Ultraviolet-B radiation effects on plants: induction of morphogenic responses

Plants raised under field conditions are acclimated to ambient levels of solar UV-B radiation. Morphogenic responses are part of the UV-B acclimation process and have been hypothesized to contribute to UV avoidance. UV-B induced morphogenic responses include inhibition of hypocotyl and stem elongation, leaf curling, leaf thickening and increased axillary branching. So far, neither the photosensory nor the signal transduction mechanism involved in UV-B mediated morphogenesis has been identified. The combination of classical photobiological techniques and Arabidopsis genetic resources comprises a powerful tool for the analysis of morphogenic responses. However, no morphogenic mutants, specifically altered in their response to UV-B, have yet been identified. In this paper we discuss the possibility that some UV-B driven morphogenic responses do not involve a dedicated photosensory system, but rather are a consequence of UV-B induced changes in secondary metabolism. UV-B induced flavonoid aglycones and phenol-oxidizing peroxidases can affect, respectively, polar auxin transport and auxin catabolism, and hence plant architecture. Integration of genetic, photobiological, biochemical and physiological approaches is necessary to fully appraise the ecophysiological role of UV-B radiation in controlling plant architecture.     

Immediate and long-term effects of radiation on the immune system of specific-pathogen-free mice

Studies on the immediate and long-term effects of radiation on the immune system of specific-pathogen-free mice are summarized in this paper. There was a striking difference in the radiation response of lymphocyte subsets; B cells consist of a fairly radiosensitive homogeneous population, whereas T cells consist of a large percentage (greater than 90 per cent) of radiosensitive and a small percentage (less than 10 per cent) of extremely radioresistant subpopulations. Ly 1+ and Ly 2+ lymphocytes appear equally radiosensitive, although the percentage of radioresistant cells was slightly larger for the former (approximately 5.5 per cent) than the latter (approximately 2.5 per cent). There was a significant strain difference in the radiosensitivity of immune-response potential in mice; immunocompetent cells of C3H mice were more radioresistant than those of BALB/c, C57BL/6, and B10.BR mice. Studies on the long-term effect of radiation on immune system in mice indicated no evidence for accelerated ageing of the immunologic functions when radiation exposure was given to young adults. Preliminary results on the enhancing effect of low dose radiation on cytotoxic T cell response in vitro are also discussed.     

A microdosimetric understanding of low-dose radiation effects

This paper presents a microdosimetric approach to the problem of radiation response by which effects produced at low doses and dose rates can be understood as the consequences of radiation absorption events in the nucleus of a single relevant cell and in its DNA. Radiation absorption at the cellular level, i.e. in the cell nucleus as a whole, is believed to act through radicals. This kind of action is called 'non-specific' and leads to the definition of an 'elemental dose' and the 'integral response probability' of a cell population. Radiation absorption at the molecular level, i.e. in sensitive parts of the DNA, is thought to act through double-strand breaks. This kind of action is called 'specific' and leads to a 'relative local efficiency'. In general, both mechanisms occur for all types of radiation; however, it is the dose contribution of both specific and non-specific effects that determines the radiation quality of a given radiation. The implications of this approach for the specification of low-dose and low dose-rate regions are discussed.     

Induction of immune activation by a novel immunomodulatory oligonucleotide without thymocyte apoptosis

Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs (CpG DNA) can potently stimulate innate immunity. While the actions of CpG DNA resemble those of LPS, these molecules stimulate distinct Toll-like receptors as well as cell types. In a previous study, we showed that a CpG ODN could induce cytokine production but, unlike LPS, did not induce thymocyte apoptosis. In this study, we have further investigated these differences using as a model a second-generation immunostimulatory oligonucleotide called HYB2048. Following administration to normal BALB/c mice, HYB2048-induced IL-12 but not IL-6 production. Under conditions in which LPS induced thymocyte apoptosis, HYB2048 did not cause significant cell death and, furthermore, did not block apoptosis induced by LPS. The levels of corticosterone induced by HYB2048 were also significantly lower than those induced by LPS. This pattern of activation could distinguish CpG DNA from LPS in its effects on the immune system.     

Nontargeted effects of ionizing radiation: implications for low-dose exposures

The traditional thinking has been that the biological effects of ionizing radiation occur in irradiated cells as a consequence of the DNA damage they incur. This implies that: 1) biological effects occur only in irratiated cells, 2) radiation traversal through the nucleus of the cell is a prerequisite to produce a biological response, and 3) DNA is the target molecule in the cell. Evidence has been emerging, however, for non-DNA targeted effects of radiation; that is, effects including mutations, chromosomal aberrations, and changes in gene expression which occur in cells that in themselves receive no radiation exposure. Two of these phenomena will be described in this paper. The first is radiation-induced genomic instability whereby biological effects, including elevated frequencies of mutations and chromosomal aberrations, arise in the distant descendants of irradiated cells. The second phenomenon has been termed the "bystander effect", whereby in a mixed population of irradiated and nonirradiated cells, biological effects arise in those cells that receive no radiation exposure. The damage signals are transmitted from cell to cell through gap junction channels, and the genetic effects observed in bystander cells appear to result from an upregulation of oxidative stress. The possible influence of these non-targeted effects of radiation of the respounse to low-dose exposures is discussed.     

Biochemical relationship of thymocyte mitogenic factor and factors enhancing humoral and cell-mediated immune responses.

Supernatants from concanavalin A-induced mouse spleen cells contain soluble factors which: 1) augment the anti-sheep erythrocyte hemolytic plaque-forming cell response of nude mouse spleen cells, 2) facilitate the generation of antigen-specific cytotoxic cells by alloantigen-stimulated thymocytes, and 3) enhance the mitogenic response of thymocytes in the presence or absence of phytohemagglutinin. The uninduced control spleen cell supernatants contained variable but significantly less biologic activity within the difference assay systems. The principle enhancing activity (apparent m.w. 35,000 to 38,000) in each of the assay systems was found to be inseparable after a multiple step purification scheme involving ammonium sulfate precipitation, two-cycle gel filtration, hydroxylapatite chromatography, and hydrophobic chromatography on Phenyl Sepharose. These results indicate that either a single factor (designated thymocyte mitogenic factor) augments both humoral and cell-mediated immune responses or, alternatively, the different biologic activities are mediated by different factors that share a common core structure.     

Targeted nanotherapy for induction of therapeutic immune responses

Nanotechnology permits the design of therapeutic devices with defined structure and molecular composition. Modular designs employing surface-bound ligands provide specific homing devices for loaded cargo, and biocompatible and biodegradable constructs provide surrogate temporary microenvironments. We first present a case for developing 'smart' modular constructs as immunogenic vaccines to prime immune memory against specific pathogens where current vaccines fail. Second, we argue that nanotherapeutic intervention can harness pivotal molecular pathways recently discovered to regulate lineage development between pathogenic TH17 cells associated with autoimmune disease, versus tolerogenic regulatory T cells (Treg). Underpinned by molecular mechanisms that enable exquisitely specific responses in adaptive immunity, targeted nanodevices designed to stimulate either immune aggression or immune tolerance signify the birth of a new era in therapeutics.     

Immune modulation and apoptosis induction: Two sides of the antitumoral activity of imiquimod

Imiquimod, the first member of the imidazoquinoline family of immune response modifiers, has proven good clinical efficacy against basal cell carcinomas and actinic keratoses in several independent studies. In addition, there is recent evidence that imiquimod is also efficacious against other tumors such as cutaneous metastases of malignant melanoma or vascular tumors. Imiquimod exerts its antitumoral effect, at least in part, through binding to TLR-7 and TLR-8 on dendritic cells followed by secretion of a multitude of proinflammatory cytokines. The net result of this proinflammatory activity is a profound tumor-directed cellular immune response. However, recent experimental and clinical data indicate that imiquimod also possesses considerable direct pro-apoptotic activity against tumor cells both in vitro and in vivo. This novel mode of action appears to be independent of membrane bound death receptors, but involves caspase activation. Induction of apoptosis by imiquimod is, at least in part, presumably mediated through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent activation of caspase-9. The structural analogue, resiquimod, exhibited very limited, if any, such pro-apoptotic activity, possibly due to its lacking ability to enter the cell. Bypassing molecular mechanisms of apoptosis deficiency by a topical compound may be of great utility for treating certain cutaneous tumors.     

Synergistic effects of arsenic trioxide and radiation in osteosarcoma cells through the induction of both autophagy and apoptosis

Osteosarcoma is the most common primary malignant bone tumor, occurring mainly in children and adolescents, and survival largely depends on their response to chemotherapy. However, the risk of relapse and adverse outcomes is still high. We investigated the synergistic anti-cancer effects of ionizing radiation combined with arsenic trioxide (ATO) and the mechanisms underlying apoptosis or autophagy induced by combined radiation and ATO treatment in human osteosarcoma cells. We found that exposure to radiation increased the population of HOS cells in the G(2)/M phase within 12 h in a time-dependent manner. Radiation combined with ATO induced a significantly prolonged G(2)/M arrest, consequently enhancing cell death. Furthermore, combined treatment resulted in enhanced ROS generation compared to treatment with ATO or radiation alone. The enhanced cytotoxic effect of combined treatment occurred from the increased induction of autophagy and apoptosis through inhibition of the PI3K/Akt signaling pathway in HOS cells. The combined treatment of HOS cells pretreated with Z-VAD, 3-MA or PEG-catalase resulted in a significant reduction of cytotoxicity. In addition, G(2)/M arrest and ROS generation could be involved in the underlying mechanisms. The data suggest that a combination of radiation and ATO could be a new potential therapeutic strategy for the treatment of osteosarcoma.     

Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis

Vesicular stomatitis virus (VSV) matrix (M) protein can directly induce apoptosis by inhibiting host gene expression when it is expressed in the absence of other viral components. Previously, we found that the M protein gene complexed to DOTAP-cholesterol liposome (Lip-MP) can suppress malignant tumor growth in vitro and in vivo; however, little is known regarding the biological effect of Lip-MP combined with radiation. The present study was designed to determine whether Lip-MP could enhance the antitumor activity of radiation. LLC cells treated with a combination of Lip-MP and radiation displayed apparently increased apoptosis compared with those treated with Lip-MP or radiation alone. Mice bearing LLC or Meth A tumors were treated with intratumoral or intravenous injections of Lip-MP and radiation. The combined treatment significantly reduced mean tumor volumes compared with either treatment alone in both tumor models and prolonged the survival time in Meth A tumor models and the intravenous injection group of LLC tumor models. Moreover, the antitumor effects of Lip-MP combined with radiation were greater than their additive effects when compared with the expected effects of the combined treatment in vivo. This study suggests that Lip-MP enhanced the antitumor activity of radiation by increasing the induction of apoptosis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. X-B. Du, J-Y. Lang and J-R XU––contributed equally to this work.     

Glacier foreland colonisation: distinguishing between short-term and long-term effects of climate change

By comparing short-term (6 years) observations with long-term (>100 years) community changes reconstructed from the chronosequence along a glacier foreland, I show that the colonisation of recently deglaciated terrain by invertebrates may constitute a process reacting sensitively to temperature fluctuations. Early colonising stages (<30 years old) currently develop faster, and intermediate successional stages (30-50 years old) slower, than would be indicated by the long-term chronosequence pattern. These differences between the chronosequence approach and direct observation can be explained by a simple model relating the rate of community evolution to the temperature record. It would mean that an increase of 0.6°C in summer temperatures approximately doubled the speed of initial colonisation, whereas later successional stages were less sensitive to climate change. The present situation appears to result from unusually warm summers around 1950 and a warm period accelerating glacier retreat since 1980. In contrast to the long-term trend, all except the youngest communities have suffered a loss in diversity in recent years.     

Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans

Novel anti-inflammatory effects of insulin have recently been described, and insulin therapy to maintain euglycemia suppresses the plasma levels of free fatty acids (FFA) and increases the survival of critically ill patients. We aimed to explore the effect of short-term high levels of plasma FFA on the inflammatory response to a low dose of endotoxin. Fourteen healthy male volunteers underwent the following two trials in a randomized crossover design: 1) continuous infusion of 20% Intralipid [0.7 ml.kg(-1).h(-1) (1.54 g/kg)] for 11 h, and 2) infusion of isotonic saline for 11 h (control). In each trial, heparin was given to activate lipoprotein lipase, and an intravenous bolus of endotoxin (0.1 ng/kg) was given after 6 h of Intralipid/saline infusion. Blood samples and muscle and fat biopsies were obtained before the Intralipid/saline infusion and before as well as after infusion of an endotoxin bolus. Plasma levels of FFA, triglycerides, and glycerol were markedly increased during the Intralipid infusion. Endotoxin exposure induced an increase in plasma levels of TNF-alpha, IL-6, and neutrophils and further stimulated gene expression of TNF-alpha and IL-6 in both skeletal muscle and adipose tissue. The systemic inflammatory response to endotoxin was significantly pronounced during Intralipid infusion. Short-term hyperlipidemia enhances the inflammatory response to endotoxin, and skeletal muscle and adipose tissue are capable of producing essential inflammatory mediators after endotoxin stimulation.     

Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors

Survival in the majority of high-grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and survival prediction. Factors associated with long-term survival have not been extensively studied using unbiased genome-wide expression analyses. In the current study, gene expression microarray profiles of HGA from long-term survivors were interrogated for discovery of survival-associated biological factors. Ontology analyses revealed that increased expression of immune function-related genes was the predominant biological factor that positively correlated with longer survival. A notable T cell signature was present within this prognostic immune gene set. Using immune cell-specific gene classifiers, both T cell-associated and myeloid linage-associated genes were shown to be enriched in HGA from long-term versus short-term survivors. Association of immune function and cell-specific genes with survival was confirmed independently in a larger publicly available glioblastoma gene expression microarray data set. Histology was used to validate the results of microarray analyses in a larger cohort of long-term survivors of HGA. Multivariate analyses demonstrated that increased immune cell infiltration was a significant independent variable contributing to longer survival, as was Karnofsky/Lansky performance score. These data provide evidence of a prognostic anti-tumor adaptive immune response and rationale for future development of immunotherapy in HGA.     

Th17 cell induction and immune regulatory effects

The T help 1 (Th1) and Th2 cell classification have provided the framework for understanding CD4⁺ T cell biology and the interplay between innate and adaptive immunity for almost two decades. Recent studies have defined a previously unknown arm of the CD4⁺ T cell effector response, the Th17 lineage, which promises to change our understanding of immune regulation, immune pathogenesis and host defense. The factors that specify differentiation of IL‐17 producing effector T cells from naïve T cell precursors are being rapidly discovered and are providing insights into mechanisms by which signals from cells of the innate immune system guide alternative pathways of Th1, Th2, or Th17 development. In this review, we will focus on recent studies that have identified new subsets of Th cells, new insights regarding the induced generation and differentiation mechanisms of Th17 cells and immune regulatory effects. J. Cell. Physiol. 211: 273–278, 2007. © 2007 Wiley‐Liss, Inc.     

Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo Th cell responses

It has recently been established that FcRs are involved in the triggering of type II and III inflammatory responses. Although FcR is not believed to be involved in the regulation of T cell function, the in vivo contribution of FcRs to T cell function still remains unclear. We analyzed in vivo responses of delayed-type hypersensitivity and proliferation of CD4+ T cells to Ags in FcRgamma-/- mice lacking the expression and function of FcgammaRI, FcgammaRIII, and FcepsilonRI. We found that the delayed-type hypersensitivity response in FcRgamma-/- mice is significantly decreased compared with that in wild-type mice. Moreover, the secondary responses of proliferation and cytokine production as well as the Ab formation by CD4+ T cells from FcRgamma-/- mice to Ag and normal APCs were also reduced. In contrast, in vitro primary T cell proliferative responses upon stimulation with anti-TCR Ab or MLR as well as in vivo primary response against staphylococcus enterotoxin B administration were not different between T cells from FcRgamma-/- and wild-type mice. In addition, the Ag presentation function of APCs from unimmunized FcRgamma-/- mice was normal. On the other hand, Ab-deficient mice also revealed impaired T cell responses. These results demonstrate that the defective T cell responses in FcRgamma-/- mice were due to impaired Ag presentation during in vivo priming not to a defect in T cells. Therefore, they suggest that the FcRs on APCs mediate efficient priming of Th cell responses in vivo in an immune complex-dependent manner.