Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50% increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA.     

The acute inflammatory response in experimentally-induced pleural edema

Zusammenfassung Untersuchungen der auffallendsten Veränderungen des pleuralen Exsudates nach experimentellem Pleuralödem bei der Ratte sowie über die Ausbreitung des RISA aus den Pleuralgefässen in die Intercostalhautflüssigkeit sprechen dafür, dass sich die entzündliche Reaktion besonders langsam entwickelt, da sie selbst 5 h nach Farbinjektion noch nicht sichtbar wurde.     

The origin of hemopoietic cells in ectopic implants of spleen and marrow

Summary Spleen and marrow tissues were cross-transplanted between CBA and CBA/HT6 mice. The majority of karyotypes in the regenerated implants were of recipient origin indicating that these implants are chimeric structures with the stroma of donor origin providing a framework for the proliferation of the recipient's hemopoietic stem cell.Supported by NIH Grant AM25510-01 and DOE contract 79EV00899. R. Khademi is currently with University of Isfahan, Iran.     

Transplantation of human cortex with Alzheimer's disease into rat occipital cortex; a model for the study of Alzheimer disease

Senile dementia of the Alzheimer type (SDAT) is a major problem in the human senescent population. As this pathology cannot be reproduced in animals, research into its development is greatly impeded. The technique of implantation of the nervous tissue has been utilized in order to establish an animal model and to test the possible existence of a transmissible agent. When human temporal cortex with Alzheimer's disease is implanted in the occipital cortex of 7-week-old rats, human cerebral tissue containing abundant tangles induces in the receiver cortex a reactive fibrous gliosis. In the processes of the astrocytes, twisted filaments are evident among bundles of normal filaments. These alterations could be induced by the metabolising of abnormal filament subunits or by some infectious agent introduced by the implant.     

Influence of melatonin,constant light,or blinding on reproductive system of gerbils (Meriones unguiculatus)

Summary Male and female gerbils were implanted s.c. with a pellet containing 2 mg melatonin/23 mg beeswax every 2 weeks for a total of 3 implants. A significant depression of ovarian and uterine weight was noted in female gerbils receiving melatonin implants. In the melatonin-treated male gerbils, growth of the accessory organs was significantly inhibited although testis size was not depressed.Supported by NSF grant No. BMS-74-06276 and Population Council grant No. M 74.87.     

Stimulation of proliferation of rat spleen cells, in vitro, by a nonspecific acute inflammatory exudate. Modulation of cell response to phytohemagglutinin (PHA)]

The effect of an acute non-specific inflammatory exudate with mitogenic activity on macrophages in culture has been tested on the spontaneous and PHA-induced DNA synthesis of spleen cells in vitro. Stimulatory effect of this exudate was observed on spontaneous DNA synthesis which was detectable over a range of 1 : 4 to 1 : 4,000 concentrations. After optimal PHA stimulation, an inhibition of mitogen-induced DNA synthesis was observed when the cells were exposed to the highest concentrations (up to 1 : 128) of the exudate. Thereafter, the phenomenon could be reversed and the stimulation was maximal at a concentration of 1 : 2,000. When a sub-optimal dose of PHA was used, the simulatory effect was more pronounced and detected from 1 : 8 up to 1 : 4,000 concentrations.     

Knockout of the Bcmo1 gene results in an inflammatory response in female lung, which is suppressed by dietary beta-carotene

Beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^?/?) mice accumulate beta-carotene (BC) similarly to humans, whereas wild-type (Bcmo1 ^+/+) mice efficiently cleave BC. Bcmo1 ^?/? mice are therefore suitable to investigate BC-induced alterations in gene expression in lung, assessed by microarray analysis. Bcmo1 ^?/? mice receiving control diet had increased expression of inflammatory genes as compared to BC-supplemented Bcmo1 ^?/? mice and Bcmo1 ^+/+ mice that received either control or BC-supplemented diets. Differential gene expression in Bcmo1 ^?/? mice was confirmed by real-time quantitative PCR. Histochemical analysis indeed showed an increase in inflammatory cells in lungs of control Bcmo1 ^?/? mice. Supported by metabolite and gene-expression data, we hypothesize that the increased inflammatory response is due to an altered BC metabolism, resulting in an increased vitamin A requirement in Bcmo1 ^?/? mice. This suggests that effects of BC may depend on inter-individual variations in BC-metabolizing enzymes, such as the frequently occurring human polymorphisms in BCMO1.     

Abortive effect of autologous anti-alpha-fetoprotein antibodies in the rat]

Female Commentry Rats 80--85 days old, were immunized by 5 intramuscular injections of Mouse alphafetoprotein (AFP) and then mated. After fertilization a supplementary injections was administered. The animals were bled at different times and killed immediately after the last bleeding on the 19 or 20th day of gestation. Titers of AFP and of autologous anti-AFP antibodies in the maternal blood were determined as well as the AFP concentration in the pooled amniotic fluids from live embryos of each litter. Compared to non-immunized control series, the total of live and dead embryos per litter in animals immunized with Mouse AFP showed no difference. However, the number of live embryos was on the average 50% lower than that in the control series. The serum titers of AFP and of antibodies to autologous AFP in immunized pregnant Rats bearing dead embryos decreased concomitantly with the number of live embryos. The results reported herein demonstrate that the presence of anti-autologous AFP antibodies in pregnant Rats correlates with the interruption of development in a significant proportions of embryos. This suggests that certain spontaneous abortions in the Rat and perhaps in other mammals can be explained by the rupture of immunological tolerance to autologous AFP.     

IL-18 in inflammatory and autoimmune disease

Inflammation serves as the first line of defense in response to tissue injury, guiding the immune system to ensure preservation of the host. The inflammatory response can be divided into a quick initial phase mediated mainly by innate immune cells including neutrophils and macrophages, followed by a late phase that is dominated by lymphocytes. Early in the new millennium, a key component of the inflammatory reaction was discovered with the identification of a number of cytosolic sensor proteins (Nod-like receptors) that assembled into a common structure, the ‘inflammasome’. This structure includes an enzyme, caspase-1, which upon activation cleaves pro-forms of cytokines leading to subsequent release of active IL-1 and IL-18. This review focuses on the role of IL-18 in inflammatory responses with emphasis on autoimmune diseases.     

Interpretation of the gingival inflammatory infiltrate]

The investigation of tooth eruption in dermoid cysts of the ovary allows one to observe in the chorion at the level of the epithelial attachment, an anatomical component that seems to correspond to a local system of defense. Up until now this has been considered to be a secondary inflammatory response resulting from the bacterial or mechanical assault. This component is found to form when the tooth erupts and constitutes an important element in the physico-pathogical process and of the immune response of the dental organ.     

Altered proteostasis in aging and heat shock response in C. elegans revealed by analysis of the global and de novo synthesized proteome

Protein misfolding and aggregation as a consequence of impaired protein homeostasis (proteostasis) not only characterizes numerous age-related diseases but also the aging process itself. Functionally related to the aging process are, among others, ribosomal proteins, suggesting an intimate link between proteostasis and aging. We determined by iTRAQ quantitative proteomic analysis in C. elegans how the proteome changes with age and in response to heat shock. Levels of ribosomal proteins and mitochondrial chaperones were decreased in aged animals, supporting the notion that proteostasis is altered during aging. Mitochondrial enzymes of the tricarboxylic acid cycle and the electron transport chain were also reduced, consistent with an age-associated energy impairment. Moreover, we observed an age-associated decline in the heat shock response. In order to determine how protein synthesis is altered in aging and in response to heat shock, we complemented our global analysis by determining the de novo proteome. For that, we established a novel method that enables both the visualization and identification of de novo synthesized proteins, by incorporating the non-canonical methionine analogue, azidohomoalanine (AHA), into the nascent polypeptides, followed by reacting the azide group of AHA by ‘click chemistry’ with an alkyne-labeled tag. Our analysis of AHA-tagged peptides demonstrated that the decreased abundance of, for example, ribosomal proteins in aged animals is not solely due to degradation but also reflects a relative decrease in their synthesis. Interestingly, although the net rate of protein synthesis is reduced in aged animals, our analyses indicate that the synthesis of certain proteins such as the vitellogenins increases with age.     

Development of a multifunctional sales response model with the diagnostic aid of artificial neural networks

This paper proposes an approach that models and forecasts sales through a flexible parametric response function (multifunctional), allowing for differentiated behavioural assumptions of the response determinants to be specified, and uses neural network modelling as a re‐specification tool for the response model in order to improve forecasting performance. An initial experiment on a sample of sales data demonstrates feasibility and gives comparative insights via alternative model specifications. Copyright © 2005 John Wiley & Sons, Ltd.     

Epstein-barr virus and inflammatory bowel disease

Zusammenfassung Die Häufigkeit und der Antikörpertiter gegen Epstein-Barr-Virus (EBV) wurde in Patienten mit Ulkus-Colitis und Crohn's Krankheit, eine granulomatische Abnormalität ähnlich zur Sarkoidose untersucht und normale Häufigkeit und Antikörpertiter gegen EBV bei ihnen gefunden.

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Supported by Research Contract No. NIH-69-2078 within the Special Virus Cancer Program of the National Cancer Institute, National Institutes of Health, USPHS, National Institutes of Health Grant No. AM 05126 and the National Foundation for Ileitis and Colitis, Inc., New York, New York.

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Dr.Grotsky is a recipient of a National Institutes of Health Graduate Training Grant in Gastroenterology, No. Am 05126.

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Dr.Hirshaut is a recipient of a National Cancer Institute Grant No. CA 08748 an a grant from the New York Cancer Research Institute.

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Dr.Glade is a recipient of a Research Career Development Award No. A1-46371 of the USPHS.     

Hypersensitivity to endotoxin hepatotoxicity in rats with inflammatory lesions

Summary The ratio of sinusoidal nonparenchymal cells to hepatocytes in rat liver was significantly increased following induction of inflammation, and decreased after subsequent exposure to endotoxin, particularly in the region around the terminal portal venules. Rats with inflammatory lesions were more sensitive to endotoxin hepatocytotoxicity than normal controls, as judged from the dose-dependent increase in activity of serum transaminases and from the extent of liver tissue injury. In addition, these animals, which were already in a state of depletion of hepatic glycogen, demonstrated marked hyperglycemia 24 h after endotoxin administration in small doses of less than 2 mg/kg.     

Testosterone changes the electric organ discharge and external morphology of the mormyrid fish, Gnathonemus petersii (Mormyriformes)

Effects of silastic and pellet methyltestosterone implants on the waveform of the electric organ discharge of the weakly electric African mormyrid, Gnathonemus petersii, were investigated. Within seven days of implantation, the duration of the discharge increased dramatically while the associated peak power frequency of the Fourier spectrum decreased in all treated fish. By day 35, hormone-treated fish exhibited up to five-fold increases in EOD duration, as well as multiple discharges and variations in the shape of the positive phase of the discharge. Testosterone treatment also changed body morphology, making immature and adult female fish resemble adult males.     

Transplantation of human cortex with Alzheimer's disease into rat occipital cortex; a model for the study of Alzheimer disease

Summary Senile dementia of the Alzheimer type (SDAT) is a major problem in the human senescent population. As this pathology cannot be reproduced in animals, research into its development is greatly impeded. The technique of implantation of the nervous tissue has been utilized in order to establish an animal model and to test the possible existence of a transmissible agent. When human temporal cortex with Alzheimer's disease is implanted in the occipital cortex of 7-week-old rats, human cerebral tissue containing abundant tangles induces in the receiver cortex a reactive fibrous gliosis. In the processes of the astrocytes, twisted filaments are evident among bundles of normal filaments. These alterations could be induced by the metabolising of abnormal filament subunits or by some infectious agent introduced by the implant.This study is supported by grant No. 2.4517.82 of Fonds de la Recherche Fondamentale Collective of Belgium.     

Impulse response analysis in vector autoregressions with unknown lag order

We show that the effects of overfitting and underfitting a vector autoregressive (VAR) model are strongly asymmetric for VAR summary statistics involving higher‐order dynamics (such as impulse response functions, variance decompositions, or long‐run forecasts) . Underfit models often underestimate the true dynamics of the population process and may result in spuriously tight confidence intervals. These insights are important for applied work, regardless of how the lag order is determined. In addition, they provide a new perspective on the trade‐offs between alternative lag order selection criteria. We provide evidence that, contrary to conventional wisdom, for many statistics of interest to VAR users the point and interval estimates based on the AIC compare favourably to those based on the more parsimonious Schwarz Information Criterion and Hannan – Quinn Criterion. Copyright © 2001 John Wiley & Sons, Ltd.     

Obtaining copulation solicitation displays in female canaries without estradiol implants

Female domesticated canaries (Serinus canaria) respond to conspecific song with copulation solicitation display (CSD) between 22 and 27 days after their first offspring has hatched. This period could be used to investigate the acoustical preferences of female canaries. This non-invasive method respects the natural reproductive cycle and could be an alternative to the invasive method of estradiol implants.     

Green leaf volatiles interrupt aggregation pheromone response in bark beetles infesting southern pines

Summary Green leaf volatiles were shown to interrupt responses to aggregation pheromones of three species of bark beetles (Coleoptera: Scolytidae) which infest pines in the southern United States [the southern pine beetle,Dendroctonus frontalis Zimm.; the four-spined engraver,Ips avulsus (Eichhoff); and the five-spined engraver,Ips grandicollis (Eichhoff)]. The order of effectiveness of the compounds tested for each species was hexanal>hexanal+hexan-1-ol>hexan-1-ol. Neither hexanal, hexan-1-ol nor hexanal+hexan-1-ol was as effective in interrupting pheromone responses ofD. frontalis as verbenone, a known inhibitor of this species. Other than interspecific chemical signals, this is the first report of an interruptant forIps species, and the only report of a pheromone interruptant active for bothIps andDendroctonus species.     

Comparison of the production rates of bacteria in the rumen estimated by using labelled live and formaldehyde treated mixed bacterial cells

The bacteria production rates in the rumen have been estimated by injecting 14C- and 35S-labelled mixed rumen bacteria, either live or killed by treatment with formaldehyde, into the rumen and applying isotope dilution technique. The rate of bacteria production when estimated by using either live- or dead-(protected-)labelled bacterial cells were comparable.