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At least 217 records · Page 12Linked to original sources
PubMed2005

alpha2-adrenoceptors inhibit the intracellular Ca2+ response to electrical stimulation in normal and injured sensory neurons, with increased inhibition of calcitonin gene-related peptide expressing neurons after injury.

Nerve injury resulting in chronic pain is associated with novel excitatory effects of norepinephrine on injured peripheral nerve terminals and their cell bodies, due to actions on alpha2-adrenoceptors. Paradoxically, alpha2-adrenoceptor agonists administered near peripheral terminals or their cell bodies results in analgesia, not pain. This study tested, using intracellular Ca2+ response to stimulation, the effects of alpha2-adrenoceptor agonists on injured sensory neurons and classified their neuronal phenotype. Dorsal root ganglion cells from normal and spinal nerve-ligated rats were dissociated and activated twice with electrical field stimulation, while measuring Fura-2 fluorescence. Cells were perfused between stimulations with vehicle or alpha2-adrenoceptor agonists alone or with antagonists. Cells were considered inhibited if the ratio of their peak Ca2+ response to the second stimulus divided by the first was less than the 2.5th percentile for vehicle controls. alpha2-, But not alpha1-adrenoceptor agonists inhibited the Ca2+ response in a concentration related fashion, and this inhibition was blocked by alpha2-adrenoceptor antagonists. Clonidine inhibited a similar percentage of cells in the normal and spinal nerve-ligated group. In both groups, the large majority of clonidine-inhibited cells stained for isolectin B4. Spinal nerve ligation resulted in a 4-10-fold increase in the percentage of clonidine inhibited cells which immunostained for calcitonin gene-related peptide. These data are consistent with the known inhibition of Ca2+ currents by alpha2-adrenoceptors and suggest that, at the level of intracellular Ca2+, the key determinant of neurotransmitter release, alpha2-adrenoceptors are inhibitory after nerve injury, not excitatory. There is a shift in phenotype of sensory neurons which are inhibited by clonidine after nerve injury, which may explain clonidine's increased potency in the treatment of neuropathic compared with acute pain.

Animals↗
PubMed2002

In siblings with similar genetic susceptibility for inflammatory bowel disease, smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis.

BACKGROUND AND AIMS: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. PATIENTS: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. RESULTS: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50-5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2-0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type-in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6-92; p<0.0001). CONCLUSIONS: Smoking is a strong environmental risk factor for Crohn's disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent "protective" effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.

Adult↗
PubMed1976

Biosynthesis of plasma membrane components by SV40-virus-transformed 3T3 mouse cells temperature sensitive for expression of some transformed cell properties.

We have studied the plasma membranes of an SV40-transformed 3T3 cell line temperature sensitive for the transformed growth phenotype (ts H6-15 cells), and have found that they vary little as a function of temperature of cultivation. Analysis by polyacrylamide gel electrophoresis was performed on plasma membranes prepared from ts H6-15 cells cultured at the permissive (32 degrees C) and non-permissive (39 degrees C) temperatures and radioactively-labelled in several ways. No significant differences were seen when the electrophoretic patterns of polypeptides of the plasma membranes of ts H6-15 cells, grown through 3-4 generations in medium containing radioactive leucine (32 degrees C and 39 degrees C temperatures) were compared. Plasma membranes derived from cells similarly grown in medium with radioactive glucosamine indicated that extensive alterations in the intrinsic glycopeptides occurred in association with alteration in growth phenotype. A shift towards decreased synthesis of large molecular weight (congruent to 100 000-160 000) glycopeptides occurred in cells grown at the temperature of non-transformed growth (39 degrees C). A decrease in amount of a 120 000 molecular weight glycopeptide at 39 degrees C was the most prominent of these alterations. We have studied the surface exposure of polypeptides and glycopeptides of intact cells grown at 32 and 39 degrees C, using lactoperoxidase-catalyzed iodination, NaBH4 reduction of galactose oxidase-treated cells, and metabolic-labelling with glucosamine of trypsin-sensitive molecules. We found no major qualitative differences between whole cell extracts or between plasma membrane preparations of cells cultivated at the permissive and non-permissive temperatures. Of special interest was the observation that the formation and surface exposure of a trypsin-sensitive, 240 000 molecular weight polypeptide appeared not to be ts in ts H6-15 cells. The significance of these observations will be discussed.

Cell Fractionation↗
PubMed1994

Both naive and memory CD4 T cell subsets become anergic during MAIDS and each subset can sustain disease.

Infection of C57BL/6 mice with the LP-BM5 mixture of retroviruses causes a severe murine acquired immunodeficiency syndrome (MAIDS). After infection, the entire CD4 T cell population shifts to a memory/activated phenotype and the CD4 cells become anergic to further stimulation. This drastic shift in phenotype could result either from a response of naive cells to the virus or its products and/or from the selective expansion of cells already having a memory phenotype. We have investigated whether both naive and memory CD4 T cells can be anergized during BM5 infection and whether each subset is sufficient for disease development. We show that V beta 3/V alpha 11 TCR transgenic mice that have > 98% CD4 T cells with naive phenotype develop MAIDS. Their spleens and lymph nodes become enlarged, their CD4 population expressing the TCR transgene shifts to a memory/activated phenotype, and the CD4 cells neither proliferate nor secrete IL-2 in response to specific Ag, a fragment of pigeon cytochrome C, or to mitogens. Adult thymectomized mice, having memory but not naive CD4 T cells, also developed MAIDS and anergy of the CD4 T cell population at a rate and extent comparable to normal control mice. Furthermore, CD4 T cells from mice primed with keyhole limpet hemocyanin 6 wk before infection with BM5 also became unresponsive to KLH during MAIDS. Thus, both naive and memory CD4 T cells are rendered anergic by the BM5 virus infection and it is likely that each subset is sufficient to sustain the development of MAIDS.

Animals↗
PubMed2001

Functional analysis of the hexose transporter homologue HXT5 in Saccharomyces cerevisiae.

The HXT5 gene encodes a functional hexose transporter that has moderate affinity for glucose (K(m)=10 mM), moderate to low affinity for fructose (K(m)=40 mM) and low affinity for mannose (K(m)>100 mM). The sole presence of Hxt5p in an otherwise hexose transport null mutant is sufficient to sustain a flux through glycolysis from glucose to fermentative products. However, the presence of HXT5 as the sole hexose transporter gene results in extremely poor growth on glucose, which suggests the involvement of glucose repression in the transcriptional regulation of HXT5. From Northern blot analysis on the members of the HXT family and studies with HXT5 tagged with the green fluorescent protein (GFP), it is evident that HXT5 is transcribed and translated during conditions of relatively slow growth, during growth on non-fermentable carbon sources and in particular during sporulation. In wild-type batch cultivations on fermentable carbon sources, Hxt5p is abundant in stationary phase or after depletion of the fermentable carbon source, which seems independent of the carbon source. The deletion of HXT5 does not result in a clear phenotype. A shift of stationary phase cells to fresh glucose medium resulted in somewhat slower resumption of growth in the hxt5 deletion strain compared to the wild-type strain. The abundance of Hxt5p during stationary phase, sporulation and low glucose conditions suggests that HXT5 is a 'reserve' transporter, which might be involved in the initial uptake of glucose after the appearance of glucose. Other possible functions of the protein encoded by HXT5 will be discussed in the context of the results.

Blotting, Northern↗
PubMed1984

Natural cytotoxicity in lymphatic metastasis. II. In vivo studies with BSp73 variants differing in metastatic capacity.

The survival of cloned variants of the BSp73 tumor differing in susceptibility to natural killer (NK) and macrophage-mediated cytotoxicity in vitro was evaluated in syngeneic animals. The cytocidal effect was assayed by whole-body determination of (125I)5-iodo-2'-deoxyuridine (125IUdR) retention in intact animals and in animals depleted of phagocytes and/or radiation-sensitive lymphocytes. The following results were obtained: (1) In the peritoneal cavity, survival of the susceptible tumor cells (variant AS) was significantly higher in rats pretreated with radiation and silica than in untreated rats. (2) Cold target competition, response modification by C. parvum, and correlation of label excretion with survival of animals supported the notion that excretion rates of radioactivity were in fact determined by natural cytotoxicity in vivo. (3) Tumor cells resistant to natural cytotoxicity in vitro (variant ASML) were nevertheless killed in vivo (IP) by NK cells and macrophages. (4) Additional elements of tumor cell destruction were active upon IV injection of both AS- and ASML-derived cells, since rapid label excretion was observed irrespective of irradiation and silica treatment or addition of excess unlabeled competitor cells. The apparent increase in susceptibility of ASML cells in vivo might be due to a shift in phenotype induced by microenvironmental factors. No evidence was gained that differences in metastatic capacity exhibited by the variants might relate to differential action of natural cytotoxicity on these cells.

Animals↗
PubMed1989

Reactivation of thyroglobulin gene expression in transformed thyroid cells by 5-azacytidine.

Transformed rat thyroid cells fail to express thyroglobulin. Cells transformed with a Kirsten murine sarcoma virus carrying a temperature-sensitive ras allele lose their transformation phenotype when shifted to the nonpermissive (39 degrees C) temperature. The thyroglobulin promoter, however, remains inactive. Similarly, transfection of these cells with a thyroglobulin promoter fused to a neomycin resistance reporter gene does not produce clones resistant to G418. Treatment of the transfected cells with the DNA demethylating agent 5-azacytidine reactivates the thyroglobulin promoter and yields stable G418-resistant clones. We show that thyroglobulin promoter activity is correlated with the presence of a thyroid-specific nuclear factor, TgTF1. TgTF1 cannot be detected in transformed cells but reappears after treatment with 5-azacytidine at 39 degrees C. Restoration of Ras activity at 33 degrees C leads to the rapid loss of TgTF1 and G418 resistance.

Animals↗
PubMed2006

Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.

Adipose Tissue↗
PubMed2026

Interplay between DNA and RNA methylation shapes cancer cell plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Humans↗
PubMed1989

Spectroscopic studies of cyanobacterial phycobilisomes lacking core polypeptides.

Synechococcus sp. PCC 7002 (Agmenellum quadruplicatum PR6) genes encoding two highly conserved phycobilisome core polypeptides, a small linker polypeptide (LC8, apcC) and the allophycocyanin-B alpha-subunit (alpha APB, apcD), respectively, were interrupted by insertion of restriction fragments carrying the neomycin phosphotransferase gene of Tn5. The interrupted genes were used to transform Synechococcus sp. PCC 7002 to kanamycin resistance. The apcC- mutant assembled phycobilisomes lacking the LC8 polypeptide and the apcD- mutant assembled phycobilisomes lacking alpha APB. No other differences between the compositions of the mutant and wild-type phycobilisomes were detected. The apcC- strain grew about 25% more slowly than the wild-type, and its phycobilisomes dissociated more rapidly in 0.33 M Na/K-PO4 (pH 8.0) or in 0.75 M Na/K-PO4 at pH 8.0, at 40 degrees C, than did those of the wild-type. The phycobilisomes of this mutant were indistinguishable from those of the wild-type with respect to absorption and circular dichroism spectra, as well as time-resolved fluorescence emission. Steady-state emission spectra indicate a small decrease in long wavelength (680 nm) emission from the apcC- phycobilisomes and a complementary increase in shorter wavelength (665 nm) emission, relative to wild-type phycobilisomes. Strain apcD- phycobilisomes appear to be functionally indistinguishable from those of the wild-type, in spite of the absence of the two alpha APB subunits which bear terminal acceptor bilins. The only spectroscopic difference was seen in the steady-state fluorescence emission, for which the emission of the mutant was about 15% higher than that of the wild-type and was slightly blue-shifted. A phenotype has yet to be found for the apcD- mutation.

Cloning, Molecular↗
PubMed2000

Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells.

Benzo(a)pyrene (BaP) modulates vascular smooth muscle cells (vSMCs) from a quiescent to proliferative phenotype, a shift associated with activation of L1Md retrotransposon [K.P. Lu, K.S. Ramos, Biochem. Biophys. Res. Commun. 253 (1998) 828-833]. The present studies were conducted to evaluate L1Md activation profiles in murine vSMCs treated with BaP or its oxidative metabolites, and to screen for possible insertional mutations into p53 and retinoblastoma (RB) genes. We also sought to examine the profile of DNA damage and repair in BaP-treated vSMCs. Northern analysis revealed that BaP (0. 03-3microM), and its major reactive 7,8-diol metabolite (0. 03-3microM), activate L1Md gene in a concentration-dependent manner. Two other metabolites, 3-OH BaP and 3,6-BaP quinone (0.03-3microM), as well as hydrogen peroxide (25-75microM) also activated L1Md. No insertional mutations into either p53 or RB genes were observed in vSMCs treated with BaP in vitro, although a slight elevation of p53 mRNA was observed as early as 4h after chemical challenge. Treatment of vSMCs with 3 or 30microM BaP for 4h increased unscheduled DNA synthesis (UDS) 1.4- and 2.5-fold, respectively. Challenge with 0. 3microM BaP for 24h inhibited DNA repair capacity in vSMCs for up to 48h. These results demonstrate that BaP and its oxidative metabolites activate L1Md retrotransposon in vSMCs, which coupled to DNA damage and inhibition of DNA repair are part of the atherogenic response elicited by BaP and related hydrocarbons.

Animals↗
PubMed2005

Functional genomics in antibacterial drug discovery.

Antibacterial drug discovery has experienced a paradigm shift from phenotypic screening for antibacterial activity to rational inhibition of preselected targets. Functional genomics techniques are implemented at various stages of the early drug discovery process and play a central role in target validation and mode of action determination. The spectrum of methods ranges from genetic manipulations (e.g. knockout studies, mutation analyses and the construction of conditional mutants) to transcriptome and proteome expression profiling. Functional genomics supports antibacterial drug discovery by improving knowledge on gene function, bacterial physiology and virulence and the effects of antibiotics on bacterial metabolism.

Animals↗
PubMed2004

A pair of membrane-embedded acidic residues in the NuoK subunit of Escherichia coli NDH-1, a counterpart of the ND4L subunit of the mitochondrial complex I, are required for high ubiquinone reductase activity.

The ND4L subunit of mitochondrial NADH:ubiquinone oxidoreductase (complex I) is an integral membrane protein that contains two highly conserved glutamates within putative trans-membrane helices. We employed complex I from Escherichia coli (NDH-1) to study the role of these residues by site-directed mutagenesis. The conserved glutamates of the NuoK subunit, E36 and E72, were replaced by either Asp or Gln residues, and the effects of the mutations on cell growth and catalysis of electron transfer from deamino-NADH to ubiquinone analogues were examined. Additional mutants that carried acidic residues at selected positions within this domain were also prepared and analyzed. The results indicated that two closely located membrane-embedded acidic residues in NuoK are essential for high rates of ubiquinone reduction, a prerequisite for the growth of cytochrome bo-deficient E. coli cells on malate as the main carbon source. The two acidic residues do not have to be on adjacent helices, and mutual location on the same helix, either helix 2 or 3, at an interval of three amino acids (about one turn of the putative helix), resulted in high activity and good growth phenotypes. Nevertheless, shifting only one of them, either E36 or E72, toward the periplasmic side of the membrane by about one turn of the helix severely hampered activity and growth, whereas moving both acidic residues together to that deeper membrane position stimulated the ubiquinone reductase activity of the enzyme but not cell growth on malate, suggesting impaired energy conservation in this mutant.

Amino Acid Sequence↗
PubMed2006

Plakoglobin deficiency protects keratinocytes from apoptosis.

The armadillo family protein plakoglobin (Pg) is a well-characterized component of anchoring junctions, where it functions to mediate cell-cell adhesion and maintain epithelial tissue integrity. Although its closest homolog beta-catenin acts in the Wnt signaling pathway to dictate cell fate and promote proliferation and survival, the role of Pg in these processes is not well understood. Here, we investigate how Pg affects the survival of mouse keratinocytes by challenging both Pg-null cells and their heterozygote counterparts with apoptotic stimuli. Our results indicate that Pg deletion protects keratinocytes from apoptosis, with null cells exhibiting delayed mitochondrial cytochrome c release and activation of caspase-3. Pg-null keratinocytes also exhibit increased messenger RNA and protein levels of the anti-apoptotic molecule Bcl-X(L) compared to heterozygote controls. Importantly, reintroduction of Pg into the null cells shifts their phenotype towards that of the Pg+/- keratinocytes, providing further evidence that Pg plays a direct role in regulating cell survival. Taken together, our results suggest that in addition to its adhesive role in epithelia, Pg may also function in contrast to the pro-survival tendencies of beta-catenin, to potentiate death in cells damaged by apoptotic stimuli, perhaps limiting the potential for the propagation of mutations and cellular transformation.

Animals↗
PubMed2003

Identification of a 5-nucleotide sequence that controls expression of the ica locus in Staphylococcus aureus and characterization of the DNA-binding properties of IcaR.

Biofilm formation is an important aspect of the pathogenesis of staphylococcal infections. A beta-1,6-linked N-acetyl glucosamine polysaccharide is critical to biofilm elaboration and is synthesized by proteins encoded by the intercellular adhesion (ica) locus. These studies were undertaken to characterize the mechanism by which transcription of the ica locus in S. aureus is regulated using isogenic S. aureus MN8 and MN8 mucoid (MN8m) strains, the latter of which constitutively overproduces biofilm. Transformation of the ica locus from MN8m to the ica knock-out mutants of two strains, MN8 and NCTC 10833, conferred a strong biofilm-producing phenotype. Sequence analysis revealed a 5-nucleotide deletion within the promoter region of the ica locus in MN8m compared with the sequence in the wild-type locus. Deletion or substitution of these 5 nucleotides within the wild-type ica locus augmented transcription of the ica locus and induced the strong biofilm-producing phenotype. Gel shift analysis demonstrated that a protein(s) within cell-free lysates from strain MN8 bind(s) specifically to oligonucleotides representative of the wild-type ica promoter sequence and that this binding is greatly diminished by the deletion or substitution of the 5 nucleotides. DNase I footprint analysis revealed that purified IcaR, thought to be a regulator of ica transcription, also binds to the ica promoter sequence just upstream of the ica start codon, but its affinity for the ica promoter is unaffected by deletion of the 5-nucleotide motif. These findings identify a 5-nucleotide motif within the ica promoter region that has a functional role in transcriptional regulation of the ica locus that is independent of IcaR, and also show that IcaR binds to the promoter region of the S. aureus ica locus.

Bacterial Adhesion↗
PubMed2004

Role and development of TH1/TH2 immune responses in the lungs.

The development of T helper 1 (Th1) and Th2 responses is dependent on the cells and early signals of the innate immune system. Following inhalation of pulmonary pathogens, lung antigen-presenting cells (APCs) ingest the microbe, begin to process antigen, and migrate to peripheral lymphoid tissues (i.e., LALNs). It is in the lymph node that the APC-T cell interaction takes place; therefore, the microenvironment of the lymph node significantly influences the developing T cell response (Th1 vs Th2). Several factors can determine the nature of the T cell response, including cytokines, chemokines, microbial virulence factors, and dendritic cell phenotype. A shift in the Th1/Th2 balance in the lungs can result in chronic infection, allergic disease, and immunopathology. This review discusses the mechanisms of developing Th1/Th2 pulmonary responses, the counterregulation of Th1/Th2 immunity, and the consequences of immune deviation in the lungs.

Journal Article↗
PubMed2003

The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-gamma-producing cells.

BACKGROUND: In experimental models, imidazoquinolines exhibit several immunomodulatory activities via Toll-like receptor signaling on cells of the innate immunity. OBJECTIVE: The aim of our study was to investigate whether R-848 (Resiquimod), a small-molecular-weight synthetic compound belonging to the imidazoquinoline family and known for its ability to substantially delay the onset of recurrent genital herpes lesions in both animals and human beings, could influence, at least in vitro, the cytokine production profile of human hapten- or allergen-specific T cells. METHODS: Ampicillin- and Der p 1-specific T-cell lines were derived from peripheral blood of allergic donors in the absence or presence of R-848 and assessed by flow cytometry at the single-cell level for their ability to produce IL-4 and/or IFN-gamma. RESULTS: R-848 induced both hapten- and allergen-specific circulating T cells, including T(H)2 effectors, to produce IFN-gamma and even to lose the ability to produce IL-4, thus shifting their phenotype of cytokine production to a type 0 (T(H)0) or even T(H)1 profile. This effect was associated with an increase in the production of IL-12, IFN-alpha, IL-18, TNF-alpha, IL-10, and IL-15 by CD14(+) cells, as well as an increase in the proportions of IFN-gamma-producing CD3(-)CD16(+) (natural killer) cells. CONCLUSIONS: These results suggest that R-848, and probably other imidazoquinolines, might be used as adjuvants in view of novel allergen-specific immunotherapeutic regimens for the treatment of allergic disorders.

Adjuvants, Immunologic↗
PubMed2000

Evolutionary changes over the fifty-year history of a hybrid population of sunflowers (Helianthus).

Although there are many studies of the evolution and ecology of hybrid zones, few extend over long enough time periods to track evolutionary changes in the zones or assess the ultimate outcome of hybridization. Here we describe the current genetic and morphological composition of a hybrid sunflower population relative to its initial makeup 50 years ago. It appears that few genetically pure parental plants remain in the hybrid population and the average phenotype has shifted from an initial bias toward Helianthus bolanderi to a predominance of H. annuus-like plants. The similarity to H. annuus is more pronounced for morphology than for neutral genetic markers. In contrast to the shift in morphology that occurred primarily in the past 40 years, overall pollen viability increased to its current level during the first 10 to 15 years of hybridization, indicating the presence of strong fertility selection. Dramatic differences are seen in morphology, genetics, and pollen viability between the eastern and western halves of the population, thus confirming observations by previous authors and suggesting that selection pressures in the two halves differ. The trends seen in this hybrid population over the past 50 years suggest that H. bolanderi is undergoing genetic assimilation, and this trend may be representative of its fate throughout its range.

Biological Evolution↗