiation states of these cells. Our findings show that co-expression of TIGIT and Helios refines the definition of immunosenescent CD8+ T cells and challenge the current dogma of late differentiation stage as proxy for T-cell immunosenescence.

One of many major issues that plagues Internet voting is the potential for a distributed denial of service attack on the voting servers. These denial of service attacks are harmful because they block voting during the downtime. In addition, most current online voting protocols are centralized with only one voting server, making such an attack likely to disenfranchise some voters. The question is how to combat these attacks. One solution is to distribute the servers in a parallel manner, so in case one server goes down, the others can still provide service to voters. Whereas many online voting systems assume the constant availability of the voting infrastructure, we focus on the event that a server becomes unavailable. We extend a previously established online voting protocol, Helios, by adding multiserver capability. These servers communicate using the Paxos protocol, an algorithm for fault tolerant distributed environments. An analysis of this solution concludes that a multi-server Helios network communicating through the Paxos protocol promises safety and robustness.

Background: Human immunodeficiency virus type 1 (HIV-1) causes impairment of T and B cell responses, which begins during the acute phase of infection and is not completely restored by antiretroviral treatment. Regulatory T cell (Tregs) can improve overall disease outcome by controlling chronic inflammation but may also suppress beneficial HIV-1 specific immune responses. We aimed to analyze the profile of Tregs and their correlation with the status of T cells activation, the expression of IL-2 and IFNγ and the profile of HIV-1 specific antibodies response in Mozambican people living chronically with HIV-1 (PLWH-C). Results: In PLWH-C, the proportion of total Tregs was positively correlated with the proportion of IL-2+CD4 T cells (r = 0.647; p = 0.032) and IL-2+IFNγ+CD8 T cells (r = 0.551; p = 0.014), while the proportions of Helios+Tregs correlated inversely with levels of IL-2+CD8 T cells (r = − 0.541; p = 0.017). Overall, PLWH-C, with (82%) or without virologic suppression (64%), were seronegative for at least HIV-1 p31, gp160 or p24, and the breadth of antibody responses was positively correlated with proportions of CD38+HLA-DR+CD8 T cells (r = 0.620; p = 0.012), viral load (r = 0.452; p = 0.040) and inversely with absolute CD4 T cells count (r = − 0.481; p = 0.027). Analysis of all individuals living HIV-1 showed that the breadth of HIV-1 antibody responses was inversely correlated with the proportion of Helios+Tregs (r = − 0.45; p = 0.02). Conclusion: Among Mozambican people living with HIV-1, seronegativity to some HIV-1 proteins is common, particularly in virologically suppressed individuals. Furthermore, lower diversity of HIV-specific antibodies is correlated to lower immune activation, lower viral replication and higher CD4 counts, in PLWH-C. Elevation in the proportion of Helios+Tregs is related to a reduction of CD8 T expressing intracellular IL-2, in PLWH-C, but may contribute to impairment of B cell function. [ABSTRACT FROM AUTHOR]

Treg therapy holds promise as a potentially curative approach to establish immune tolerance in transplantation and autoimmune disease. An outstanding question is whether therapeutic Tregs have the potential to transdifferentiate into effector T‐cells and, thus, exacerbate rather than suppress immune responses. In mice, the transcription factor Helios is thought to promote Treg lineage stability in a range of inflammatory contexts. In humans, the role of Helios in Tregs is less clear, in part, due to the inability to enrich and study subsets of Helios‐positive versus Helios‐negative Tregs. Using an in vitro expansion system, we found that loss of high Helios expression and emergence of an intermediate Helios (Heliosmid)‐expressing population correlated with Treg destabilization. We used CRISPR/Cas9 to genetically ablate Helios expression in human naive or memory Tregs and found that Helios‐KO and unedited Tregs were equivalent in their suppressive function and stability in inflammation. Thus, high Helios expression is a marker, but not a driver, of human Treg stability in vitro. These data highlight the importance of monitoring Helios expression in therapeutic Treg manufacturing and provide new insight into the biological function of this transcription factor in human T‐cells. [ABSTRACT FROM AUTHOR]

Katarzyna Sznurkowska,1 Justyna Luty,2 Ewa Bryl,2 Jacek M Witkowski,3 Blanka Hermann-Okoniewska,4 Piotr Landowski,1 Marta Kosek,1 Agnieszka Szlagatys-Sidorkiewicz1 1Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland; 2Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland; 3Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland; 4Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, PolandCorrespondence: Katarzyna SznurkowskaDepartment of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk, Nowe Ogrody 1-6, Gdańsk 80-803, PolandTel +58 663625861Fax +48 58 764 04 40Email k.sznurkowska@gumed.edu.plBackground/Aims: The proportions of intestinal and peripheral regulatory T cells (Tregs) in pediatric inflammatory bowel disease (IBD) were poorly investigated, as well as different subsets of these cells. Helios and Neuropilin-1 were proposed as markers differentiating between thymic and peripheral Tregs. Therefore, the aim of current work was to investigate the proportions of Tregs and expression of Helios and Neuropilin-1 in Tregs in peripheral blood and intestinal mucosa of children with inflammatory bowel disease.Materials and methods: Fifteen patients newly diagnosed with inflammatory bowel disease: ulcerative colitis (n=7) and Crohn’s disease (n=8) were included in the study. Nine children who presented with no abnormalities in colonoscopy served as a control group. Quantification of regulatory T cells of the CD4+CD25highFOXP3+ phenotype, as well as Helios+ and Neuropilin-1+ in peripheral blood and bowel mucosa was based on multicolor flow cytometry.Results: The rates of circulating and intestinal Tregs were significantly higher in the studied group than in the control group. The rate of intestinal T regulatory lymphocytes was significantly higher than circulating Tregs in patients with IBD, but not in the control group. The median proportion of circulating FOXP3+Helios+ cells amounted to 24.83% in IBD patients and 15.93% in the controls. The median proportion of circulating FOXP3+Nrp-1+ cells was 34.23% in IBD and 21.01% in the control group. No statistically significant differences were noted for the circulating FOXP3+Helios+ cells and FOXP3+Nrp-1+ cells between the studied and the control group.Conclusion: The rates of circulating and intestinal T regulatory cells are increased in naïve pediatric patients with IBD. The rate of Tregs is higher in intestinal mucosa than in peripheral blood in patients with IBD. Flow cytometry is a valuable method assessing the composition of infiltrates in inflamed tissue. Helios and Neuropilin-1 likely cannot serve as markers to differentiate between natural and adaptive Tregs.Keywords: T regulatory cells, circulating Tregs, intestinal Tregs, Helios, Neuropilin-1, IBD, inflammatory bowel disease, children

Changes in the climate conditions of the steppe zone of Ukraine, frequent placement of spring barley after the sunflower predecessor and many other reasons, cause the necessity to improve the system of basic tillage for spring barley in the direction of its minimization taking into account the technologies of growing crops. The issue of basic tillage for spring barley after sunflower, which is fairly common predecessor today, has not been studied yet. In this case, based on the complex experimental studies the effect of different types of basic tillage and their impact on the yield of spring barley in the Luhansk region has been studied. The aim of the research was to determine the best methods of basic tillage for spring barley with general background post-harvest residues of all field crops, application of mineral fertilizers and the influence of these factors on the yield of spring barley in Luhansk region. The following types of spring barley were sown during the experiment – Adapt, Stalker, Helios, Vakula. As a result of the conducted researches the best indicators were obtained at non-shelf tillage with the usage of modern aggregates and with joint application of Ammonium nitrate and Diammonium phosphate, at all biometric indicators of the studied culture. Since such tillage has not only loosened it well, but also ensured better accumulation and retention of moisture, which further affected the yield of spring barley plants in the area of insufficient moisture. Such strains as Stalker and Helios had the highest rates with the combined use of Ammonium Nitrate and Diammonium Phosphate in shelfless tillage at the level of 47,5 c/ha and 58,8 c/ha accordingly. Shelf tillage gave less results with such a fertilizer system. The lowest indicators were in the variant of disking in all studied samples

Four new epigraphic finds from the Mihalıççık District encourage us to reconsider the role that villages and associations played among those who made dedications to the divine pair Hosios kai Dikaios. According to the distribution of the evidence, the cult originated and remained concentrated on the north-east of Phrygia Epiktetos, but spread all over western Asia Minor and even beyond. After surveying the documents known previously especially thanks to M. Ricl (1991; 1992a; 2008) and classifying elements of the dedication formula, slightly improved readings and interpretations are offered for the five inscriptions (re-) published by H. Güney (2018a): twice, the imperial slave Chryseros is attested as fulfilling vows to the gods together with his fellow villagers (nos. 2, 3); three other instances, however, involve associations: perhaps a Β̣[ακχῖ]ον, the obscure Παρ[---]διᾶται, and the Κταηνοῖ, further specified as the Βαχῖον τὸ περὶ Τύραννον (nos. 4, 5, 1). The combined evidence catalogued by Ricl and Güney adds up to some 185 dedications to Hosios kai Dikaios, including, in their views, 17 cases that originated from village communities, compared to only two by associations. The present study argues instead that the ascertained evidence for villages is only six and that this is on par with the documentation of associations. All six of the latter can be identified as Dionysiac thiasoi.

We propose a definition of ballot secrecy as an indistinguishability game in the computational model of cryptography. Our definition improves upon earlier definitions to ensure ballot secrecy is preserved in the presence of an adversary that controls ballot collection. We also propose a definition of ballot independence as an adaptation of an indistinguishability game for asymmetric encryption. We prove relations between our definitions. In particular, we prove ballot independence is sufficient for ballot secrecy in voting systems with zero-knowledge tallying proofs. Moreover, we prove that building systems from non-malleable asymmetric encryption schemes suffices for ballot secrecy, thereby eliminating the expense of ballot-secrecy proofs for a class of encryption-based voting systems. We demonstrate applicability of our results by analysing the Helios voting system and its mixnet variant. Our analysis reveals that Helios does not satisfy ballot secrecy in the presence of an adversary that controls ballot collection. The vulnerability cannot be detected by earlier definitions of ballot secrecy, because they do not consider such adversaries. We adopt non-malleable ballots as a fix and prove that the fixed system satisfies ballot secrecy. [ABSTRACT FROM AUTHOR]

Foxp3+ regulatory T cells (Tregs) represent a special lineage of CD4+ T cells. Analysis of Treg response during primary and secondary influenza virus infection clearly demonstrates a robust accumulation of Tregs into the infected lungs and the existence of a population of long‐lived antigen‐specific memory Tregs in the same tissues after resolution of the infection. However, it remains unknown whether these Tregs co‐express Helios, a member of the Ikaros transcription factor family. In this study, Foxp3+Helios+ and Foxp3+Helios‐ Tregs in the lungs, mLNs and spleens of influenza virus‐infected and uninfected control mice were tracked. The data show that while there is a co‐existence of Foxp3+Helios+ and Foxp3+Helios‐ Tregs in the tissues, the accumulated Tregs in the lungs and lung‐draining mediastinal lymph nodes (mLNs) of the infected mice are highly enriched for Foxp3+Helios+ cells. It was further demonstrated that, after the clearance of primary infection, Foxp3+Helios+ cells have the ability to persist in the tissues over their Helios‐ counterparts. More importantly, Foxp3+Helios+ Tregs accumulated in an accelerated kinetics during recall response to reinfection. In vitro analysis of Treg suppressive function revealed that Foxp3+Helios+ Tregs are more capable of suppressing influenza virus‐specific CD8+ T cell activation, cytokine production and proliferation. Together, the data provide new insights into Treg responses during primary and secondary influenza virus infection and suggest that Foxp3+Helios+ Tregs predominantly drive the Treg responses. [ABSTRACT FROM AUTHOR]

Background: Regulatory CD4+ T cells (Tregs) exhibit functional alterations in patients with multiple sclerosis (MS). Transforming growth factor (TGF)-β is a key regulator of Treg development and function. Objective: The objective of this study is to determine whether the expression of functionally relevant TGF-β-regulated molecules is altered in Tregs from patients with MS. Methods: Expression of nine Treg markers was analyzed by multi-color flow cytometry in CD4+ T cells and Treg subpopulations of 31 untreated MS patients and age- and sex-matched healthy donors (HDs). Correlations between Treg marker expression and clinical variables were sought. Results: Expression of the transcription factor Helios, which defines thymic-derived Tregs, was decreased in this Treg subpopulation. The frequency of peripherally generated Tregs was increased in patients with MS, particularly in patients with progressive MS. Low frequencies of thymic-derived Tregs were associated with magnetic resonance imaging (MRI) lesion-burden and a high relapse rate. Four surface markers associated with TGF-β signaling (ABCA1, BTLA, DNAM-1, and GARP) were differentially expressed on Tregs from patients with MS and HDs. Expression levels of CD73, CD103, ABCA1, and PAR2 showed strong correlations with disease severity. Conclusion: We have identified novel markers abnormally expressed on Tregs from patients with MS that could detect patients with severe disease. [ABSTRACT FROM AUTHOR]

It appears that Apollo's identification with the physical sun is predominantly understood in modern scholarship as a philosophical interpretation of a traditional religious belief. More precisely, it is often understood as an application of physical allegoresis on the tenets of traditional religion and thus attributed to a later stratum of Greek thought. A new evaluation of ancient evidence presented here reveals that the Apollo-sun identification was present in Greek ethnographic context from the earliest period and cannot be reduced to a philosophical reinterpretation of traditional myth and religion. At the same time, the authors interested in the interpretation of traditional religion in terms of natural philosophy were especially prone to use the Apollo-sun identification in their works, since it was able to provide substantial support for their hermeneutic approach. [ABSTRACT FROM AUTHOR]

In Laws, 945 b-948 b, Plato introduces the figure of eúthӯnoi or "inspectors" relating them directly to the common cult of Helios and Apollo. In doing so, I argue Plato has intended to connect both Republic and Laws through the Idea of Good. So the divine couple Helios-Apollo would be an author's wink to his immediate readers, the Academy members, so that they can perceive there a veiled allusion to the most important object of learning: Good (Helios or the Sun), to whom Plato, according to some indirect testimonies, would have identified with "the One" (Apollo). Thus, the old writer of the Laws would keep on showing a genuine interest in Philosophy as an inescapable background in legal matters and the essential basis for his legislation. [ABSTRACT FROM AUTHOR]

Abstract Background Helios is important for functional and phenotype stability of regulatory T cells (Tregs). However, the role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+ Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios. Method Multicolor flow cytometry was performed to analyze Helios+ Tregs in peripheral blood from MG patients and healthy donors (HDs). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of soluble GITRL/GITR in plasma. Tregs were isolated via magnetic separation and treated with recombinant GITRL and GITR-Fc. Membrane GITRL on Tregs and expression of Helios and other markers (FOXP3, CD25, CD39, CTLA-4, PD-L1 and IL-10) involved in immunosuppressive activity were determined by flow cytometry. Result Both Helios+ Tregs and soluble GITR were decreased in generalized MG (GMG) patients (n = 14), compared with HDs (n = 14) and ocular MG (OMG) patients (n = 16). Helios+ Tregs possessed greater immunosuppressive capacity compared to Helios− Tregs. Further analysis indicates soluble GITR was negatively correlated with quantitative MG score and promoted Helios expression and enhanced function of Tregs independently of membrane GITRL. Conclusion This work demonstrates abnormal changes in Helios+ Tregs and soluble GITR in MG, as well as direct regulation of Helios by GITR in the context of Tregs. This work provides new insight into the role of GITR in the regulatory pathway of Helios and pathogenesis of MG.

The existence of various T regulatory cell (Treg) subsets in colorectal cancer (CRC) could play a variety of functions in the regulation of anti-cancer immunity. We studied correlations between CD4+ Treg subsets with the expression of immunological checkpoints on CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 in CRC patients with early and advanced TNM staging. Strong positive correlations were found between frequencies of FoxP3+ Tregs and FoxP3+Helios+ Tregs with frequencies of various immune checkpoint-expressing CD4+ T cells in the tumor microenvironment (TME). However, there were strong negative correlations between frequencies of FoxP3−Helios− T cells and these immune checkpoint-expressing CD4+ T cells. Specifically, in the TME, we found that the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, FoxP3+Helios− Tregs, and FoxP3−Helios− T cells with CD4+LAG-3+ T cells and CD4+CTLA-4+ T cells were higher in patients with early stages, suggesting the potential of these highly immunosuppressive cells in inhibiting inflammatory responses in the TME. However, the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, and FoxP3−Helios− T cells with CD4+TIM-3+ T cells were higher in patients with advanced stages. This is the first study to explore correlations of Treg subpopulations with immune checkpoint-expressing CD4+ T cells in CRC based on clinicopathological features of CRC patients. The findings of our study provide a justification for focusing on these cells that possess highly immunosuppressive features. Understanding the correlations between different immune checkpoints and Treg subsets in CRC patients has the potential to enhance our understanding of core mechanisms of Treg-mediated immunosuppression in cancer.

Regulatory T (Treg) cells play an important role in immune tolerance and contribute to the prevention of autoimmune diseases, including rheumatoid arthritis (RA). The differentiation, function and stability of Treg cells is controlled by members of the Ikaros zinc finger transcription factor family. In this study, we aimed to reveal how the expression of Ikaros transcription factors is affected by disease activity in RA. Therefore, we analyzed the ex vivo expression of Ikaros, Helios, Aiolos and Eos in Treg cells, Th17 cells and Th1 cells from RA patients by flow cytometry. We found significantly reduced expression of Helios, Aiolos and Eos in Treg cells from RA patients as compared to healthy controls. Moreover, Helios and Aiolos levels correlated with disease activity, as assessed by DAS28-CRP. In addition, Ikaros, Helios and Aiolos were significantly downregulated in Th1 cells from RA patients, while no difference between healthy individuals and RA was observed in Th17 cells. In summary, Helios and Aiolos expression in Treg cells correlates with disease activity and the expression levels of Ikaros transcription factors are diminished in Treg cells from RA patients. This observation could explain the reduced stability of Treg cells in RA.