The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, ...its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.
Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, ...studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that ...are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly ...understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a−/− mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155fl/fl mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.
•miR-155 is necessary for spontaneous Tfh cell accumulation in Mir146a−/− mice•miR-155 promotes differentiation of naive T cells into Tfh cells•miR-155 directly targets multiple regulatory genes in Tfh cells•miR-155 plays a T cell-intrinsic role during Tfh cell formation in Mir146a−/− mice
Mechanisms that control chronic, low-grade inflammation are poorly understood despite the propensity of this condition to progress to serious diseases. O’Connell and colleagues demonstrate that miR-155 and miR-146a regulate T follicular helper cell development, spontaneous germinal center formation, and autoantibody production in a mouse model of chronic inflammation.
MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely ...unresolved. Because miRNAs function by repressing specific mRNAs through direct 3'UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3'UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155⁻/⁻ primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology.
Radiomics involves the extraction of quantitative information from annotated Computed-Tomography (CT) images, and has been used to predict outcomes in Head and Neck Squamous Cell Carcinoma (HNSCC). ...Subjecting combined Radiomics and Clinical features to Machine Learning (ML) could offer better predictions of clinical outcomes. This study is a comparative performance analysis of ML models with Clinical, Radiomics, and Clinico-Radiomic datasets for predicting four outcomes of HNSCC treated with Curative Radiation Therapy (RT): Distant Metastases, Locoregional Recurrence, New Primary, and Residual Disease.
The study used retrospective data of 311 HNSCC patients treated with radiotherapy between 2013-2018 at our centre. Binary prediction models were developed for the four outcomes with Clinical-only, Clinico-Radiomic, and Radiomics-only datasets, using three different ML classification algorithms namely, Random Forest (RF), Kernel Support Vector Machine (KSVM), and XGBoost. The best-performing ML algorithms of the three dataset groups was then compared.
The Clinico-Radiomic dataset using KSVM classifier provided the best prediction. Predicted mean testing accuracy for Distant Metastases, Locoregional Recurrence, New Primary, and Residual Disease was 97%, 72%, 99%, and 96%, respectively. The mean area under the receiver operating curve (AUC) was calculated and displayed for all the models using three dataset groups.
Clinico-Radiomic dataset improved the predictive ability of ML models over clinical features alone, while models built using Radiomics performed poorly. Radiomics data could therefore effectively supplement clinical data in predicting outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Decades of research went into understanding immune cell development and function without awareness that consideration of a key element, microRNA (miRNA), was lacking. The discovery of miRNAs as ...regulators of developmental events in model organisms suggested to many investigators that miRNA might be involved in the immune system. In the past few years, widespread examination of this possibility has produced notable results. Results have shown that miRNAs affect mammalian immune cell differentiation, the outcome of immune responses to infection and the development of diseases of immunological origin. Some miRNAs repress expression of target proteins with well established functions in hematopoiesis. Here we bring together much of this work, which has so far only scratched the surface of this very fertile field of investigation, and show how the results illuminate many historic questions about hematopoiesis and immune function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is now well known that gene expression is intricately regulated inside each cell especially in mammals. There are multiple layers of gene regulation active inside a cell at a given point of time. ...Gene expression is regulated post-transcriptionally by microRNAs and other factors. Mechanistically, microRNAs are known to bind to the 3' UTR of mRNAs and cause repression of gene expression and the number of known microRNAs continues to increase every day. Dysregulated microRNA signatures in different types of cancer are being uncovered consistently implying their importance in cellular homeostasis. However when studied in isolation in mouse models, clear-cut cellular and molecular mechanisms have been described only for a select few microRNAs. What is the reason behind this discrepancy? Are microRNAs small players in gene regulation helping only to fine tune gene expression? Or are their roles tissue and cell type-specific with single-cell level effects on mRNA expression and microRNA threshold levels? Or does it all come down to the technical limitations of high-throughput techniques, resulting in false positive results? In this review, we will assess the challenges facing the field and potential avenues for resolving the cellular and molecular mechanisms of these small but important regulators of gene expression.
Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs ...(miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.
The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that ...small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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