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This paper investigates a low leakage power 8 T (LP8T) SRAM cell with high read and write stability. The proposed LP8T (PLP8T) SRAM cell has separate write and read bit lines. As an outcome, the read disturbance is removed. Furthermore, the utilization of a schmitt-trigger (ST) inverter enhances the read stability. Moreover, the write assist technique can enhance the writing ability. When compared to conventional-6 T SRAM, the PLP8T SRAM cell improves HSNM, RSNM, and WSNM by 1.4× 2.3 × and 1.3× respectively. The PLP8T SRAM's read and write access times are lowered by 53.24 and 42.18%, respectively. The PLP8T SRAM has a 50% lower read and write power than conventional-6 T SRAM. In addition, there will be a sufficient improvement when compared to chang10T, HSWA9T, SEDFC8TT, and ST11T SRAM cells. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with hyperactive innate and adaptive immune systems that cause dermatological, cardiovascular, renal, and neuropsychiatric problems in patients. SLE's multifactorial nature and complex pathogenesis present significant challenges in its clinical classification. In addition, unpredictable treatment responses in patients emphasize the need for highly specific and sensitive SLE biomarkers that can assist in understanding the exact pathogenesis and, thereby, lead to the identification of novel therapeutic targets. Recent studies on microRNA (miRNA), a non-coding region involved in the regulation of gene expression, indicate its importance in the development of the immune system and thus in the pathogenesis of various autoimmune disorders such as SLE. miRNAs are fascinating biomarker prospects for SLE categorization and disease monitoring owing to their small size and high stability. In this paper, we have discussed the involvement of a wide range of miRNAs in the regulation of SLE inflammation and how their modulation can be a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Soft errors are the primary concern in space and terrestrial integrated circuit applications. When a charged particle from space collides with a scaled memory circuit, a transient pulse is generated across the sensitive storage node, causing a bit flip throughout the storage nodes. This bit flip is stated as a soft error, which affects the semiconductor memory architecture's stability and reliability. This paper presents a 10 T SRAM (STS-10 T) cell that mitigates soft error challenges even at space temperature. To demonstrate the relative performance of the STS-10 T, existing radiation-hardened memory cells, such as the Quatro-10 T, PS10T, NS-10 T, RHBD-10 T, 10 T-SRAM, RHMD-10 T, QUCCE-10 T, and SIS-10 T, were evaluated. The read stability of the proposed STS-10 T memory cell is 2.6x/ 3x/ 1.5x/ 1.4x/ 1.25x/ 1.6x/ 2.03 × greater than that of the existing Quatro-10 T/ NS-10 T/ PS-10 T/ RHBD-10 T/ RHMD-10 T/ QUCCE-10 T/ SIS-10 T memory cells, respectively. Moreover, 1.48x/ 1.17x/ 1.18x/ 1.4x/ 1.01x/ 1.27x/ 1.45x/ 1.43 × greater write ability than Quatro-10 T/ NS-10 T/ PS-10 T/ RHBD-10 T/ 10 T-SRAM/ RHMD-10 T/ QUCCE-10 T/ SIS10T. In addition, when the supply voltage is at 1 V, the read and write access time, hold power, and critical charge is also improved. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this review is to discuss the significance of IL-17 in SLE and the potential of IL-17-targeted therapy. Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs and tissues throughout the body. It is characterized by overactive B and T cells and loss of immune tolerance to autoantigens. Interleukin-17 (IL-17) is a cytokine that promotes inflammation and has been implicated in the pathogenesis of several autoimmune diseases as well as inflammatory diseases. In in vitro cellular experiments in lupus susceptible mice or SLE patients, there is substantial evidence that IL-17 is a highly promising therapeutic target. Methods: We searched papers from PubMed database using the search terms, such as interleukin-17, systemic lupus erythematosus, treatment targets, T cells, lupus nephritis, and other relevant terms. Results: We discuss in this paper the molecular mechanisms of IL-17 expression, Th17 cell proliferation, and the relationship between IL-17 and Th17. The significance of IL-17 in SLE and the potential of IL-17-targeted therapy are further discussed in detail. Conclusion: IL-17 has a very high potential for the development as a star target in SLE. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising modality for anti-cancer treatment. Its efficacy is quite remarkable in hematological tumors. Owing to their excellent clinical results, gene- modified cell therapies, including T cells, natural killer (NK) cells, and macrophages, are being actively studied in both academia and industry. However, the protocol to make CAR immune cells is too complicated, so it is still unclear how to efficiently produce the potent CAR immune cells. To manufacture effective CAR immune cells, we need to be aware of not only how to obtain highly infective viral particles, but also how to transduce CAR genes into immune cells. In this paper, we provide detailed information on spinoculation, which is one of the best known protocols to transduce genes into immune cells, in a methodological view. Our data indicate that gene transduction is significantly dependent on speed and duration of centrifugation, concentration and number of viral particles, the concentration of polybrene, and number of infected immune cells. In addition, we investigated on the optimal polyethylene glycol (PEG) solution to concentrate the viral supernatant and the optimized DNA ratios transfected into 293T cells to produce high titer of viral particles. This study provides useful information for practical production of the gene-modified immune cells using viral vectors. [ABSTRACT FROM AUTHOR]

This paper proposes a modified Schmitt-trigger (ST)-based single-ended 11 T (MST11T) SRAM cell. The proposed cell is best suited to ultra-low voltage applications. Two ST-based cross-coupled inverters comprise the storage cell of the proposed MST11T bit cell. In comparison with conventional inverters, ST-based inverters have sharp voltage transfer characteristics. As a result, the proposed bit cell's stability performance increases. The proposed SRAM cell's leakage power consumption is reduced because of the use of stacked N-type transistors. For the read operation of the proposed bit cell, the read decoupled technique is used. As a result, the read static noise margin (RSNM) has greatly improved. The proposed bit cell's write static noise margin (WSNM) is increased by adopting feedback-cutting methodology. The performance of the proposed bit cell is compared with that of conventional 6 T, conventional 8 T, Schmitt-trigger 10 T (known as ST2), modified PMOS-PMOS-NMOS-based cell core 10 T (MPPN10T), feedback-cutting 11 T (FC11T), Schmitt-trigger 11 T (ST11), and Schmitt-trigger 12 T (ST12T) cells. According to the simulation results, the proposed MST11T SRAM cell has RSNM of 2.42, 1.18, 1.71, 1.30, and 1.80 times higher when compared to 6 T, FC11T, ST2, MPPN10T, and ST12T, respectively. The WSNM of the proposed bit cell has been increased by 1.56, 2.44, 1.28, 1.71, 1.35, 1.52, and 1.02 times, respectively, over 6 T, 8 T, ST2, MPPN10T, FC11T, ST11T, and ST12T. Furthermore, the suggested cell has a read delay that is 1.32, 1.79, and 1.53 times lower than ST11T, FC11T, and ST12T, respectively. The proposed bit cell has a write delay that is 1.14 and 1.63 times lower than FC11T and ST11T, respectively. The proposed MST11T bit-cell consumes 3.74, 1.56, 4.59, 5.38, and 4.83 times less leakage power than the 8 T, ST2, MPPN10T, FC11T, and ST12 bit-cells, respectively. When compared to 8 T/ST2/MPPN10T/ST12T at 0.2 V supply voltage, the enhanced facts incur a 4.87/3.79/3.78/1.97 penalty in write delay. The figure of merit (FOM) is derived as a result of this extensive access to the revolutionary SRAM cell performance, i.e., offering greater values at a 0.2 V DC supply voltage. In addition, the paper examines the impact of manufacturing process and temperature changes on MST11T cell enactment, as well as the circuit robustness using HSPICE with 7-nm FinFET technology. [ABSTRACT FROM AUTHOR]

Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency characterized by absence of functional T lymphocytes. It is a paediatric emergency, which is life-threatening when recognized too late. The clinical presentation varies from the classical form of SCID through atypical SCID to Omenn syndrome. In addition, there is a considerable immunological variation, which can hamper the diagnosis. In this educational review, we describe the immunopathological background, clinical presentations and diagnostic process of SCID, as well as the therapeutic possibilities. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects. [ABSTRACT FROM AUTHOR]

COVID-19 together with variants have caused an unprecedented amount of mental and economic turmoil with ever increasing fatality and no proven therapies in sight. The healthcare industry is racing to find a cure with multitude of clinical trials underway to access the efficacy of repurposed antivirals, however the much needed insights into the dynamics of pathogenesis of SARS-CoV-2 and corresponding pharmacology of antivirals are lacking. This paper introduces systematic pathological model learning of COVID-19 dynamics followed by derivative free optimization based multi objective drug rescheduling. The pathological model learnt from clinical data of severe COVID-19 patients treated with remdesivir could additionally predict immune T cells response and resulted in a dramatic reduction in remdesivir dose and schedule leading to lower toxicities, however maintaining a high virological efficacy. [ABSTRACT FROM AUTHOR]

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years. [ABSTRACT FROM AUTHOR]

A mathematical model for the quantitative analysis of the interaction between cancer cells and cell-mediated immune system with two discrete-time delays, considering the role of antibodies, is studied in this paper. The model is analyzed both analytically and numerically to understand the dynamics of interaction delay and proliferation enhancement effect delay in the eradication of cancer. Hopf bifurcation occurs when one-time delay crosses the critical value in the absence of the other. It is also observed that as we increase any of the delays, it will increase the cancer burden. The analysis shows that a cancer-free state cannot be obtained solely by the killing rate of cytotoxic T-lymphocytes, but humoral response in combination with cell-mediated immune responses plays an important role to eradicate cancer. [ABSTRACT FROM AUTHOR]

The cellular adaptive immune response to influenza has been analyzed through several recent mathematical models. In particular, Zarnitsyna et al. (Front Immunol 7:1–9, 2016) show how central memory CD8+ T cells reach a plateau after repeated infections, and analyze their role in the immune response to further challenges. In this paper, we further investigate the theoretical features of that model by extracting from the infection dynamics a discrete map that describes the build-up of memory cells. Furthermore, we show how the model by Zarnitsyna et al. (Front Immunol 7:1–9, 2016) can be viewed as a fast-scale approximation of a model allowing for recruitment of target epithelial cells. Finally, we analyze which components of the model are essential to understand the progressive build-up of immune memory. This is performed through the analysis of simplified versions of the model that include some components only of immune response. The analysis performed may also provide a theoretical framework for understanding the conditions under which two-dose vaccination strategies can be helpful. [ABSTRACT FROM AUTHOR]

Treatment failure or relapse due to tumor escape caused by reduction in target antigen expression has become a challenge in the field of CART therapy. Target antigen density is closely related to the effectiveness of CART therapy, and reduced or lost target antigen expression limits the efficacy of CART therapy and hinders the durability of CAR T cells. Epigenetic drugs can regulate histones for molecular modifications to regulate the transcriptional, translational and post-translational modification processes of target agents, and we demonstrated for the first time the role in regulating CD22 expression and its effect on the efficacy of CD22 CART. In this paper, we found that Chidamide promoted the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhanced the function of CD22 CART. As for mechanisms, we demonstrated that Chidamide did not affect CD22 mRNA transcription, but significantly increased the expression of total CD22 protein, indicating that Chidamide may upregulate cell surface CD22 expression by affecting the distribution of CD22 protein. In summary, our results suggest that Chidamide may enhance the efficacy of CD22 CART by inhibiting histone deacetylases to regulate post-transcriptional modifications that affect protein distribution to increase the expression of CD22 on the cell surface. [ABSTRACT FROM AUTHOR]

Biologic agents (BA) are able to induce an adaptive immune response in a proportion of exposed patients with the onset of anti-drug antibodies (ADA), which are usually responsible for hypersensitivity reactions (HR). Drug desensitization (DD) for BA allows transient clinical tolerance to the drug in reactive patients. The paper aimed to analyse the modification of drug-specific immune responses along DD in two patients with previous ADA-mediated HR (anaphylaxis) to rituximab and tocilizumab. The in vivo and in vitro assays of humoral and cellular response to drugs were carried out in a longitudinal manner throughout the DD cycles. We observed a progressive decrease of the pre-procedure ADA titer with negativization during the DD cycles in both patients. The monitoring of the drug-specific effector cell response showed the decrease in the BA-induced proliferation, while T cell response to unrelated antigens resulted unmodified along the DD cycles. Lastly, the increase of circulating drug-specific Treg cells mainly producing IL-35 were shown during the DD treatment. This study provides evidence that DD treatment to two BA inhibits humoral and cellular anti-drug response by increasing regulatory T cells and cytokines in an antigen-restricted manner. These modifications could contribute to the safety of the procedure. [ABSTRACT FROM AUTHOR]

An interesting inference drawn by some COVID-19 epidemiological models is that there exists a proportion of the population who are not susceptible to infection—even at the start of the current pandemic. This paper introduces a model of the immune response to a virus. This is based upon the same sort of mean-field dynamics as used in epidemiology. However, in place of the location, clinical status, and other attributes of people in an epidemiological model, we consider the state of a virus, B and T-lymphocytes, and the antibodies they generate. Our aim is to formalise some key hypotheses as to the mechanism of resistance. We present a series of simple simulations illustrating changes to the dynamics of the immune response under these hypotheses. These include attenuated viral cell entry, pre-existing cross-reactive humoral (antibody-mediated) immunity, and enhanced T-cell dependent immunity. Finally, we illustrate the potential application of this sort of model by illustrating variational inversion (using simulated data) of this model to illustrate its use in testing hypotheses. In principle, this furnishes a fast and efficient immunological assay—based on sequential serology—that provides a (1) quantitative measure of latent immunological responses and (2) a Bayes optimal classification of the different kinds of immunological response (c.f., glucose tolerance tests used to test for insulin resistance). This may be especially useful in assessing SARS-CoV-2 vaccines. [ABSTRACT FROM AUTHOR]

In the literature, several mathematical models have been formulated and developed to describe the within-host dynamics of either human immunodeficiency virus (HIV) or human T-lymphotropic virus type I (HTLV-I) monoinfections. In this paper, we formulate and analyze a novel within-host dynamics model of HTLV-HIV coinfection taking into consideration the response of cytotoxic T lymphocytes (CTLs). The uninfected CD 4 + T cells can be infected via HIV by two mechanisms, free-to-cell and infected-to-cell. On the other hand, the HTLV-I has two modes for transmission, (i) horizontal, via direct infected-to-cell touch, and (ii) vertical, by mitotic division of active HTLV-infected cells. It is well known that the intracellular time delays play an important role in within-host virus dynamics. In this work, we consider six types of distributed-time delays. We investigate the fundamental properties of solutions. Then, we calculate the steady states of the model in terms of threshold parameters. Moreover, we study the global stability of the steady states by using the Lyapunov method. We conduct numerical simulations to illustrate and support our theoretical results. In addition, we discuss the effect of multiple time delays on stability of the steady states of the system. [ABSTRACT FROM AUTHOR]

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities. [ABSTRACT FROM AUTHOR]

Objective and design: This systematic review aims to establish the role of CD8 + T lymphocytes in COPD. Methods: Forty-eight papers published in the last 15 years were identified for inclusion. Results: CD8 + T-cells are increased in the lungs of patients with COPD (17 studies, 16 positive) whereas in the circulation, findings were inconclusive. Activation of CD8 + T-cells was enhanced in lungs (four studies, three positive) but cell phenotype was unclear. There was substantial evidence of a higher proportion of type 1 CD8 + (Tc1) cells in COPD (11 studies, 9 positive), though the population of type 2 (Tc2) cells was also increased (5 studies, 4 positive). CD8 + T-cells in COPD exhibited greater expression of cytotoxic proteins (five studies, five positive). Studies assessed a variety of questions so evidence was insufficient to draw firm conclusions. The role of CD8 + T-cells at acute exacerbation of COPD and also their contribution to alveolar destruction can only be hypothesised at this stage. Conclusions: Not only is the number of CD8 + T-cells increased in COPD, these cells have increased capacity to exert effector functions and are likely to contribute to disease pathogenesis. Several mechanisms highlighted show promise for future investigation to consolidate current knowledge. [ABSTRACT FROM AUTHOR]

Evaluation of the frequency of chromosome translocations in peripheral blood T-lymphocytes is a generally accepted method of retrospective biodosimetry. Accidental contamination of the Techa River (Chelyabinsk Oblast) in 1950s with bone-seeking long-lived strontium-90 gave an opportunity to evaluate the effect of local red bone marrow (RBM) exposure on translocation formation in the peripheral T-lymphocytes of local inhabitants. The studies of the inhabitants using fluorescent in situ hybridization (FISH) showed that RBM doses calculated based on FISH results were lower than those estimated based on 90Sr body burden measurements. The current study presents analytical review of the published data dealing with the most important processes of the T-lymphocyte development and formation of chromosome aberrations: characteristics of the main compartments where the exposure of T-cell occurs; assessment of the time spent by T-lymphocytes and their progenitors in these compartments; analysis of the dynamics of T-cell populations (proliferation and death); age-related aspects. The paper presents a concept of T-cell Genus (TG) united all the progeny of T progenitor with inheritable specific aberrations that could have developed in bone marrow. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa. [ABSTRACT FROM AUTHOR]

Despite recent improvements in the treatment of systemic lupus erythematosus (SLE), disease activity, comorbidities and drug toxicity significantly contribute to the risk of progressive irreversible damage accrual and increased mortality in patients with this chronic disease. Moreover, even lupus patients in remission often report residual symptoms, such as fatigue, which have a considerable impact on their health-related quality of life. In recent decades, SLE treatment has moved from the use of hydroxychloroquine, systemic glucocorticosteroids and conventional immunosuppressive drugs to biologic agents, of which belimumab is the first and only biologic agent approved for the treatment for SLE to date. Novel therapies targeting interferons, cytokines and their receptors, intracellular signals, plasma cells, T lymphocytes and co-stimulatory molecules are being evaluated. In the context of a holistic approach, growing evidence is emerging of the importance of correct lifestyle habits in the management of lupus manifestations and comorbidities. The aim of this paper is to provide an overview of current pharmacological and non-pharmacological treatment options and emerging therapies in SLE. [ABSTRACT FROM AUTHOR]

This paper seeks to unveil the niche of delay differential equation in harmonizing low HIV viral haul and thereby articulating the adopted model, to delve into structured treatment interruptions. Therefore, an ordinary differential equation is schemed to consist of three components such as untainted CD4+ T-cells, tainted CD4+ T-cells (HIV) and CTL. A discrete time delay is ushered to the formulated model in order to account for vital components, such as intracellular delay and HIV latency which were missing in previous works but have been advocated for future research. It was divested that when the reproductive number was less than unity, the disease free equilibrium of the model was asymptotically stable. Hence the adopted model with or without the delay component articulates less production of virions as per the decline rate. Therefore CD4+ T-cells in the blood remains constant at δ 1 / δ 3 , hence declining the virions level in the blood. As per the adopted model, the best STI practice is intimated for compliance. [ABSTRACT FROM AUTHOR]

HIV preferentially infects activated CD4+ T cells. Current antiretroviral therapy cannot eradicate the virus. Viral infection of other cells such as macrophages may contribute to viral persistence during antiretroviral therapy. In addition to cell-free virus infection, macrophages can also get infected when engulfing infected CD4+ T cells as innate immune sentinels. How macrophages affect the dynamics of HIV infection remains unclear. In this paper, we develop an HIV model that includes the infection of CD4+ T cells and macrophages via cell-free virus infection and cell-to-cell viral transmission. We derive the basic reproduction number and obtain the local and global stability of the steady states. Sensitivity and viral dynamics simulations show that even when the infection of CD4+ T cells is completely blocked by therapy, virus can still persist and the steady-state viral load is not sensitive to the change of treatment efficacy. Analysis of the relative contributions to viral replication shows that cell-free virus infection leads to the majority of macrophage infection. Viral transmission from infected CD4+ T cells to macrophages during engulfment accounts for a small fraction of the macrophage infection and has a negligible effect on the total viral production. These results suggest that macrophage infection can be a source contributing to HIV persistence during suppressive therapy. Improving drug efficacies in heterogeneous target cells is crucial for achieving HIV eradication in infected individuals. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a new human infectious disease. The etiology for this outbreak is a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus far, related research on COVID-19 is still in preliminary stage. This paper summarized the latest outcomes of corresponding study from Chinese centers and clarified the hematopoietic abnormality caused by SARS-CoV-2 and potential mechanism. Lymphopenia was common in the early stage after the onset of COVID-19. A significant decrease was observed in peripheral CD4+ and CD8+ T lymphocytes. As the illness progressed, neutrophilia emerged in several cases, and patients with severe critical pulmonary conditions showed higher neutrophils than common type. Thrombocytopenia was resulting from the consumption and/or the reduced production of platelets in damaged lungs. Anemia was not observed notably, but the decrease in hemoglobin was frequent. The activation of monocyte-macrophage system aggravates the immune damage of lung and other tissues, which leads to the increase of D-dimer, prothrombin time, and platelet consumption. [ABSTRACT FROM AUTHOR]

In this paper, we study the asymptotic and stability dynamics of a chemotaxis model in volume filling constraints on HIV-1-incorporating cytotoxic T lymphocytes (CTLs) cells in defense mechanism against the virus infection. The system of uninfected CD 4 + T -cells, infected and CTL defense cells is globally well-defined in Ω × (0 , ∞) , with uninfected CD 4 + T and CTL cells remaining bounded, while the HIV-1-activated cells decay to the null state at time t = ∞ . Routh–Hurwitz criteria yields asymptotical stability of the system, if the CTL threshold value is sufficiently large with CTL decay small, and instability otherwise. In control theory, it is implied that a bounded control yields the system not completely controllable, but bounded input-bounded output stable (b.i.b.o.-stable) with stabilizability and detectability not guaranteed. If guaranteed, the system is asymptotically stable if and only if it is b.i.b.o.-stable. In addition, numerical simulation results of the model are provided. [ABSTRACT FROM AUTHOR]

Immunoinformatics is a science that helps to create significant immunological information using bioinformatics softwares and applications. One of the most important applications of immunoinformatics is the prediction of a variety of specific epitopes for B cell recognition and T cell through MHC class I and II molecules. This method reduces costs and time compared to laboratory tests. In this state-of-the-art review, we review about 50 papers to find the latest and most used immunoinformatic tools as well as their applications for predicting the viral, bacterial and tumoral structural and linear epitopes of B and T cells. In the clinic, the main application of prediction of epitopes is for designing peptide-based vaccines. Peptide-based vaccines are a considerably potential alternative to low-cost vaccines that may reduce the risks related to the production of common vaccines. [ABSTRACT FROM AUTHOR]

Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical model is formulated to investigate the dynamics of HIV infection. The model incorporates two routes of infection (namely cell-to-cell transmission and virus-to-cell infection), two types of adaptive immune responses (i.e., cellular and antibody immune response) and two intracellular delays (viz., the eclipse phase and virus production period). By constructing Lyapunov functionals, we show that the global dynamics of the model can be explicitly determined by five reproduction numbers. Using the uncertainty and sensitivity analyses, we obtain the mean values and standard deviation of the five reproduction numbers and find that the reproduction numbers are most sensitive to the death rate of infected cells, viral clearance rate and immune parameters. We further compare four related HIV models and show that cell-to-cell transmission, immune responses and time delays can substantially affect the dynamical behavior of the system. Specifically, cell-to-cell transmission increases the concentration of infected cells. Inclusion of cytotoxic T lymphocyte and virus production delay can significantly reduce the viral load and infected cell concentration, and generate a higher level of uninfected CD4+ T cells. The analytical and numerical results may help to improve the understanding of HIV dynamics. [ABSTRACT FROM AUTHOR]

Purpose: The human peroxiredoxin-5 (hPRDX5) is a member of the family of antioxidant enzymes, which could resist immunosuppression by promoting immune organs development, lymphocyte proliferation and up-regulation of the levels of serum cytokines. However, being a recombinant protein, the hPRDX5 exhibits some problems including the high production cost and bad tissue penetration. Compared to macromolecular therapeutic agents, synthetic peptides have several advantages as drug candidates, such as lower manufacturing costs, reduced immunogenicity, and better organ or tumor penetration. The purpose of this research was to design the novel peptides come from hPRDX5 that can block the interaction of PD-1 and PD-L1.Methods: Herein in this work, we firstly confirmed the inhibitory activity of hPRDX5 on the binding of PD-L1 to PD-1 based on the previous observation, subsequently, in silico proteolysis and rational design (such as alanine scanning mutagenesis and truncation) were used to automate the design of new peptides derived from hPRDX5 with anti-tumour activity.Results: We found that the most potent peptide could block the PD-1/PD-L1 interaction effectively with an IC50 of 0.646 μM, and could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Moreover, experiments with tumor-bearing mice models showed that the peptide IMB-P6-10 could effectively inhibit tumor growth and showed extraordinary low acute toxicity in vivo.Conclusions: The peptides described in this paper may provide novel low-molecular-weight drug candidates for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

It has become anticipated that regenerative medicine will extend into the field of veterinary medicine as new treatments for various disorders. Although the use of allogeneic stem cells for tissue regeneration is more attractive than that of autologous cells in emergencies, the therapeutic potential of allogeneic transplantation is often limited by allo-immune responses inducing graft rejection. Therefore, a methodology for quantifying and monitoring alloreactive T cells is necessary for evaluating allo-immune responses. The mixed lymphocyte reaction (MLR) is widely used to evaluate T cell alloreactivity. In human, flow cytometric MLR with carboxyfluorescein diacetate succinimidyl ester has been established and used as a more useful assay than conventional MLR with radioisotope labeling. However, the available information about alloreactivity based on the differences of dog major histocompatibility complex (MHC) (dog leukocyte antigen, DLA) is quite limited in dog. In this paper, we describe our established flow cytometric MLR method that can quantify the T cell alloreactivity while distinguishing cell phenotypes in dog, and T cell alloreactivity among DLA-type matched pairs was significantly lower than DLA-mismatched pairs, suggesting that our developed flow cytometric MLR method is useful for quantifying T cell alloreactivity. In addition, we demonstrated the advantage of DLA homozygous cells as a donor (stimulator) for allogeneic transplantation. We also elucidated that the frequency of alloreactive T cell precursors was almost the same as that of mouse and human (1–10%). To our knowledge, this is the first report to focus on the degree of allo-immune responses in dog based on the differences of DLA polymorphisms. [ABSTRACT FROM AUTHOR]

The human adaptive immune response is known to weaken in advanced age, resulting in increased severity of pathogen-born illness, poor vaccine efficacy, and a higher prevalence of cancer in the elderly. Age-related erosion of the T cell compartment has been implicated as a likely cause, but the underlying mechanisms driving this immunosenescence have not been quantitatively modeled and systematically analyzed. T cell receptor diversity, or the extent of pathogen-derived antigen responsiveness of the T cell pool, is known to diminish with age, but inherent experimental difficulties preclude accurate analysis on the full organismal level. In this paper, we formulate a mechanistic mathematical model of T cell population dynamics on the immunoclonal subpopulation level, which provides quantitative estimates of diversity. We define different estimates for diversity that depend on the individual number of cells in a specific immunoclone. We show that diversity decreases with age primarily due to diminished thymic output of new T cells and the resulting overall loss of small immunoclones. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a pathological condition that predominantly affects neurons. It represents a large spectrum of disorders with heterogeneous symptoms and distinct clinical features. In addition to the devastating effects it can have on the affected individual, it constitutes a heavy burden to the society in terms of health care costs. Although the exact cause of neurodegeneration is not known, there are plenty of evidences supporting the notion that the immune system is strongly associated with various forms of neurodegenerative diseases. Given the numerous functions of immune cells, a change in their expression can either be beneficial or deleterious to the host. A better understanding of the molecular and cellular processes in neurodegeneration is therefore needed. This could facilitate the development of new therapeutic targets and provide effective means to dampen the progression of neurodegenerative disorders. The overarching aim of this paper is to provide an overview of the roles that the innate and adaptive immune systems play in the central nervous system, and to discuss their beneficial or detrimental effects during neurodegeneration. This paper also critically examines the contribution of immune and inflammatory-mediated responses in the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyloid lateral sclerosis by illustrating key findings from animal and human studies. [ABSTRACT FROM AUTHOR]

Virus can disseminate between uninfected target cells via two modes, namely, the diffusion-limited cell-free viral spread and the direct cell-to-cell transfer using virological synapses. To examine how these two viral infection modes impact the viral dynamics, in this paper, we propose and analyze a general viral infection model that incorporates these two viral infection modes. The model also includes nonlinear target-cell dynamics, infinitely distributed intracellular delays, nonlinear incidences, and concentration-dependent clearance rates. It is shown that the numbers of secondly infected cells through the cell-free infection mode and the cell-to-cell infection mode both contribute to the basic reproduction number. Under some reasonable assumptions, the model exhibits a global threshold dynamics: the infection is cleared out if the basic reproduction number is less than one and the infection persists if the basic reproduction number is larger than one. Two specific examples are provided to illustrate that our theoretical results cover and improve some existing ones. When the underlying assumptions are not satisfied, oscillations via global Hopf bifurcation can be observed. A brief simulation of two-parameter bifurcation analysis is given to explore the joint impacts on viral dynamics for the interplay between nonlinear target-cell dynamics and intracellular delays. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Celiac disease is a chronic inflammatory condition of the small intestine caused by aberrant adaptive immune response to gluten protein from wheat and related cereal plants. Over 90% of celiac disease patients carry the HLA-DQ2.5 allotype and HLA-DQ2.5 presents gluten peptides to gluten-reactive CD4+ T cells in celiac disease patients. A large number of HLA-DQ2.5-restricted gluten T cell epitopes have been identified over the years. These epitopes are in general proline-rich and contain at least one glutamic acid residue that is generated from glutamine in the native gluten protein by deamidation. The deamidation is mediated by the enzyme transglutaminase 2 (TG2). It has been shown that the same T cell could recognize several different HLA-DQ2.5-restricted gluten T cell epitopes due to sequence similarities. In this paper, we demonstrate that three T cell clones derived from duodenal biopsies of different celiac disease patients are able to respond to at least five different gluten T cell epitopes within the DQ2.5-glia-γ4 epitope family, including two novel epitopes. [ABSTRACT FROM AUTHOR]

Since the discovery of HLA 60 years ago, it has contributed to the understanding of the immune system as well as of the pathogenesis of several diseases. Aside from its essential role in determining donor-recipient immune compatibility in organ transplantation, HLA genotyping is meanwhile performed routinely as part of the diagnostic work-up of certain autoimmune diseases. Considering the ability of HLA to influence thymic selection as well as peripheral anergy of T cells, its role in the pathogenesis of autoimmunity is understandable. The aim of this paper is to provide a brief overview of the role and current clinical relevance of HLA-B27 in spondyloarthritis and HLA-B51 in Behçet's disease as well as HLA-DQ2/DQ8 in celiac disease and HLA-DRB1 in rheumatoid arthritis and to discuss possible future implications. [ABSTRACT FROM AUTHOR]

Exosomes are nanovesicles shed by cells as a means of communication with other cells. Exosomes contain mRNAs, microRNAs (miRs) and functional proteins. In the present paper, we develop a mathematical model of tumor-immune interaction by means of exosomes shed by pancreatic cancer cells and dendritic cells. Cancer cells’ exosomes contain miRs that promote their proliferation and that inhibit immune response by dendritic cells, and by CD4+ and CD8+ T cells. Dendritic cells release exosomes with proteins that induce apoptosis of cancer cells and that block regulatory T cells. Simulations of the model show how the size of the pancreatic cancer can be determined by measurement of specific miRs (miR-21 and miR-203 in the case of pancreatic cancer), suggesting these miRs as biomarkers for cancer. [ABSTRACT FROM AUTHOR]

Caspase-1-mediated pyroptosis is the predominance for driving CD4+ T cells death. Dying infected CD4+ T cells can release inflammatory signals which attract more uninfected CD4+ T cells to die. This paper is devoted to developing a diffusive mathematical model which can make useful contributions to understanding caspase-1-mediated pyroptosis by inflammatory cytokines IL-1β released from infected cells in the within-host environment. The well-posedness of solutions, basic reproduction number, threshold dynamics are investigated for spatially heterogeneous infection. Travelling wave solutions for spatially homogeneous infection are studied. Numerical computations reveal that the spatially heterogeneous infection can make R0>1, that is, it can induce the persistence of virus compared to the spatially homogeneous infection. We also find that the random movements of virus have no effect on basic reproduction number for the spatially homogeneous model, while it may result in less infection risk for the spatially heterogeneous model, under some suitable parameters. Further, the death of infected CD4+ cells which are caused by pyroptosis can make R0<1, that is, it can induce the extinction of virus, regardless of whether or not the parameters are spatially dependent. [ABSTRACT FROM AUTHOR]

Our increasing understanding of the etiology of celiac disease, previously considered a simple food hypersensitivity disorder caused by an immune response to cereal gluten proteins, challenges established concepts of autoimmunity. HLA is a chief genetic determinant, and certain HLA-DQ allotypes predispose to the disease by presenting posttranslationally modified (deamidated) gluten peptides to CD4 T cells. The deamidation of gluten peptides is mediated by transglutaminase 2. Strikingly, celiac disease patients generate highly disease-specific autoantibodies to the transglutaminase 2 enzyme. The dual role of transglutaminase 2 in celiac disease is hardly coincidental. This paper reviews the genetic mapping and involvement of MHC class II genes in disease pathogenesis, and discusses the evidence that MHC class II genes, via the involvement of transglutaminase 2, influence the generation of celiac disease-specific autoantibodies. [ABSTRACT FROM AUTHOR]

In this paper, we study the HIV infection model based on fractional derivative with particular focus on the degree of T-cell depletion that can be caused by viral cytopathicity. The arbitrary order of the fractional derivatives gives an additional degree of freedom to fit more realistic levels of CD4 cell depletion seen in many AIDS patients. We propose an implicit numerical scheme for the fractional-order HIV model using a finite difference approximation of the Caputo derivative. The fractional system has two equilibrium points, namely the uninfected equilibrium point and the infected equilibrium point. We investigate the stability of both equilibrium points. Further we examine the dynamical behavior of the system by finding a bifurcation point based on the viral death rate and the number of new virions produced by infected CD4 T-cells to investigate the influence of the fractional derivative on the HIV dynamics. Finally numerical simulations are carried out to illustrate the analytical results. [ABSTRACT FROM AUTHOR]

In this paper, we construct an HIV infection model which includes latent infection, logistic growth for healthy CD4 T-cells, and antiretroviral therapy. We obtain the global asymptotic stability of the uninfected equilibrium by constructing a Lyapunov function, and we give a sufficient condition for the local asymptotic stability of the infected equilibrium. We also use the latin hypercube sampling technique to identify the key parameters in determining the stability of the infected equilibrium. By numerical simulations, we observe that the model without logistic growth would underestimate the number of infectious virions, while the model without latent infection would overestimate the number of infectious virions. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The article presents abstracts of research papers related to head and neck surgery, which were presented at the seventy-fifth annual meeting of the German Society for Oto-Rhino-Laryngology. The meeting was held from May 19, 2004 to May 23, 2004 in Bad Reichenhall, Germany. One of the research papers was related to tumor-reactive memory T cells in head and neck cancer patients. Optimization of cancer vaccine trials for the treatment of head and neck cancer depends mainly on tumor-reactive T lymphocytes.

This paper describes a bi-specific antibody, which was called BIS20×3. It retargets CD3ε-positive cells (T-cells) to CD20-positive cells and was obtained by hybrid-hybridoma fusion. BIS20×3 could be isolated readily from quadroma culture supernatant and retained all the signalling characteristics associated with both of its chains. Cross-linking of BIS20×3 on Ramos cells leads to DNA fragmentation percentages similar to those obtained after Rituximab-cross-linking. Cross-linking of BIS20×3 on T-cells using cross-linking F(ab′)2-fragments induced T-cell activation. Indirect cross-linking of T-cell-bound BIS20×3 via Ramos cells hyper-activated the T-cells. Furthermore, it was demonstrated that BIS20×3 effectively re-targets T-cells to B-cells, leading to high B-cell cytotoxicity. The results presented in this paper show that BIS20×3 is fully functional in retargeting T-cells to B-cells and suggest that B-cell lymphomas may represent ideal targets for T-cell retargeting bi-specific antibodies, because the retargeted T-cell is maximally stimulated in the presence of B-cells. Additionally, since B-cells may up-regulate CD95/Fas expression upon binding of CD20-directed antibodies, B-cells will become even more sensitive for T-cell mediated killing via CD95L/FasL, and therefore supports the intention to use T-cell retargeting bi-specific antibodies recognizing CD20 on B-cell malignancies as a treatment modality for these diseases. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

This paper presents an SEU-resilient 12 T SRAM bitcell. Simulation results demonstrate that it has higher critical charge than the traditional 6 T cell. Alpha and proton testing results validate that it has a lower soft error rate compared to the reference designs for all data patterns and supply voltage levels. The improvement in SEU tolerance is achieved at the expense of 2X area penalty. [ABSTRACT FROM AUTHOR]

The aim of this paper was to look for predictors of abatacept (ABA) therapy discontinuation in patients with rheumatoid arthritis (RA). Seventy-one RA patients treated with ABA were followed up. Demographical, clinical, and laboratory parameters of the patients, including peripheral blood T and B cell populations, different rheumatoid factor and anti-cyclic citrullinated peptide autoantibodies isotypes, and serum free light chains were evaluated. Comparing patients who discontinued ABA with those still in therapy we observed: a higher proportion of smokers (51.9 vs 25.6 %; p = 0.03); a non significant lower proportion of anti-cyclic citrullinated peptide positivity (76 vs 89.5 %; p = 0.13); a lower proportion of terminally differentiated effector memory cells (TDEM) among total CD8+ T lymphocytes at baseline (22.0 % (7.8-39.2) vs 38.7 % (20.7-55.9); p = 0.002). Logistic multivariate analysis showed that only the proportion of CD8+TDEM T cells was an independent predictive factor of therapy discontinuation (OR (95 % IC) = 6.2 (1.2 to 30.8); p = 0.026). Receiver-operating characteristic analysis showed a significant performance of this biomarker for prediction of therapy discontinuation (using a cut-off of 30.6 %: AUC: 0.760 ± 0.07; p = 0.002). Patients with a low proportion of CD8+TDEM at baseline had a higher probability of discontinuing the treatment during time (log-rank test: p < 0.01). T cell characterization for identification of TDEM CD8+ T cells might be a useful test to predict discontinuation of ABA therapy. [ABSTRACT FROM AUTHOR]

It is currently postulated that steroid-sensitive idiopathic nephrotic syndrome (SSNS) and steroid-resistant idiopathic nephrotic syndrome (SRNS), which are not related to the mutation of a gene coding for podocyte structures or for glomerular basement membrane proteins, result from a circulating factor affecting podocyte shape and function. T lymphocytes have for a long time been suspected to be involved in the pathophysiology of these diseases. The successful treatment of steroid-dependant nephrotic syndrome with rituximab suggests a potential role for B lymphocytes. Clinical and experimental data indicate roles for cytokines IL-13, TNFα, circulating cardiotrophin-like cytokine factor 1 (member of the IL-6 family), circulating hemopexin, radical oxygen species, and the soluble urokinase-type plasminogen activator receptor (suPAR) in the development of nephrotic syndrome. Podocyte metabolism modifications-leading to the overexpression of the podocyte B7-1antigen (CD 80), hypoactivity of the podocyte enzyme sphingomyelin phosphodiesterase acid-like 3 b (SMPDL3b), and to the podocyte production of a hyposialylated form of the angiopoietin-like 4 (Angptl4)-are mechanisms possibly involved in the changes in the podocyte cytoskeleton leading to SSNS and or SRNS. Different multifactorial pathophysiological mechanisms can be advocated for SSNS and SRNS. The present paper reviews the experimental and clinical data upon which the different hypotheses are based and reports their possible clinical applications. [ABSTRACT FROM AUTHOR]

Background: Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa). Patients and methods: The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters. Results: Higher FOXP3/CD3 [OS: p = 0.016, HR 1.29, 95 % confidence intervals (95 % CIs 1.05-1.59)] and FOXP3/CD8 (OS: p = 0.013, HR 1.32, 95 % CIs 1.06-1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95 % CIs 1.05-1.67, p = 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 ( p = 0.070, HR 0.80, 95 % CIs 0.63-1.02) and CD3 ( p = 0.113, HR 0.84, 95 % CIs 0.68-1.04) infiltration values. Conclusions: A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02903-w [ABSTRACT FROM AUTHOR]