Turnover of mRNA is a key mechanism in regulated gene expression. In addition to turnover pathways for normal transcripts, there are surveillance mechanisms that degrade aberrant mRNAs. mRNA decay is regulated in response to cellular signals and coordinated with other mRNA-metabolic processes. When considering the control of gene expression, the focus has traditionally been on transcriptional regulation. Recently, however, the large contribution made by mRNA decay has become difficult to ignore. Large-scale analyses indicate that as many as half of all changes in the amounts of mRNA in some responses can be attributed to altered rates of decay. In this article, we discuss some of the mechanisms that are used by the cell to mediate and regulate this intriguing process.

The highways and byways of mRNA decay.

Christensen, R. (2002), Plane Answers to Complex Questions: The Theory of Linear Models (3rd ed.), New York: Springer-Verlag. Crocker, D. C. (1980), Review of Linear Regression Analysis, by G. A. F. Seber, Technometrics, 22, 130. Datta, B. N. (1995), Numerical Linear Algebra and Applications, Paci c Grove, CA: Brooks/Cole. Draper, N. R. (2002), “Applied Regression Analysis Bibliography Update 2000–2001,” Communications in Statistics: Theory and Methods, 2051– 2075. Golub, G. H., and Van Loan, C. F. (1996), Matrix Computations (3rd ed.), Baltimore, MD: Johns Hopkins University Press. Graybill, F. A. (2000), Theory and Application of the Linear Model, Paci c Grove, CA: Brooks/Cole. Hocking, R. R. (2003), Methods and Applications of Linear Models: Regression and the Analysis of Variance (2nd ed.), New York: Wiley. Porat, B. (1993), Digital Processing of Random Signals, Englewood Cliffs, NJ: Prentice-Hall. Ravishanker, N., and Dey, D. K. (2002), A First Course in Linear Model Theory, Boca Raton, FL: Chapman and Hall/CRC. White, H. (1984), Asymptotic Theory for Econometricians, Orlando, FL: Academic Press.

Generalized Estimating Equations

The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-γ. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2−/− common cytokine receptor chain γ [γc]−/−) or IFN-γ signaling (IFN-γ−/− or IFN-γRα−/−) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell–derived IFN-γ during pregnancy, RAG-2−/−γc−/− females were engrafted with bone marrow from IFN-γ−/− mice, IFN-γ signal-disrupted mice (IFN-γRα−/− or signal transducer and activator of transcription [Stat]-1−/−), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-γ−/− mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-γRα−/− or Stat-1−/− mice overproduced uNK cells, all of which were immature. Grafts from IFN-γ−/−, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-γ to pregnant RAG-2−/−γc−/− mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell–derived IFN-γ modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.

/pdf/interferon-g-contributes-to-initiation-of-uterine-vascular-2vekdx2jkv.pdf

Interferon γ Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy

The development of lymphoid organs can be viewed as a continuum. At one end are the 'canonical' secondary lymphoid organs, including lymph nodes and spleen; at the other end are 'ectopic' or tertiary lymphoid organs, which are cellular accumulations arising during chronic inflammation by the process of lymphoid neogenesis. Secondary lymphoid organs are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoid organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations. Between these two boundaries are other types of lymphoid tissues that are less developmentally but more environmentally regulated, such as Peyer's patches, nasal-associated lymphoid tissue, bronchial-associated lymphoid tissue and inducible bronchial-associated lymphoid tissue. Their regulation, functions and potential effects are discussed here.

https://www.researchgate.net/profile/Rawad_Mounzer/publication/7229162_Lymphoid_organ_development_from_ontogeny_to_neogenesis/links/0046352b3794360d97000000.pdf

Lymphoid organ development: from ontogeny to neogenesis

Neutrophil-specific genes are abundant in PBMC microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions. The functionality and pathogenicity of these LDGs have not been characterized. We developed a technique to purify LDGs from lupus PBMCs and assessed their phenotype, function, and potential role in disease pathogenesis. LDGs, their autologous lupus neutrophils, and healthy control neutrophils were compared with regard to their microbicidal and phagocytic capacities, generation of reactive oxygen species, activation status, inflammatory cytokine profile, and type I IFN expression and signatures. The capacity of LDGs to kill endothelial cells and their antiangiogenic potential were also assessed. LDGs display an activated phenotype, secrete increased levels of type I IFNs, TNF-alpha, and IFN-gamma, but show impaired phagocytic potential. LDGs induce significant endothelial cell cytotoxicity and synthesize sufficient levels of type I IFNs to disrupt the capacity of endothelial progenitor cells to differentiate into mature endothelial cells. LDG depletion restores the functional capacity of endothelial progenitor cells. We conclude that lupus LDGs are proinflammatory and display pathogenic features, including the capacity to synthesize type I IFNs. They may play an important dual role in premature cardiovascular disease development in systemic lupus erythematosus by simultaneously mediating enhanced vascular damage and inhibiting vascular repair.

A Distinct Subset of Proinflammatory Neutrophils Isolated from Patients with Systemic Lupus Erythematosus Induces Vascular Damage and Synthesizes Type I IFNs

Lymphoid aggregates (LA) develop during the proliferative phase of the menstrual cycle in the human uterine endometrium (EM). They contain mostly CD8+ T cells and B cells. As these LA are absent immediately following menses, they may arise by division of cells resident in the EM, or by division of a limited number of precursor cells that traffic into the EM during the early proliferative phase of the menstrual cycle. Alternatively, they may arise by the continuous trafficking of cells into the EM throughout the proliferative phase of the menstrual cycle. In this study we investigated the distribution and frequency of CD8+ T cells in the aggregates using expression of Vbeta2 or Vbeta8 as markers of clonality and Ki-67 as a marker of dividing cells. Confocal microscopic analysis of endometrial tissues showed the random distribution of CD8+ T cells within aggregates within the same sample and in aggregates from different samples. Furthermore, comparisons of the distribution of Vbeta2 and Vb8 with expected values predicted from Poisson distribution values were not significantly different, suggesting that CD8+ T cells do not arise by division from single precursors. A low level of T-cell division within LAs was confirmed by positive staining for Ki-67. Dividing T cells were randomly dispersed throughout the LA and the frequency of dividing cells did not vary greatly between aggregates within the same tissue. Nearest-neighbour analysis of dividing cells showed no statistically significant deviations from a random distribution. Taken together, these results suggest that LA develop during the menstrual cycle largely by the trafficking of cells to nucleation sites within the EM, rather than by division of a limited number of precursor cells.

CD8+ T cells in human uterine endometrial lymphoid aggregates: evidence for accumulation of cells by trafficking.

Chemokines are critical for the recruitment of effector immune cells to sites of infection. Mice lacking the chemokine receptor CCR1 have defects in neutrophil trafficking and proliferation. In the present study, we tested the susceptibility of CCR1 knockout mice to infection with the obligate intracellular protozoan parasite Toxoplasma gondii . In comparison with parental wild-type mice, CCR1−/− mice exhibited dramatically increased mortality to T. gondii in association with an increased tissue parasite load. No differences were observed in Ag-specific T cell proliferation or in cytokine responses between mutant and wild-type mice. However, the influx of PMNs to the peripheral blood and to the liver were reduced in CCR1−/− mice during early infection. Our results suggest that CCR1-dependent migration of neutrophils to the blood and tissues may have a significant impact in controlling parasite replication.

/pdf/mice-lacking-the-chemokine-receptor-ccr1-show-increased-uh02noo44v.pdf

Mice lacking the chemokine receptor CCR1 show increased susceptibility to Toxoplasma gondii infection.

Problem

Human uterine macrophages must maintain an environment hospitable to implantation and pregnancy and simultaneously provide protection against pathogens. Although macrophages comprise a significant portion of leukocytes within the uterine endometrium, the activation profile and functional response of these cells to endotoxin are unknown.



Method of Study

Flow cytometric analysis of surface receptors and intracellular markers expressed by macrophages isolated from human endometria was performed. Uterine macrophages were stimulated with LPS. Cytokines, chemokines, and growth factors expressed by these cells were analyzed using Bio-Plex analysis.



Results

CD163high human endometrial macrophages constitutively secrete both pro- and anti-inflammatory cytokines as well as pro-angiogenic factors and secretion of these factors is LPS-inducible.



Conclusion

A major population of human uterine macrophages is alternatively activated. These cells secrete factors in response to LPS that are involved in the activation of immune responses and tissue homeostasis.

A subset of human uterine endometrial macrophages is alternatively activated.

Ocular toxoplasmosis is a potentially blinding intraocular inflammation. The intent of this study was to investigate the role of Fas-FasL interaction in a murine model of acquired ocular toxoplasmosis induced by intracameral inoculation of Toxoplasma gondii. Intraocular inflammation, Fas and FasL expression on lymphocytes and on ocular tissues, the occurrence of apoptosis, and the frequency of CD8(+) and CD4(+) T cells in the infected eyes were analyzed in C57BL/6 (B6) mice. Susceptibility to parasite-induced intraocular inflammation was observed in Fas-deficient (B6-lpr) and FasL-deficient (B6-gld) mice. Inoculation of 5,000 T. gondii tachyzoites induced significant intraocular inflammation associated with increase of Fas and FasL expression in the inoculated eyes of wild-type B6 mice. Flow cytometry demonstrated a significant increase of Fas and FasL expression on the splenocytes from naive mice incubated in vitro with the parasite and on the splenocytes harvested from the infected mice at day 8 after parasite inoculation. Apoptosis of inflammatory cells and cells in ocular tissues was seen, and a greater frequency of CD8(+) than CD4(+) T cells was observed in the infected eyes. The intensity of intraocular inflammation was greater in B6-lpr and B6-gld mice than in wild-type B6 mice (P < 0.05). The results suggest that Fas-FasL interaction associated with apoptosis is involved in the pathogenesis of acquired ocular toxoplasmosis in mice.

Fas-FasL interaction involved in pathogenesis of ocular toxoplasmosis in mice.

Autoantibody responses to endometrial and serum antigens are a common feature of endometriosis. We have shown that the serum autoantibody response in endometriosis to a number of previously identified antigens, including alpha2-Heremans Schmidt glycoprotein and carbonic anhydrase, is specific for a carbohydrate epitope common to these proteins. Removal of carbohydrate moieties from these antigens resulted in a loss of antibody binding. Antibody reactivity was abolished following adsorption with the lectin jacalin, which specifically binds the Thomsen-Friedenreich (T) antigen (Gal beta1-3GalNAc). Demonstration that the autoantibodies also reacted with other Thomsen-Friedenreich antigen-bearing proteins, such as serum IgA1, hemopexin, and MMP-9, confirmed that this glycotope is involved in the autoantibody response. However, the autoantibody binding requires the presence of at least one sialic acid residue. Thus, the glycotope involved may be a sialylated T antigen. These findings allow us to hypothesize a number of mechanisms whereby the autoimmune response plays a direct role in several aspects of the disease process. The proposed mechanisms take into account the salient endocrine dependency of endometriotic lesions and other aspects of the disease process such as aberrant matrix metalloproteinase function and the ability of endometrial cells to implant at ectopic sites. The anti-T-like response may also be indicative of an underlying genetic defect in glycosylation or in the control of glycosylation by steroid sex hormones. Further characterization of this autoimmune response may prove useful in the development of serum-based diagnostic tests for endometriosis and may lead to the development of therapeutic strategies.

Autoantibody responses to carbohydrate epitopes in endometriosis.

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