bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin‐1 (IL‐1α and IL‐1β) and its receptors (IL‐1RI, IL‐1RII, and IL‐1Ra) in prostate carcinoma
Authors: Ricote Mónica , García‐Tuñón Ignacio , Bethencourt Fermín R. , Fraile Benito , Paniagua Ricardo , Royuela Mar
Published: March 2004

BACKGROUND

The principal components of the interleukin‐1 (IL‐1) family are two secreted factors (IL‐1α and IL‐1β), two transmembrane receptors (IL‐1RI [biologically active] and IL‐1RII [inert receptor]), and a natural antagonist receptor of IL‐1 function (IL‐1Ra). Changes in the expression pattern of these IL‐1 members have been reported to be related to disease progression. The objective of the current study was to evaluate these changes in prostatic tissue by means of immunohistochemistry and Western blot analysis.

METHODS

Immunohistochemical and Western blot analyses were performed in 20 normal samples, 35 samples of benign prostatic hyperplasia (BPH) and 27 samples from patients with prostate carcinoma (PC).

RESULTS

In normal prostate samples, immunoreactions to IL‐1β and IL‐1RI were positive, whereas there were no immunoreactions observed to IL‐1α, IL‐1RII, or IL‐1Ra. In BPH, in addition to immunoreactions to IL‐1β and IL‐1RI, immunoreactions to IL‐1α, IL‐1RII, and IL‐1Ra were observed in many samples. In samples of PC with low Gleason grade, most tumors had positive immunoreactions to IL‐1α and IL‐1RI. In samples of PC with high Gleason grade, immunoreactions were seen only to IL‐1α, IL‐1RI, and IL‐1RII.

CONCLUSIONS

The current results suggested that high expression levels of IL‐1α and IL1‐RI in epithelial cells in BPH and PC samples were involved in cell proliferation and that the loss of immunoexpression of IL‐1β and IL‐1Ra was a characteristic feature of PC compared with normal prostate samples and BPH. Because this loss is progressive up to a complete absence of immunoexpression in PC of high Gleason grade, the evaluation of IL‐1β and IL‐1Ra in PC may be significant in assessing for malignancy. Cancer 2004;100:1388–96. © 2004 American Cancer Society.
Anthropometric variables, physical activity, and incidence of ovarian cancer
Authors: Anderson Jeffrey P. , Ross Julie A. , Folsom Aaron R.
Published: March 2004

BACKGROUND

Reports on the relation between anthropometric variables (height, weight) and physical activity with ovarian cancer have been inconclusive. The objective of the current study was to extend investigation of potential associations in the Iowa Women's Health Study cohort.

METHODS

The relation between self‐reported anthropometric variables and incident ovarian cancer was studied in a prospective cohort of women ages 55–69 years who were followed for 15 years. Two hundred twenty‐three incident cases of epithelial ovarian cancer were identified by linkage to a cancer registry.

RESULTS

No association was found overall between ovarian cancer and height, but a positive association was observed for serous ovarian cancers (relative risk [RR], 1.86 for highest quartile vs. lowest quartile; 95% confidence interval [95% CI], 1.06–3.29). Although current body mass index (BMI) was not associated with ovarian cancer, a BMI ≥ 30 kg/m2 at age 18 years appeared to be associated positively with ovarian cancer (multivariate‐adjusted RR, 1.83 for BMI ≥ 30 kg/m2 vs. BMI < 25 kg/m2; 95% CI, 0.90–3.72), and this association was stronger after exclusion of the first 2 years of follow‐up (RR, 2.15; 95% CI, 1.05–4.40). In a multivariate analysis, waist‐to‐hip ratio was associated with ovarian cancer (RR, 1.59 for highest quartile vs. lowest quartile; 95% CI, 1.05–2.40), but a linear dose response was not found. An index that combined the frequency and intensity of leisure‐time physical activity was associated positively with ovarian cancer incidence (multivariate‐adjusted RR, 1.42 for high activity vs. low activity; 95% CI, 1.03–1.97). This association was particularly strong for frequency of vigorous physical activity (multivariate‐adjusted RR, 2.38 for > 4 times per week vs. rarely/never; 95% CI, 1.29–4.38).

CONCLUSIONS

Anthropometric variables were not major risk factors for ovarian cancer in the cohort studied; however, high BMI in early adulthood and frequent and vigorous physical activity may increase the risk of ovarian cancer among postmenopausal women. Cancer 2004;100:1515–21. © 2004 American Cancer Society.
Low‐curvature image simplifiers: Global regularity of smooth solutions and Laplacian limiting schemes
Authors: Bertozzi Andrea L. , Greer John B.
Published: March 2004

We consider a class of fourth‐order nonlinear diffusion equations motivated by Tumblin and Turk's “low‐curvature image simplifiers” for image denoising and segmentation. The PDE for the image intensity u is of the form

where g(s) = k2/(k2 + s2) is a “curvature” threshold and λ denotes a fidelity‐matching parameter. We derive a priori bounds for Δu that allow us to prove global regularity of smooth solutions in one space dimension, and a geometric constraint for finite‐time singularities from smooth initial data in two space dimensions. This is in sharp contrast to the second‐order Perona‐Malik equation (an ill‐posed problem), on which the original LCIS method is modeled. The estimates also allow us to design a finite difference scheme that satisfies discrete versions of the estimates, in particular, a priori bounds on the smoothness estimator in both one and two space dimensions. We present computational results that show the effectiveness of such algorithms. Our results are connected to recent results for fourth‐order lubrication‐type equations and the design of positivity‐preserving schemes for such equations. This connection also has relevance for other related fourth‐order imaging equations. © 2004 Wiley Periodicals, Inc.
Syntheses and Morphologies of Carbon Microsolenoid Composites and Double Negative Microcoils
Authors: Yang S. , Chen X. , Motojima S.
Published: March 2004

Novel carbon microsolenoid composites with central straight nanopores along the coil axes and double negative microcoils with helically formed nanopores along the fiber axes were prepared by a two‐step CVD process using carbon microcoil (CMC) templates. The as‐grown CMC templates were synthesized at 780 °C, and the pyrolytic carbon layer (Py‐C) was coated in‐situ at 860 °C on the surface, then the core CMCs were preferentially oxidized at 700 °C for 10 min in air. In the carbon microsolenoids, the straight, central nanopores, with a diameter of 0–600 nm, were derived from the central pores existing along the coil axis of the source, regularly‐coiled CMC templates, while the double negative microcoils were derived from the burnt‐out core CMC templates in the carbon microsolenoids. The morphology and microstructure of the novel carbon materials were observed and analyzed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetry (TG), and X‐ray diffraction (XRD).
Atomic Layer Deposition of Hafnium Dioxide Films from Hafnium Hydroxylamide and Water
Authors: Kukli K. , Ritala M. , Leskelä M. , Sajavaara T. , Keinonen J. , Jones A.C. , Tobin N.L.
Published: March 2004

HfO2 films were grown by atomic layer deposition (ALD) from a new liquid precursor, Hf(ONEt2)4 and H2O, at temperatures between 250 °C and 350 °C on borosilicate glass and Si(100) substrates. The highest growth rate was achieved at 300 °C, whereas the growth was essentially slower at 250 °C and ceased at 350 °C. The films possessed an O:Hf ratio of 2.15 ± 0.12, as determined by ion beam analysis. The films were weakly crystallized, showing X‐ray diffraction (XRD) peaks characteristic of monoclinic phase. The refractive index of the films varied between 1.93 and 1.96. The effective permittivities of the dielectric layers in Al/HfO2/n‐Si(100) capacitor structures were close to 10.
A linkage study of 12 IDDM susceptibility loci in the Finnish population
Authors: Laine Antti‐Pekka , Nejentsev Sergei , Veijola Riitta , Korpinen Eija , Sjöroos Minna , Simell Olli , Knip Mikael , Åkerblom Hans K , Ilonen Jorma
Published: March 2004

Background

HLA region is the major locus (IDDM1) of type 1 diabetes (T1D) susceptibility. It explains approximately 50% of the genetic background of T1D, indicating additional genetic determinants. Genome scans and candidate gene studies have generated several chromosomal candidate regions that may have a role in T1D development.

Methods

We tested 12 of these loci for linkage in 107 Finnish T1D multiplex families using 23 microsatellite markers and 2 SNPs. Families were stratified according to the HLA status and sharing at the DQB1 gene.

Results

We found no significant or suggestive MLS in our unstratified families outside the IDDM1 locus. The highest MLS was seen close to the IDDM9 region marker D3S3576 at 3q21‐q25 (MLS = 1.05). This marker also had a global p‐value of 0.0032 (ETDT) in maternal transmissions. IDDM6 and 12q12‐q15 region showed MLS = 1.1 and MLS = 1.3 respectively in HLA‐DQB1*0302/x (x ≠ HLA − DQB1*02) stratified families. IDDM12 showed MLS = 2.0 in HLA‐DQB1 identical sib pairs. Linkage at IDDM12 was supported by a global p‐value of 0.0006 (uncorrected) in ETDT. For IDDM2, p‐values of 0.028 and 0.009 were observed in ETDT with MspI – 2221 SNP in unstratified and HLA‐DQB1*0302/x‐stratified families respectively.

Conclusions

Our results are consistent with previous findings of linkage or association to T1D at IDDM2, IDDM6, IDDM9, IDDM12 and 12q12‐q15 regions but do not unambiguously confirm them. A larger sample set is required to gain statistical power needed to confirm our findings in the Finnish population. Copyright © 2004 John Wiley & Sons, Ltd.
Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood
Authors: Sadauskaitė‐Kuehne Vaiva , Ludvigsson Johnny , Padaiga Žilvinas , Jašinskienė Edita , Samuelsson Ulf
Published: March 2004

Background

Early weaning diet, early introduction of breast milk substitution and cow's milk have been shown to increase the risk of type 1 diabetes later in life. It is also shown that older maternal age, maternal education, preeclampsia, prematurity, neonatal illness and neonatal icterus caused by blood group incompatibility, infections and stress might be risk factors for type 1 diabetes. We aimed to determine whether early nutrition is an independent risk factor for diabetes despite other life events.

Methods

Data from 517 children (268 boys and 249 girls) in south‐east of Sweden and 286 children (133 boys and 153 girls) in Lithuania in the age group of 0 to 15 years with newly diagnosed type 1 diabetes mellitus were included into analysis. Three age‐ and sex‐matched healthy controls were randomly selected. Response rate in control families in Sweden was 72.9% and in Lithuania 94.8%. Information was collected via questionnaires.

Results

Exclusive breastfeeding longer than five months (odds ratio 0.54, 95% confidence interval 0.36–0.81) and total breastfeeding longer than 7 (0.56, 0.38–0.84) or 9 months (0.61, 0.38–0.84), breastfeeding substitution that started later than the third month (0.57, 0.33–0.98) among Swedish children 5 to 9 years old and later than the seventh month (0.24, 0.07–0.84) among all Swedish children is protective against diabetes when adjusted for all other above‐listed risk factors. In Lithuania, exclusive breastfeeding longer than two months in the age group of 5 to 9 years is protective (0.58, 0.34–0.99) when adjusted for other factors.

Conclusions

Longer exclusive and total breastfeeding appears as an independent protective factor against type 1 diabetes. Copyright © 2004 John Wiley & Sons, Ltd.
Pharmacological approach to diabetic retinopathy
Authors: José Pedro De La Cruz M. D. , José Antonio González‐Correa M. D. , Ana Guerrero M. D. , Felipe Sánchez de la Cuesta M. D.
Published: March 2004

Diabetic retinopathy is the most frequent cause of legal blindness in the population of 30‐to‐70‐year olds. Whether retinopathy appears or not depends mainly on the duration of the disease and the degree of metabolic control the patient maintains. High blood glucose values lead to important changes in cellular metabolism and the main effects of these alterations are endothelial dysfunction that sets in motion the morphological process of diabetic retinopathy.

The biochemical lesions caused by prolonged hyperglycemia can be positively influenced, but usually not normalized, pharmacologically with some groups of drugs, which are now under development. This makes tight control of glycemia a key measure in preventing the onset or progression of diabetic retinopathy, together with an effective program of ophthalmologic detection and follow‐up in patients with diabetes. Regarding the role of endothelial dysfunction, antiplatelet drugs have been shown to slow some aspects of the evolution of diabetic retinopathy in its initial stages, mainly a lower degree of microaneurysms. However, a new approach to controlling endothelial dysfunction shows promise, mainly through the vascular endothelial growth factor (VEGF) inhibitors. These agents may prove to be especially useful in the treatment of proliferative diabetic retinopathy. Other encouraging results have been obtained in studies of antioxidant drugs and inhibitors of the formation of advanced glycation end products.

Once retinal lesions appear, preventive measures need to be redoubled, with special attention to controlling glycemia; however, it is also necessary to resort to laser photocoagulation. This intervention aims to eliminate areas of ischemia and to diminish the formation of retinal exudates. If this measure fails or if vitreous hemorrhage appears, the only remaining therapeutic measure is vitrectomy. Copyright © 2004 John Wiley & Sons, Ltd.
Periostin is expressed within the developing teeth at the sites of epithelial–mesenchymal interaction
Authors: Kruzynska‐Frejtag Agnieszka , Wang Jian , Maeda Manabu , Rogers Rhonda , Krug Edward , Hoffman Stanley , Markwald Roger R. , Conway Simon J.
Published: March 2004

Periostin was originally isolated as an osteoblast‐specific factor that functions as a cell adhesion molecule for preosteoblasts and is thought to be involved in osteoblast recruitment, attachment, and spreading. The protein was renamed “periostin” because of its expression in the periosteum and periodontal ligament, indicating a potential role in bone and maintenance of tooth structure. Periostin has structural similarity to insect fasciclin‐I and can be induced by TGF‐β and Bmp2. Because tooth and periodontium development is a well‐described genetic model for organogenesis governed by a reciprocal set of epithelial–mesenchymal interactions, thought to be controlled by various TGF‐β superfamily members, we investigated whether periostin is present during tooth morphogenesis. Both periostin mRNA and protein expression were analyzed throughout normal tooth development (embryonic day [E] 9.5–newborn) and within both Bmp4‐ and Msx2‐null embryos. Periostin mRNA is initially present within the E9.5 first branchial arch epithelium and then shifts to underlying ectomesenchyme. Both mRNA and protein are asymmetrically localized to the lingual/palatal and buccal side during the early epithelial–mesenchymal interactions. Periostin is also present in dental papilla cells and within the trans‐differentiating odontoblasts during the bell and hard tissue formation stages of tooth development. We suggest that periostin plays multiple roles as a primary responder molecule during tooth development and may be linked to deposition and organization of other extracellular matrix adhesion molecules during maintenance of the adult tooth, particularly at the sites of hard‐soft tissue interface. Developmental Dynamics 229:857–868, 2004. © 2004 Wiley‐Liss, Inc.
PI3K inhibitors block skeletogenesis but not patterning in sea urchin embryos
Authors: Bradham C.A. , Miranda E.L. , McClay D.R.
Published: March 2004

Skeletogenesis in the sea urchin embryo is a simple model of biomineralization, pattern formation, and cell–cell communication during embryonic development. The calcium carbonate skeletal spicules are secreted by primary mesenchyme cells (PMCs), but the skeletal pattern is dictated by the embryonic ectoderm. Although the process of skeletogenesis is well characterized, there is little molecular understanding of the basis of patterning within this system. In this study, we examined the contribution of phosphatidylinositide 3‐kinase (PI3K)‐mediated signaling to the skeletogenic process in sea urchin embryos by using the well‐established PI3K inhibitors LY294002 and wortmannin. Our results show that PI3K inhibitors specifically and reversibly block skeletogenesis, and that this blockade occurs within the PMCs rather than in the ectoderm, because the inhibitors block spiculogenesis in cultured micromeres. Our results are consistent with a model in which PI3K signaling is required, not for pattern sensing or interpretation but rather for the biomineralization process itself in the sea urchin embryo. Developmental Dynamics 229:713–721, 2004. © 2004 Wiley‐Liss, Inc.
Atlas of Hox gene expression in the developing kidney
Authors: Patterson Larry T. , Potter S. Steven
Published: March 2004

Hox genes often play important roles in segment identity determination and organogenesis. To better understand the roles of Hox genes during kidney development, we performed an extensive analysis of their expression patterns. Section in situ hybridizations were used to define the expression of 37 Hox genes at embryonic day (E) 12.5, E13.5, E15.5, and E17.5 of kidney development. Several interesting principles emerged. First, the concept of colinearity was preserved. Hox genes from the more 3′ positions in clusters were more often expressed in the ureteric bud, which is derived from the anterior of the intermediate mesoderm. Second, Hox genes were expressed throughout the ureteric bud without any segment specificity. Third, in the different segments of the forming nephron we did observe overlapping domains of Hox gene expression, which initiated distally at the junction between the nephron and ureteric bud, and extended proximally variable distances. Finally, we observed that paralogous Hox genes often showed surprisingly diverse expression patterns. Indeed, contiguous genes on a single cluster more often showed similar expression patterns than paralogs. In summary, the resulting atlas of Hox gene expression provides a foundation for further study of the overlapping functions Hox genes in the developing kidney. Developmental Dynamics 229:771–779, 2004 © 2004 Wiley‐Liss, Inc.
Notch signaling can regulate endoderm formation in zebrafish
Authors: Kikuchi Yutaka , Verkade Heather , Reiter Jeremy F. , Kim Cheol‐Hee , Chitnis Ajay B. , Kuroiwa Atsushi , Stainier Didier Y.R.
Published: March 2004

Early in vertebrate development, the processes of gastrulation lead to the formation of the three germ layers: ectoderm, mesoderm, and endoderm. The mechanisms leading to the segregation of the endoderm and mesoderm are not well understood. In mid‐blastula stage zebrafish embryos, single marginal cells can give rise to both endoderm and mesoderm (reviewed by Warga and Stainier [2002] The guts of endoderm formation. In: Solnica‐Krezel L, editor. Pattern formation in zebrafish. Berlin: Springer‐Verlag. p 28–47). By the late blastula stage, however, single marginal cells generally give rise to either endoderm or mesoderm. To investigate this segregation of the blastoderm into cells with either endodermal or mesodermal fates, we analyzed the role of Notch signaling in this process. We show that deltaC, deltaD, and notch1 are expressed in the marginal domain of blastula stage embryos and that this expression is dependent on Nodal signaling. Activation of Notch signaling from an early stage leads to a reduction of endodermal cells, as assessed by sox17 and foxA2 expression. We further find that this reduction in endoderm formation by the activation of Notch signaling is preceded by a reduction in the expression of bonnie and clyde (bon) and faust/gata5, two genes necessary for endoderm formation (Reiter et al. [1999] Genes Dev 13:2983–2995; Reiter et al. [2001] Development 128:125–135; Kikuchi et al. [2001] Genes Dev 14:1279–1289). However, activation of Notch signaling in bon mutant embryos leads to a further reduction in endodermal cells, also arguing for a bon‐independent role for Notch signaling in endoderm formation. Altogether, these results suggest that Notch signaling plays a role in the formation of the endoderm, possibly in its segregation from the mesoderm. Developmental Dynamics 229:756–762, 2004. © 2004 Wiley‐Liss, Inc.
T‐box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers
Authors: Christoffels Vincent M. , Hoogaars Willem M.H. , Tessari Alessandra , Clout Danielle E.W. , Moorman Antoon F.M. , Campione Marina
Published: March 2004

Specific regions of the embryonic heart tube differentiate into atrial and ventricular chamber myocardium, whereas the inflow tract, atrioventricular canal, inner curvatures, and outflow tract do not. These regions express Tbx2, a transcriptional repressor. Here, we tested its role in chamber formation. The temporal and spatial pattern of Tbx2 mRNA and protein expression in mouse hearts was found to be complementary to that of chamber myocardium‐specific genes Nppa, Cx40, Cx43, and Chisel, and was conserved in human. In vitro, Tbx2 repressed the activity of regulatory fragments of Cx40, Cx43, and Nppa. Hearts of transgenic embryos that expressed Tbx2 in the prechamber myocardium completely failed to form chambers and to express the chamber myocardium‐specific genes Nppa, Cx40, and Chisel, whereas other cardiac genes were normally expressed. These findings provide the first evidence that Tbx2 is a determinant in the local repression of chamber‐specific gene expression and chamber differentiation. Developmental Dynamics 229:763–770, 2004. © 2004 Wiley‐Liss, Inc.
Microarray analysis of retinoid‐dependent gene activity during rat embryogenesis: Increased collagen fibril production in a model of retinoid insufficiency
Authors: Flentke George R. , Baker Mei W. , Docterman Kimberly E. , Power Susan , Lough John , Smith Susan M.
Published: March 2004

Retinoic acid (RA) is an essential mediator of embryogenesis. Some, but not all, of its targets have been identified. We previously developed a rat model of gestational retinoid deficiency (RAD; Power et al. [1999] Dev. Dyn. 216:469–480) and generated embryos with developmental impairments that closely resemble genetic and dietary models of retinoid insufficiency. Here, we used microarray analysis and expression profiling to identify 88 transcripts whose abundance was altered under conditions of retinoid insufficiency, as compared with normal embryos. Among these, the induction by RAD of genes involved in collagen I synthesis (COL1A1, IA2 and VA2, prolyl‐4‐hydroxylase‐α1) and protein galactosylation (galactokinase, ABO galactosyltransferase, UDP‐galactose transporter‐related protein) was especially noteworthy because extracellular matrix regulates many developmental events. We also identified several genes involved with stress responses (cathepsin H, UBC2E, IGFBP3, smoothelin). Real‐time polymerase chain reaction analysis of selected candidates revealed excellent agreement with the array findings. Further validation came from the demonstration that these genes were similarly dysregulated in two genetic models of retinoid insufficiency, the retinol binding protein null‐mutant embryo and the Raldh2 null‐mutant embryo. In situ hybridization of RAD embryos found increased collagen IA1 and IGFBP3 mRNA within the connective mesenchyme and vasculature, respectively, and a failure to repress the growth factor midkine within the RAD neural tube. Many of the identified genes were not known previously to respond to retinoid status and will provide new insights to retinoid roles and to the consequences of retinoid insufficiency. Developmental Dynamics 229:886–898, 2004. © 2004 Wiley‐Liss, Inc.
IL‐1 acts on antigen‐presenting cells to enhance the in vivo proliferation of antigen‐stimulated naive CD4 T cells via a CD28‐dependent mechanism that does not involve increased expression of CD28 ligands
Authors: Khoruts Alexander , Osness Richard E. , Jenkins Marc K.
Published: March 2004

The basis of the adjuvant effect of IL‐1 on the clonal expansion of Ag‐specific CD4 T cells was measured in vivo using the TCR transgenic T cell adoptive transfer method. Injection ofAg plus IL‐1 caused naive CD4 T cells to proliferate to a greater extent than did injection of Ag alone. The T cells had to express CD28 to experience the beneficial effect of IL‐1 whereas the hosthad to express the type I IL‐1R, raising the possibility that IL‐1's adjuvant properties were related to induction of CD28 ligands on APC. Surprisingly, however, expression of CD28 ligands on DC and B cells was not affected by IL‐1. Therefore, the adjuvant properties of IL‐1 depend on a basal level of CD28 signaling but cannot be explained by enhanced CD28 signaling due to CD28 ligand induction.
The role of Toll‐like receptor 4 versus interleukin‐12 in immunity to respiratory syncytial virus
Authors: Ehl Stephan , Bischoff Ruth , Ostler Tobias , Vallbracht Simone , Schulte‐Mönting Jürgen , Poltorak Alexander , Freudenberg Marina
Published: March 2004

Toll‐like receptors (TLR) and IL‐12 represent key elements of innate immunity. Using C57BL/10 ScCr mice it was shown that TLR4 is important for control of infection with respiratory syncytial virus (RSV). Since these mice have an additional defect in the IL‐12R, we reinvestigated immunity to RSV in several C57BL/10 and BALB/c mouse strains lacking a functional TLR4, a functional IL‐12–IL‐12R interaction or both. In the absence of a functional IL‐12 axis, early virus control was impaired in C57BL/10 mice, but not in BALB/c mice. By contrast, TLR4 had no impact on RSV elimination. Pulmonary NK cell recruitment was impaired in IL‐12 deficient BALB/c mice and NK cytotoxicity was reduced in IL‐12/IL‐12R‐deficient mice of both genetic backgrounds. Absence of TLR4 had no impact on NK cell recruitment or NK activity nor on recruitment of other pulmonary inflammatory cells. Activation of RSV‐specific T cell immunity, including T cell mediated immunopathology, was normal in all mutant strains. These findings clearly argue against a significant role for TLR4 and define a limited role for IL‐12 in primary murine RSV infection.
Phenotypic classification of human CD8+ T cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector function
Authors: Tomiyama Hiroko , Takata Hiroshi , Matsuda Tomoko , Takiguchi Masafumi
Published: March 2004

Phenotypic classification of human CD8+ T cells using three cell surface markers, CD27, CD28 and CD45RA, was recently suggested to be useful for identification of naive, memory and effector CD8+ T cells. However, it still remains unclear whether such classification precisely reflects functional classification of CD8+ T cells. To clarify this, we characterized each CD27CD28CD45RA subset of total and human cytomegalovirus (HCMV)‐specific CD8+ T cells by analyzing the expression of perforin and two chemokine receptors, CCR5 and CCR7, as well as their function. An inverse correlation between perforin and CD27 expression was found in all four CD28CD45RA subsets. Therefore, to achieve a phenotypic classification of CD8+ T cells that moreprecisely reflects their function, the CD27+ subset was divided into CD27low and CD27high subsets based on the expression level of CD27. Functional and flow cytometric analyses of CD27CD28CD45RA subsets showed that this phenotypic classification reflects functional classification of CD8+ T cells. HCMV‐specific CD8+ T cells from healthy HCMV‐seropositive individuals were predominantly found in effector and memory/effector subsets, indicating that HCMV‐specific effector CD8+ T cells are actively induced by HCMV replication in healthy HCMV carriers. Phenotypic analyses of CD8+ T cells using this classification will enable the characterization of antigen‐specific CD8+ T cells.
The anti‐inflammatory effects of 1,25‐dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin‐mediated T lymphocyte homing
Authors: Topilski Ian , Flaishon Liat , Naveh Yaron , Harmelin Alon , Levo Yoram , Shachar Idit
Published: March 2004

The fat soluble vitamin D3 metabolite 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], and its nuclear receptor play an important role in regulating immune responses. While 1,25(OH)2D3 is known to inhibit transcription of cytokine genes that are required for Th1 differentiation or are products of differentiated Th1 cells, its role in regulating differentiation of Th2 cells is less clear. In this study, we show that 1,25(OH)2D3 has anti‐inflammatory effects in an in vivo Th2‐dependent asthma model. In addition, we demonstrate that 1,25(OH)2D3 down‐regulates the cytoskeleton rearrangement required for promoting integrin‐mediated adhesion of naive and effector CD4+ T cells. Finally, 1,25(OH)2D3 inhibits chemokine‐induced migration of naive cells and their homing to the lymph nodes. Thus, in addition to its regulation of cytokine transcription, 1,25(OH)2D3 regulates migration of cells and thus controls the skewing of various Th subsets in the secondary lymphoid organs and inhibits Th function at sites of inflammation.
CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion
Authors: Mayne Michael , Moffatt Teri , Kong Hong , McLaren Paul J. , Fowke Keith R. , Becker Kevin G. , Namaka Mike , Schenck Annette , Bardoni Barbara , Bernstein Charles N. , Melanson Maria
Published: March 2004

DNA microarray profiling of CD4+ and CD8+ cells from non‐treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4+ cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral‐mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin‐mediated adhesion. Secondly, CYFIP2 knock‐down experiments using antisense oligodeoxynucleotides reduced fibronectin‐mediated binding in Jurkat and CD4+ cells. Thirdly, inhibition of Rac‐1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin‐mediated adhesion in Jurkat and CD4+ cells. Finally, inhibition of Rac‐1 or reduction of CYFIP2 protein decreased fibronectin‐mediated adhesion in CD4+ cells from MS patients to levels similar to controls. These studies suggest that overabndance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.
Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production
Authors: Kuroki Aki , Moll Thomas , López‐Hoyos Marcos , Fossati‐Jimack Liliane , Ibnou‐Zekri Nabila , Kikuchi Shuichi , Merino Jesús , Merino Ramón , Izui Shozo
Published: March 2004

The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of theanti‐apoptotic Bcl‐2 protein and the Y‐linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti‐DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus‐prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl‐2‐transgenic and BXSB non‐transgenic cells demonstrated that an enforced Bcl‐2 expression in B cells promoted the induction of IgG anti‐DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70‐anti‐gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl‐2 overexpression on IgG anti‐DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl‐2‐transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti‐DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.
Mini‐review: A pivotal role for innate immunity in the clearance of apoptotic cells
Authors: Roos Anja , Xu Wei , Castellano Giuseppe , Nauta Alma J. , Garred Peter , Daha Mohamed R. , van Kooten Cees
Published: March 2004

Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro‐inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement‐activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriersof genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self‐tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.
One‐ and Three‐Dimensional Coordination Polymers Containing Organic Ligands Produced Through in situ Hydrothermal Reactions
Authors: Hu Xi‐Xue , Pan Cheng‐Ling , Xu Ji‐Qing , Cui Xiao‐Bing , Yang Guang‐Di , Wang Tie‐Gang
Published: March 2004

Two novel coordination polymers of cobalt(II), [Co(µ3‐H2bbh)(phen)]n(1) and [Co(µ4‐H2bbh) (H2O)2]n(2) (phen = 1,10‐phenanthroline; H4bbh = benzene‐1,2,4,5‐tetracarbo‐1,2:4,5‐dihydrazide), in which H2bbh ligands are in situ generated by an acylation reaction of H4bta (H4bta = benzene‐1,2,4,5‐tetracarboxylic acid) with hydrazine hydrate under hydrothermal conditions have been synthesized and structurally characterized. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis, Characterization and in Vitro Study of the Cytostatic and Antiviral Activity of New Polymeric Silver(I) Complexes with Ribbon Structures Derived from the Conjugated Heterocyclic Thioamide 2‐Mercapto‐3,4,5,6‐tetra‐ hydropyrimidine
Authors: Zachariadis Panagiotis C. , Hadjikakou Sotiris K. , Hadjiliadis Nick , Skoulika Stavroula , Michaelides Adonis , Balzarini Jan , De Clercq Erik
Published: March 2004

Silver(I) bromide reacts with 2‐mercapto‐3,4,5,6‐tetrahydropyrimidine (StpmH2, C4H8N2S) in DMSO with an excess of triethylamine to give a water‐insoluble complex of formula [Ag6(μ2‐Br)6(μ2‐StpmH2)4(μ3‐StpmH2)2]n (1), while the reaction of silver(I) nitrate with StpmH2 under the same conditions gives a water‐insoluble complex of formula [{Ag4(μ2‐StpmH2)6}(NO3)4]n (2). The products were characterized by elemental analyses, and FT‐IR far‐IR, UV/Vis, 1H and 13C NMR spectroscopy. Crystal structures of complexes 1 and 2 were determined by X‐ray diffraction. Complex 1, C24H48Ag6N12S6, crystallizes in the triclinic system space group P$\bar 1$
, a = 8.041(1) Å, b = 12.838(4) Å, c = 13.281(2) Å, α = 68.40(1)°, β = 72.97(1)°, γ = 87.80(2), Z = 2, forming a one‐dimensional infinite ribbon structure by strong interatomic interactions of two μ2‐Br bonds with Ag(1). Complex 2, C24H48Ag4N16O12S6, crystallizes in the orthorhombic system, space group Cmc21, and a = 32.148(3) Å, b = 9.461(2) Å, c = 7.234(1) Å, α = β = γ = 90°, Z = 8, forming infinite Ag−S−Ag chains which are bridged to each other by a sulfur atom of μ2‐StpmH2 ligands. Complexes 1 and 2 were studied for their cytostatic activity against murine leukemia (L1210) and human T‐lymphocyte (Molt4/C8 and CEM) cells and for their antiviral activity against a wide variety of viruses. They are markedly cytostatic at 50% inhibitory concentration (IC50) values ranging from 3 to 17 μg/mL. None of the compounds showed appreciable antiviral activity at subtoxic concentrations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
sp3‐C1‐Bridged 1,3‐Me2Cp/Amido Titanium and Zirconium Complexes and Their Reactivities towards Ethylene Polymerization
Authors: Kim Tae Ho , Won Young Chul , Lee Bun Yeoul , Shin Dong Mok , Chung Young Keun
Published: March 2004

sp3‐C1‐Bridged Cp/amido titanium and zirconium complexes are synthesized by using novel fulvenes that have substituents in the 1‐, 4‐, and 6‐positions only. Thus, the nucleophilic attack of lithium tert‐butylamide on 1,4‐dimethyl‐6‐phenylfulvene, 6‐(2‐furyl)‐1,4‐dimethylfulvene and 6‐cyclohexyl‐1,4‐dimethylfulvene, and subsequent aqueous workup, yields tBuN(H)−CHR−C5H3Me2 (R = phenyl, 6; R = 2‐furyl, 7; R = cyclohexyl, 8) in 80, 88, and 60% yields, respectively. The reactions of the ligands with M(NMe2)4 (M = Ti or Zr) afford the desired bis(dimethylamido) complexes, which can be transformed by treatment with Me2SiCl2 to the dichloride complexes, (1,3‐Me2C5H2−CHR−NtBu−κN)MCl2 (M = Ti, R = phenyl, 10; M = Zr, R = phenyl, 11; M = Ti, R = 2‐furyl, 13; M = Zr, R = 2‐furyl, 14; M = Zr, R = cyclohexyl, 15). Complex 10 is very sensitive towards water, such that an oxo‐bridged dimer, (1,3‐Me2C5H2−CHPh−NHtBu)ZrCl2−μO−ZrCl2(1,3‐Me2C5H2−CHPh−NHtBu) (12), is easily formed by the abstraction of water from the solvents. The solid structures of (1,3‐Me2C5H2−CHPh−NtBu−κN)Zr(NMe2)2, 10, 11, and 12 have been determined by X‐ray crystallography. The complexes are active towards the polymerization of ethylene when activated with MAO. The activities are rather low and the molecular weight distributions are broad (Mw/Mn = 10−36). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis and Characterization of the Diastereomers Λ‐ and Δ‐[Ru(bpy)2(m‐bpy‐Gly‐L‐His‐L‐Lys)]Cl2−1H NMR Studies on Their Interactions with the Deoxynucleotide Duplex d[(5′‐CGCGAATTCGCG‐3′)2]
Authors: Myari Alexandra , Hadjiliadis Nick , Garoufis Achilleas
Published: March 2004

The synthesis and characterization of the diastereomeric complexes Λ‐ and Δ‐[Ru(bpy)2(m‐bpy‐GHK)]Cl2, (GHK = glycine‐L‐histidine‐L‐lysine, m‐bpy = 4′‐methyl‐2,2′‐bipyridine) as well as their binding properties to the deoxynucleotide duplex d(5′‐CGCGAATTCGCG‐3′)2studied by means of NMR, ESI‐MS and CD spectroscopy, are reported. The ROESY spectrum of Λ‐[Ru(bpy)2(m‐bpy‐GHK)]Cl2shows intramolecular cross peaks between the bpy H3 or H3′ protons and the aromatic H2 and H5 of the histidine imidazole ring, indicating that the peptide adopts an orientation with the imidazole ring close to the bpy ligand, possibly interacting by π‐stacking. The absence of intramolecular cross peaks between the peptide and the bipyridine ligands in the ROESY spectrum of Δ‐[Ru(bpy)2(m‐bpy‐GHK)]Cl2on the other hand, shows that in this case the peptide is far from the two bpy ligands, having a different orientation from the Λ isomer. The isomers interact with the oligonucleotide duplex differently. Δ‐[Ru(bpy)2(m‐bpy‐GHK)]Cl2binds in the oligonucleotide major groove close to the central part of the sequence. Λ‐[Ru(bpy)2(m‐bpy‐GHK)]Cl2binds, probably non selectively, approaching the helix from the minor groove. It can be concluded that the peptide (GHK) binding leads the rest of the isomer to interact with the oligonucleotide in the case of the Δ isomer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Reactivity of 2‐Aminothiazole and 2‐ or 6‐Aminobenzothiazole Derivatives Towards the Triphenylbismuth Diacetate/Catalytic Copper Diacetate Phenylation System
Authors: Miloudi Abdellah , El‐Abed Douniazad , Boyer Gérard , Finet Jean Pierre , Galy Jean Pierre , Siri Didier
Published: March 2004

The copper diacetate catalysed reaction of triphenylbismuth diacetate with 6‐aminobenzothiazole compounds afforded selectively the 6‐phenylamino derivatives in good to high yields. A similar reaction with 2‐aminothiazole or 2‐aminobenzothiazole compounds gave mixtures of the monophenylated and diphenylated products 2‐phenylaminothiazole and 2‐(N‐phenylamino)‐3‐N′‐phenylthiazole derivatives, respectively, with the diphenyl product being predominant. Semi‐empirical calculations with the SAM1/D and CHAIN methods performed on the evolution of a 2‐aminobenzothiazole − copper(III) intermediate were in good qualitative agreement with the experimental results. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis of Polyfluorinated Nitrogen‐Containing Heterocycles from Hemifluorinated Enones or Organofluorosilicon Building Blocks as Synthetic Equivalents
Authors: Chanteau Frédéric , Didier Benoît , Dondy Boniface , Doussot Pascale , Plantier‐Royon Richard , Portella Charles
Published: March 2004

A series of polyfluorinated heterocycles has been prepared by heterocyclisation of hemifluorinated enones or organofluorosilicon synthetic equivalents with different bis(nucleophiles). These polyfluorinated building blocks were obtained by treatment of acylsilanes with perfluoro organometallic reagents. The method is general and has been applied to aliphatic, aromatic and carbohydrate derivatives, to give oxazolidines, imidazolidines, benzodia‐ and ‐thiazepines, quinolines and pyrimidines bearing both a fluorine atom and a perfluoroalkyl group in vicinal positions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Umpolung of the 5‐Alkyl‐2‐dimethylamino‐1,3‐dithiolium‐4‐thiolate Mesoion and Its Application in the Synthesis of Some New Tetrathiafulvalenes
Authors: Hellberg Jonas , Dahlstedt Emma , Woldegiorgis Andreas
Published: March 2004

The 5‐alkyl‐2‐dimethylamino‐1,3‐dithiolium‐4‐thiolate mesoion could be umpoled with sulfuryl chloride to yield a dicationic electrophile 3 that reacted with various electron‐rich aromatic substrates to yield arylthio‐substituted 1,3‐dithiolium salts 13−25. Two of these compounds have been transformed to the corresponding symmetrical tetrathiafulvalenes 43 and 44, and their cyclovoltammetric behaviour recorded. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Improved Protocol for the Diastereoselective Cyclopropanation of Alkenes using Geminal Dizinc Carbenoids: A Study on the Effect of Zinc Iodide
Authors: Fournier Jean‐François , Charette André B.
Published: March 2004

A mixture of ZnI2, EtZnI·2OEt2 and CHI3 produces a gem‐dizinc carbenoid that is an efficient cyclopropanating reagent. The presence of ZnI2 allows for shorter reaction times and cleaner reactions, particularly with less reactive substrates. This modification improves the scope of the reaction and it raises important mechanistic issues about this reaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Cre recombinase‐mediated gene targeting of mesenchymal cells
Authors: Florin Lore , Alter Heike , Gröne Hermann‐Josef , Szabowski Axel , Schütz Günther , Angel Peter
Published: March 2004

Loss‐of‐function approaches by the Cre/loxP technology have provided powerful tools for functional analyses of genes of interest expressed preferentially in a particular tissue. Here we describe the generation of transgenic mouse lines expressing Cre recombinase under the control of the promoter/enhancer unit of the gene for the α2 chain of collagen type I (Col1α2). As an expression vector, we used a P1‐derived artificial chromosome (PAC), which harbors ∼100 kb carrying the col1α2 gene. The improved coding sequence of the Cre recombinase was introduced to replace the first exon of col1α2. Cre expression was determined by immunohistochemistry and Cre‐mediated onset of β‐galactosidase expression in ROSA26R‐Cre reporter mice. In four analyzed transgenic lines, Cre recombinase was efficiently expressed during embryogenesis and in adult animals in cells of mesenchymal origin, such as dermal fibroblasts, mesenchymal cells of blood vessel walls, and cells in fibrous connective tissues surrounding internal organs. genesis 38:139–144, 2004. © 2004 Wiley‐Liss, Inc.
Cell type‐specific conditional regulation of the c‐myc proto‐oncogene by combining Cre/loxP recombination and tamoxifen‐mediated activation
Authors: Jäger Richard , Maurer Jochen , Jacob Andrea , Schorle Hubert
Published: March 2004

Development of inducible genetic switches for in vivo use with transgenic mice has revolutionized many areas in modern molecular biology. Combining two techniques, Cre/loxP‐based genetic recombination and ligand‐dependent activation of a chimeric protein, we generated transgenic mice which allow for the spatiotemporal control of expression and of activity of the proto‐oncogene c‐myc. To these ends, the gene encoding the tamoxifen‐inducible c‐mycERT fusion protein (mycERT) was inserted in the ubiquitously active ROSA 26 gene locus by gene targeting. In the resulting ROSAMER allele, generalized transcription of the mycERT gene is prevented by a preceding transcriptional stop sequence which is flanked by loxP sites. Crosses of ROSAMER transgenic mice with Mox2 cre transgenic mice revealed tight control of mycERT transcription in various tissues unless the transcriptional stop sequence was removed by cre‐mediated excision. Furthermore, we were able to demonstrate tamoxifen‐dependent activation of the MycERT protein in embryonic fibroblasts derived from such mice. As a proof of principle, we demonstrate that primary neural crest cultures established from ROSAMER mice maintain their proliferative capacity in a 4‐OHT‐dependent manner. Furthermore, we demonstrate that such neural crest cells retain their differentiation potential as shown by expression of NF 160, a marker of neuronal differentiation upon 4‐OHT withdrawal. The transgenic mice produced may thus be valuable tools for studying the cell type‐specific effects of c‐myc activity in development and disease. genesis 38:145–150, 2004. © 2004 Wiley‐Liss, Inc.
Myelin‐, reactive glia‐, and scar‐derived CNS axon growth inhibitors: Expression, receptor signaling, and correlation with axon regeneration
Authors: Sandvig Axel , Berry Martin , Barrett Lee B. , Butt Arthur , Logan Ann
Published: March 2004

Axon regeneration is arrested in the injured central nervous system (CNS) by axon growth‐inhibitory ligands expressed in oligodendrocytes/myelin, NG2‐glia, and reactive astrocytes in the lesion and degenerating tracts, and by fibroblasts in scar tissue. Growth cone receptors (Rc) bind inhibitory ligands, activating a Rho‐family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include the chondroitin sulfate proteoglycans (CSPG) Neurocan, Brevican, Phosphacan, Tenascin, and NG2, as either membrane‐bound or secreted molecules; Ephrins expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte‐derived growth inhibitors Nogo, MAG, and OMgp; and membrane‐bound semaphorins (Sema) produced by meningeal fibroblasts invading the scar. No definitive CSPG Rc have been identified, although intracellular signaling through the Rho family of G‐proteins is probably common to all the inhibitory ligands. Ephrins bind to signalling Ephs. The ligand‐binding Rc for all the myelin inhibitors is NgR and requires p75NTR for transmembrane signaling. The neuropilin (NP)/plexin (Plex) Rc complex binds Sema. Strategies for promoting axon growth after CNS injury are thwarted by the plethora of inhibitory ligands and the ligand promiscuity of some of their Rc. There is also paradoxical reciprocal expression of many of the inhibitory ligands/Rc in normal and damaged neurons, and NgR expression is restricted to a limited number of neuronal populations. All these factors, together with an incomplete understanding of the normal functions of many of these molecules in the intact CNS, presently confound interpretive acumen in regenerative studies. © 2004 Wiley‐Liss, Inc.