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This prospective multicenter study aimed at investigating the safety and metabolic advantages of steroid withdrawal (SW) therapy in kidney transplant recipients with tacrolimus-mycophenolate mofetil-based immunosuppression.We analyzed 179 recipients who received kidney transplantation from March 2016 and September 2018. In 179 recipients, 114 patients maintained an immunosuppressive regimen including steroids (steroid continuation [SC] group). The remaining 65 patients were determined to withdraw steroid therapy after 6 months posttransplant (SW group). Metabolic parameters and graft functions of the two groups were evaluated.The estimated glomerular filtration rates at 12 months posttransplant were 67.29 ± 20.29 ml/min/1.73 mIn conclusion, a 6-month withdrawal of steroids in recipients with low immunological risk and stable graft function can be safely conducted and result in improvement of metabolic profiles. Stable recipients without biopsy-proven acute rejection and proteinuria can safely withdraw from steroids out of a maintenance immunosuppressive regimen 6-months posttransplant. A long-term follow-up study is needed to verify our results.

A trial was conducted to investigate the effects of dietary mannan level and β-mannanase supplementation on egg production performance, nutrient retention and blood metabolites of laying hens. Two hundred and forty Hy-Line Brown layers (52 wk-old) were randomly allotted to 6 treatments on the basis of laying performance. Each treatment had 8 replicates with 5 birds (40 birds per treatment). Laying hens were fed low or high mannan diets containing 0, 0.4 or 0.8 g β-mannanase/kg diet in a 2×3 factorial arrangement during 56 d feeding period. Laying hens fed diets supplemented with high β-mannanase level had greater (P

The aim of this study was to investigate the effect of different feeding time regimes given similar energy intake per kilogram live BW0.75 during gestation on sow’s performance. One hundred and seventy-four sows [Topigs TN 70 (Landrace × Large White, Topigs USA); parity 3.81 ± 0.16; initial BW = 211.57 ± 3.34 kg; backfat (BF) 13.70 ± 0.42 mm] were blocked by parity, farrowing date, balanced for BW and randomly assigned to 1 of 3 treatments in a randomized complete block design. Treatments included sows fed corn-soybean meal-based diet once at [0730 (control, T1), 1130 (T2), or 1530 h (T3)], with daily feed quantity kept at 1.25× maintenance energy intake [100 × (BW)0.75] kcal ME/d. Sows received 6,758, 7,434, and 8,110 kcal ME/d from days 30 to 60, days 61 to 90, days 91 to 109 of gestation, respectively. The gestation diet was formulated to contain 3,379 kcal of ME/kg, 0.70% Ca, 0.61% total P, 0.58% SID Lys, 0.26% SID Met, 0.45% SID Thr, 0.12% SID Trp, and 0.48% SID Met+Cys. Body weight and BF were recorded on days 30, 60, 90, and 109 of gestation, 24 h after farrowing and at weaning. Results showed that feeding times evaluated did not alter BW changes from day 30 to day 109 of gestation (P = 0.81) or from day 30 to weaning (P = 0.87). Similarly, feeding sows daily at 1130 h did not influence BF gains and sow reproductive performance relative to the control sows (P > 0.10). Sows fed once daily at 1530 h gained more BF compared with the control (3.69 ± 0.47 vs. 2.12 ± 0.50 mm, P = 0.04) from day 30 to day 109 of gestation. From day 30 of gestation to weaning, treatments did not influence BF gain (P = 0.24). Feeding sows daily meal at 1530 h had propensity to increase (P = 0.09) the number of piglets weaned by 0.54 piglets compared with the control sows. In conclusion, the present study demonstrated that feeding pregnant sows at 1530 h altered energy and nutrient metabolism improving their BF gain and exhibited a potential to increase the number of weaned piglets compared with conventional feeding regime.

We study the optical Quantum Transition Line Shapes (QTLS) which show the absorption power and the Quantum Transition Line Widths (QTLW) of electron-deformation potential phonon interacting systems. In order to analyze the quantum transition, we compare the magnetic field dependencies of the QTLWand the QTLS on two transition processes, namely the intra-Landau level transition process and the inter-Landau level transition process. We apply the Quantum Transport theory (QTR) to the system in the confinement of electrons by square well confinement potential. We use the projected Liouville equation method with Equilibrium Average Projection Scheme (EAPS).

Nicotine is the principal psychoactive ingredient in cigarette smoke, and has been associated with health problems in humans. However, the pure form of nicotine may prove to be a valuable pharmaceutical agent for the treatment of AD. However, the beneficial effects of nicotine remain a matter of much controversy. In order to clarify this issue, 12-month-old transgenic mice, expressing neuron-specific enolase (NSE)-controlled APPsw, were treated with low, middle, and high doses of nicotine for 6 months. Herein, we have concluded that the nicotine-treated groups evidenced improvements in behavior and increases in the nicotine acetylcholine receptor, nAchRalpha7. These findings provide experimental evidence that nicotine effects an improvement in impaired memory, and that this improvement is associated with an increase in nAchRalpha7. Thus, nicotine may prove a good preventative or therapeutic modality for AD patients.

The complexity of Alzheimer's disease (AD) has made it difficult to examine its underlying mechanisms. A gene microarray offers a solution to the complexity through parallel analysis of most of the genes expressed in the hippocampal tissues from AD-transgenic and age-matched control littermates. This study examined the potential effect of APPsw over-expression on the modulation of genes for AD. To accomplish this, an oligonucleotide array was used with the large-scale screening of the hippocampus mRNA from 12-month-old APPsw-transgenic and control mice. There was a total of 116 differentially expressed genes, 59 up-regulated and 57 down-regulated, in the hippocampal region of the transgenic mice compared with the control mice. Initially, two of each of the down-regulated (Xlr3b and Mup3) and up-regulated genes (Serpina9 and Ccr6) were chosen for further investigation if the magnitude of change in these genes on the oligonucleotide array would correspond to those in the RT-PCR analysis from APPsw-transgenic mice. We also found that the changes in the differentially expressed genes are reliable. Thus, these genes might associate with AD neuropathology in neurodegenerative process of AD, although relevance of long lists altered genes should be evaluated in a future study.

The amyloid protein precursor (APP) is cleaved in its intramembranous domain by gamma-secrease to generate amyloid beta and a free carboxyl-terminal intracellular fragment. The carboxyl-terminal of 105 amino acids of APP (APP-C105) plays a crucial role in the neuropathology of Alzheimer's disease (AD), but it is incompletely understand how APP-C105 overexpression interacts and regulates the brain function and Abeta-42 levels, and whether or not it is associated with the expressions of GSK3beta-binding proteins. To test this, transgenic mice expressing NSE-controlled APP-C105 were produced and tested for their above phenotypes. A behavioral deficit was observed in the 9 months old transgenic mice, and western blot indicated that there was a predominant expression of APP-C105 in transgenic brains compared with those of non-transgenic brains. In parallel, APP-C105 overexpression resulted in the modulation of the Abeta-42 level, gamma-secretase activity, GSK3beta-binding proteins including PS1, tau, and beta-catenin in the brains of the transgenic mice relative to the non-transgenic mice. Thus, altered expressions of these neuropathological phenotypes in APP-C105 transgenic mice could be useful targets in developing new therapeutic treatments.

The typical strategy used in analysis of antiandrogens involves the morphological changes of a marker in castrated rats Hershberger assay for the prostate, seminal vesicle, levator ani plus bulbocavernosus muscles (LABC), Cowper’s gland, and glans penis. However, there are disadvantages to this approach, such as the time required, and the results may not correspond to those in actual human exposure. To evaluate its ability for detecting antiandrogens, in vivo the dose effect of di-(2-ethylhexyl) phthalate (DEHP) and time effect of five antiandrogens, DEHP, di-n-butyl phthalate (DBP), diethyl phthalate (DEP), linuron (3-(4-dichlorophenyl)-methoxy-1-methylurea), and 2,4′-DDE (1,1-dichloro-2-( p-chlorophenyl)-2-( o-chlorophenyl)ethylene), were investigated using humanized transgenic mice coexpressing tetracycline-controlled transactivator (tTA) and the human cytochrome P450 (CYP) enzyme CYP1B1 (hCYP1B1). Adult transgenic males were treated with each of the five antiandrogens, and their tTA-driven hCYP1B1 expressions analyzed by real-time polymerase chain reaction (PCR) and/or Western blot and for O-debenzylation activity. Herein, the treatments of adult males with the five antiandrogens were shown to affect the increased levels of tTA-driven hCYP1B1 expression in both dose-dependent and repeated experiments. Thus, this novel in vivo bioassay, using humanized transgenic mice, is useful for measuring antiandrogens, and is a means to a more relevant bioas-say relating to actual human exposure.

Differential expression of the tetracycline-controlled transactivator (tTA)-driven human cytochrome p450 (CYP) 1B1 gene was found in the livers of male mice, at high levels in neonates, but at low levels in adults. The goals of this study were to determine whether the differential expression of the tTA-driven human CYP1B1 (hCYP1B1) gene in neonates and adults was testosterone dependent and whether flutamide, a representative potent antiandrogen, led to the induction of hCYP1B1. This was tested by treating castrated transgenic mice with testosterone propionate and musk extracts. It was concluded that: (i). the levels of expression of both tTA and hCYP1B1 gradually declined, with clear changes being apparent between 2 and 4 weeks of age, (ii). castration of adult males resulted in the increased expressions of both tTA and hCYP1B1 to levels similar to those found in adult females, (iii). treatment of castrated male and adult female mice with testosterone propionate and musk extracts led to the restoration of the levels of expression of hCYP1B1 in the adult males, and (iv). treatment of adult males with flutamide caused an increase in the levels of expression of hCYP1B1 in the adult females, as indicated by the antiandrogenic activity. Thus, the differential expression of the tTA-driven hCYP1B1 gene in the transgenic mice was caused by androgen, and it is possible that castrated male and adult female mice expressing the tTA-controlled hCYP1B1 could be used as the basis for a strategy for the detection of androgens and antiandrogens.

Humanized transgenic mice coexpressing tetracycline-controlled transactivator ( tTA) and human cytochrome P450 1B1 (CYP1B1) ( hCYP1B1) have been created by this group. The aims of this study was to determine if 7,12-dimethylbenz[a]anthracene (DMBA) functions as testosterone or doxycycline in its ability to induce or reduce expression of hCYP1B1 or endogenous mouse CYP1B1 (mCYP1B1). This was tested in the livers by treating castrated transgenic males and hCYP1B1/luciferase-transfected cells with DMBA. Herein, DMBA-treated group exhibited (i) gradual reduction of hCYP1B1 expression at the transcript, protein, and activity levels but gradually induced its transcript level during DMBA release; (ii) gradual reduction of hCYP1B1 at the transcript and protein levels, as in the case of doxycycline or testosterone; (iii) gradual induction of mCYP1B1 expression at the transcript and protein levels but gradually reduced its transcript level during DMBA release. In parallel, DMBA-treated transfected cells exhibited gradual increase in luciferase activity in a time- and dose-dependent manner. Thus, castrated transgenic males or in vitro system could be useful as models for the detection of polycyclic aromatic hydrocarbons (PAHs) or environmental toxicants by measuring either hCYP1B1 or mCYP1B1 expressions.

The complexity of Alzheimer's disease (AD) has made it difficult to examine its underlying mechanism. A gene microarray offers a solution to the complexity through a parallel analysis of most of the genes expressed in the brains from AD-transgenic mice. In our previous study, a total of 52 differentially expressed genes were identified in 18-month-old APPsw-transgenic mice compared to age-matched normal mice. We extended our work to better understand the relevant gene profiles from both early- and late-stage transgenic and normal mice. To accomplish this, cDNA microarray was used with the large-scale screening of the brain mRNA from transgenic and normal mice of 1 and 18 months of age. We identified a total of 48 genes, 6 up-regulated and 42 down-regulated, differentially expressed with a significant degree of induction and reduction in the brains from moderate 18-month-old transgenic mice compared to 1-month-old transgenic mice. In parallel, a total of 40 differentially expressed genes, 6 up-regulated and 34 down-regulated, were also found in the brains from moderate 18-month-old normal mice compared to 1-month-old normal mice. Thus, differentially expressed genes upon APPsw overexpression and the aging process are useful targets through which investigators can choose genes of particular interest. In the future, it will be necessary to study the function of differentially expressed genes, which are targets for developing drugs, using pharmacoproteomics.

The complexity of Alzheimer's disease (AD) has made it difficult to examine its underlying mechanism. A gene microarray offers a solution to the complexity through a parallel analysis of most of the genes expressed in the brains from AD-transgenic mice. In our previous study, a total of 52 differentially expressed genes were identified in 18-month-old APPsw-transgenic mice compared to age-matched normal mice. We extended our work to better understand the relevant gene profiles from both early- and late-stage transgenic and normal mice. To accomplish this, cDNA microarray was used with the large-scale screening of the brain mRNA from transgenic and normal mice of 1 and 18 months of age. We identified a total of 48 genes, 6 up-regulated and 42 down-regulated, differentially expressed with a significant degree of induction and reduction in the brains from moderate 18-month-old transgenic mice compared to 1-month-old transgenic mice. In parallel, a total of 40 differentially expressed genes, 6 up-regulated and 34 down-regulated, were also found in the brains from moderate 18-month-old normal mice compared to 1-month-old normal mice. Thus, differentially expressed genes upon APPsw overexpression and the aging process are useful targets through which investigators can choose genes of particular interest. In the future, it will be necessary to study the function of differentially expressed genes, which are targets for developing drugs, using pharmacoproteomics.

PEN-2 is a component of the gamma-secretase complex, which is involved in the cleavage of the beta-amyloid precursor protein. The aim of this study was to determine the mechanism by which PEN-2 overexpression regulates gamma-secretase expression and the production of Abeta-42. In order to determine this, a hybrid gene harboring human PEN-2 was constructed, and used in the transfection of SK-N-MC human neuroepitheliomal cells. This cell line was also co-transfected with a combination of human mutant presenilin 2 (hPS2m) and APPsw. Our results indicated that (i) human PEN-2 overexpression induced an increase in gamma-secretase activity and its proteins, including PS1-CTF, APH-1, and nicastrin, thus production of Abeta-42, (ii) co-transfection of human PEN-2 with both hPS2m and APPsw exerted no more profound effects on the induction of gamma-secretase proteins and its activity than did transfection with hPEN-2 alone. Thus, PEN-2 overexpression may facilitate assembly into the more active gamma-secretase complex, and may also induce an increase in activity, thus affecting Abeta-42 production.

Nonregulatable promoters have been mainly used to produce transgenic mice that express the human genes for Alzheimer's disease (AD). The aim of this study was to produce doubly transgenic mice expressing the regulatable tet promoter-controlled transactivator (tTA) and human mutant presenilin 2 (N141I, hPS2m) genes in order to examine the AD-related phenotypes at the basal and inducible levels. To achieve this, the first lineage of the transgenic line, expressing Tet/tTA and the second lineage of transgenic mice, expressing Tet/hPS2m, were created, and the doubly transgenic mice were produced by crossing the Tet/tTA-transgenic mice with the Tet/hPS2m-transgenic mice. The doubly transgenic mice and nontransgenic littermates were then treated with or without doxycycline. The results showed that removing doxycycline from the transgenic mice resulted in the induction of the transgene, a Wnt signaling defect, behavioral impairment, elevated amyloid-beta-42 and gamma-secretase activity compared with in the group given doxycyline. Moreover, the expression levels of the hPS2m transgene decreased gradually in the transgenic males, with clear changes becoming apparent between 2 and 4 wk of age. Castrating these males resulted in an increased expression level of the hPS2m gene. This was restored to the normal levels by treatment with testosterone. Therefore, tetregulated transgenic mice can be used to examine the effect of the basal or inducible expression levels of hPS2m on the pathology of AD at the "on/off" states at any stage of development.

cDNA microarray technique has been widely used for the detection and elucidation of differentially expressed genes on a large scale and at a speed never before possible. The aim of this study was to gain insight into the potentially overexpressed effects of APPsw on the modulation of genes for Alzheimer's disease (AD), which is central to understanding the complexity of AD. APPsw transgenic mice, which we previously produced, provide an important resource for identifying differentially expressed genes since this transgenic line was shown to have cognitive deficits along with Abeta-42 deposits at 12 months of age. To identify differentially expressed genes, cDNA microarray technique was conducted to get a large-scale screening of brain mRNA from 18 month-old NSE/APPsw transgenic and non-transgenic mice. A total of 52 differentially expressed genes, 10 up-regulated and 42 down-regulated, were found in the brains of moderately transgenic mice compared to non-transgenic littermates. Thus, the results suggest the need for future studies on gene functions, pathology, toxicogenomics, and pharmacogenomics.

Insulin-degrading enzyme (IDE) is a 110-kDa thiol zinc-methalloendopeptidase that can cleave small Abeta peptides and the APP intracellular domain (AICD). The aim of this study was to examine aging-related correlation of IDE with gamma-secretase-generated products involving insulin and glucose levels in transgenic brains expressing neuron-specific enolase (NSE)-controlled human mutant presenilin-2 (hPS2m). Herein, we concluded that the levels of IDE expression in transgenic brains were decreased relative to those of control mice at 15 months of age. In parallel, inhibition in the IDE expression at this age underlies to the levels-up of Abeta-42, AICD, gamma-secretase, and glucose with a level-down of insulin. Thus, IDE expression is critical target for the therapeutic trials.

Pin1 binds mitotically phosphorylated Thr231-Pro232 and Thr212-Pro213 sites on tau, and a Pin1 deficiency in mice leads to tau hyperphosphorylation. The aim of this study was to determine if the dephosphorylation or inhibition of tau and GSK3beta phosphorylation induces the Pin1 phosphorylation. To test this, human SK-N-MC cells were stably transfected with a fusion gene containing neuron-specific enolase (NSE)-controlled APPsw gene(NSE/APPsw), to induce Abeta-42. The stable transfectants were then transiently transfected with NSE/Splice, lacking human tau (NSE/Splice), or NSE/hTau, containing human tau, into the cells. The NSE/Splice- and NSE/hTau-cells were then treated with lithium. We concluded that (i) there was more C99-beta APP accumulation than C83-betaAPP in APPsw-tansfectant and thereby promoted Abeta-42 production in transfectants. (ii) the inhibition of tau and GSK3beta phosphorylations correlated with increase in Pin1 activation in NSE/hTau- cells. Thus, these observations suggest that Pin1 might have an inhibitive role in phosphorylating tau and GSK3beta for protecting against Alzheimer's disease.

Estrogen influences the processing of the amyloid beta precursor protein (APP) in the pathogenesis of Alzheimer's disease, and this effect is mediated by estrogen receptors (ERs) in activating mitogen-activated protein kinase (MAPK)-signaling pathway. To test whether the estrogenic effect on both carboxyl-terminal amino acid fragment (C-terminal) of APP (APP-C105)- and ERbeta-mediated MAPK activation in in vitro, two hybrid genes containing each human ERbeta and APP-C105 gene fused to the neuron-specific enolase (NSE) promoter were constructed and were transfected to the neuronal SK-N-MC cells. Western blot shows that the activation of JNK-signaling pathway, but not p38 and ERK, is dependent on ERbeta through estrogen treatment and APP-C105 is also mediated through estrogen in activating MAPK-signaling pathway. The results suggest that ERbeta and APP-C105 derived from APP are necessary for estrogenic effect in activating MAPK-signaling pathway.

Estrogen influences the processing of the amyloid beta precursor protein (APP) in the pathogenesis of Alzheimer's disease, and this effect is mediated by estrogen receptors (ERs) in activating mitogen-activated protein kinase (MAPK)-signaling pathway. To test whether the estrogenic effect on both carboxyl-terminal amino acid fragment (C-terminal) of APP (APP-C105)- and ERbeta-mediated MAPK activation in in vitro, two hybrid genes containing each human ERbeta and APP-C105 gene fused to the neuron-specific enolase (NSE) promoter were constructed and were transfected to the neuronal SK-N-MC cells. Western blot shows that the activation of JNK-signaling pathway, but not p38 and ERK, is dependent on ERbeta through estrogen treatment and APP-C105 is also mediated through estrogen in activating MAPK-signaling pathway. The results suggest that ERbeta and APP-C105 derived from APP are necessary for estrogenic effect in activating MAPK-signaling pathway.

In its late stage, Alzheimer's disease results in progressive muscle weakness in the arms and legs. The aim of this study was to determine whether mice expressing the skeletal muscle-specific mutant PS2 gene (a model of Alzheimer's disease) are a useful experimental system to study the protective effect of exercise on A beta-42 reduction, improvement of behavioural function and changes in metabolic parameters. With this aim in mind, the transgenic mice were subjected to treadmill exercise for 3 months. The results showed that in transgenic mice, but not in normal mice, treadmill exercise resulted in a reduction of A beta-42 deposits and an improvement in behavioural function, thereby restoring normal concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride. Thus, exercise may represent a practical therapeutic strategy for use with human patients with Alzheimer's disease.

Apoptosis is an important process in the variety of different biological system including cell death and embryonic development. Inappropriate apoptosis is implicated in many human diseases such as Alzheimer's disease. Central component of the machinery of apoptosis program in neurons of patients with Alzheimer's disease includes proteins of caspases and Bcl-2 families. We examined whether endogenous protein levels of caspases and Bcl-2 families are expressed in a differential manner during the embryonic and postnatal development of BDF1 strain. Here, all four proteins with caspases-3, -9, Bcl-2 and Bax were highly expressed between embryonic day 19 and 1 week age of early postnatal development, but thereafter the expression dramatically declined. These patterns are needed to compare the proteins in the brains of APPsw-transgenic mice that are expected to be expressed highly in the brain of adult mice. Thus, the results are useful to understand fundamentally the mechanisms of the apoptotic changes during the embryonic and postnatal development of Alzheimer's model mice.

Apoptosis is an important process in the variety of different biological system including cell death and embryonic development. Inappropriate apoptosis is implicated in many human diseases such as Alzheimer's disease. Central component of the machinery of apoptosis program in neurons of patients with Alzheimer's disease includes proteins of caspases and Bcl-2 families. We examined whether endogenous protein levels of caspases and Bcl-2 families are expressed in a differential manner during the embryonic and postnatal development of BDF1 strain. Here, all four proteins with caspases-3, -9, Bcl-2 and Bax were highly expressed between embryonic day 19 and 1 week age of early postnatal development, but thereafter the expression dramatically declined. These patterns are needed to compare the proteins in the brains of APPsw-transgenic mice that are expected to be expressed highly in the brain of adult mice. Thus, the results are useful to understand fundamentally the mechanisms of the apoptotic changes during the embryonic and postnatal development of Alzheimer's model mice.

Mutations in the APP gene lead to enhanced cleavage by the beta- and gamma-secretase, and increased Abeta formation, which are tightly associated with Alzheimer's disease (AD)-like neuropathological changes. To examine whether depositions of Abeta by APP mutations are increased, and if this is associated with potential pathogenic phenotypes, the APPsw was expressed in a transgenic line under the control of the neuron-specific enolase (NSE) promoter. A behavioral dysfunction was shown at 12 months, and intensive staining bands, with APP and Abeta-42 antibodies, were visible in the brains of transgenic mice. Of the MAPK family, both JNK and p38 were activated in the brains of transgenic mice, whereas there was no significant activation of the ERK. In parallel, tau phosphorylation was also enhanced in the transgenic relative to the control mice. Moreover, the Cox-2 levels, from Western blot and immunostaining, were increased in the brains of the transgenic line. Furthermore, there were significant caspase-3- and TUNEL-stained nuclei in the transgenic line compared to the age-matched control mice. Thus, these results suggest that NSE-controlled APPsw transgenic mice appear to be a more relevant model in neuropathological phenotypes of AD, and thus could be useful in developing new therapeutic treatments for targeting the aberrant phenotypes that appear in these mice.

We propose a new interpolating field for S$_{11}$(1535) to determine its mass from QCD sum rules. In the nonrelativistic limit, this interpolating field dominantly reduces to two quarks in the s-wave state and one quark in the p-wave state. An optimization procedure, which makes use of a duality relation, yields the interpolating field which overlaps strongly with the negative-parity baryon and at the same time does not couple at all to the low lying positive-parity baryon. Using this interpolating field and applying the conventional QCD sum rule analysis, we find that the mass of S$_{11}$ is reasonably close to the experimentally known value, even though the precise determination depends on the poorly known quark-gluon condensate. Hence our interpolating field can be used to investigate the spectral properties of S$_{11}$(1535)., Comment: 12 pages, Revtex, 1 ps figure available from authors

The breathing modes along with the spin-isospin zero modes of the ω-stabilized skyrmion are quantized using Dirac's method. The result is a hamiltonian for the nucleon, the δ-isobar and the Roper with explicit meson couplings. The linear pion coupling is used to evaluate the decay width of the Roper into πN.