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PubMed1978

Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogues.

Hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogues are known to affect serotonergic systems both in vivo and in vitro. Using a rat stomach fundus model, the 5-HT receptor binding affinities of several of these analogues were determined and compared. The most behaviorally potent analogues examined, DOB, DOM, and 5-methoxy-N,N-dimethyltryptamine, were found to possess rather high affirmities (pA2 = 7.35, 7.12, and 7.08, respectively) for the 5-HT receptors of the model system.

Amines↗
PubMed1984

Synthesis and evaluation of a novel series of N,N-dimethylisotryptamines.

A novel series of N,N-dimethylisotryptamine (isoDMT) derivatives, i.e., derivatives of 1-[2-(dimethylamino)ethyl]indole, was prepared and found to be isosteric with their corresponding N,N-dimethyltryptamine (DMT) counterparts with respect to serotonin receptor (rat fundus) affinity. Whereas the isoDMT derivatives possessed a greater affinity than did their corresponding DMT derivatives, they were relatively ineffective in displacing [3H]-5-HT binding from rat brain (cortex) homogenates. In a drug discrimination paradigm, using rats as subjects, 6-OMe-isoDMT produced effects similar to those of 5-OMe-DMT. Attempts to antagonize the discriminative stimulus effects of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) using two of the isoDMT derivatives proved unsuccessful.

Animals↗
PubMed1988

N,N-di-n-propylserotonin: binding at serotonin binding sites and a comparison with 8-hydroxy-2-(di-n-propylamino)tetralin.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a serotonergic agonist with high affinity and selectivity for a particular population of central serotonin (5-HT) binding sites (i.e., 5-HT1A sites). Because the selectivity of 8-OH-DPAT may be due to the terminal amine substituents, the di-n-propyl analogue of 5-HT (i.e., 4) and of 5-methoxytryptamine (i.e., 5) were prepared and compared with 8-OH-DPAT with respect to their binding profile. Unlike 8-OH-DPAT, neither compound 4 nor 5 displays selectivity for 5-HT1A vs 5-HT2 sites. Consistent with these results, stimulus generalization occurs with 5 both in rats trained to discriminate 8-OH-DPAT from saline and in rats trained to discriminate the 5-HT2 agonist DOM from saline. The results of this study suggest that it is not the N,N-dipropyl groups that account for selectivity, but, rather, it is some feature associated with the pyrrole portion of the indolylalkanamines that is important.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2006

Directed ortho metallation of deep cavity cavitands: functionalizing molecular concavity.

Directed ortho metallation (DOM) processes have been used to functionalize the cavity and rim of title cavitand 1. The preorganization of the host resulted in a considerable reduction in the range of products produced. Thus, whereas sixty-nine products are possible from per-functionalization, only twelve were observed when the host was treated with three different alkyllithiums.

Journal Article↗
PubMed2005

Directed ortho Metalation reaction of aryl O-carbamates on solid support.

The first Directed ortho Metalation (DoM) reaction of aryl O-carbamates on polystyrene-divinylbenzene (PS-DVB) resin using a trityl linker is described. Using low temperatures and short metalation times, a range of electrophiles have been introduced to give, after cleavage from support, substituted benzyl alcohols in high purity. [reaction: see text]

Journal Article↗
PubMed2005

Directed ortho metalation-based methodology. Halo-, nitroso-, and boro-induced ipso-desilylation. Link to an in situ Suzuki reaction.

[reaction: see text] Treatment of DoM-derived silylated aromatics 2-4 under standard electrophilic halogenation conditions cleanly affords ipso-desilyation products 5-7, while nitration of methoxy-substituted analogues 8, 9 leads to non-ipso isomers 10, 12 and 11, 13, controlled by a silicon steric effect. Sequential ipso-borodesilylation of 2a, 3a, and 20 followed by treatment with aryl halides under Pd-catalyzed conditions constitutes an in situ Suzuki-Miyaura cross-coupling protocol to biaryls and heterobiaryls 23.

Journal Article↗
PubMed2005

Directed ortho lithiation of N-alkylphenylaziridines.

The ortho lithiation-trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides. The importance of the aziridine N-substituent in this DoM reaction is stressed as well. [reaction: see text]

Journal Article↗
PubMed1998

Pre-harvest pearl millet tillers and leaves as animal food.

Feeding experiments with pre-harvest tillers and leaves of 2 varieties of pearl-millet were conducted on a research station in semi-arid Mali. Tillers were harvested at 45 to 65 days after sowing (DAS) and fed green. Leaves were harvested at 65 to 85 DAS and fed to sheep or cattle green or after 8 months conservation as hay or as silage. Intake of organic (IOM) was higher for green leaves than for tillers, showing no difference for the 2 varieties used. In vivo digestible organic matter (DOM) was highest tillers in both varieties. Nutritive value of tillers and green leaves met the quality criteria for a maintenance diet of sheep. During conservation of millet leaves, the reduction in nutritional value was less with hay than with silage. Small amounts of silage offered as a supplement to rice straw helped to meet maintenance requirements for metabolizable energy. Conserved as hay, a quality forage was obtained which on an economic scale compensated for grain yielded losses when fed to selected animals.

Animal Feed↗
PubMed1999

Feeding of dairy cattle in the forest-garden farms of Kandy, Sri Lanka.

A survey on feeding practices was conducted with 60 farmers belonging to four categories (15 farmers in each): male farmers without off-farm income (M-), male farmers with off-farm income (M+), female farmers without off-farm income (W-), and female farmers with off-farm income (W+). Data on herd size, feeds offered, milk production, chest girth, reproduction and management were collected monthly over a period of 1 year. In addition, samples of fodder and concentrates were collected monthly and analysed for dry matter (DM), organic matter (OM), crude protein (CP) and in vitro organic matter digestibility (OMD). Of the 550 rations analysed, grass was included in 99.8% of all rations, followed by gliricidia (65%), creepers (50%) and jak leaves (32%). Consequently, the rations were high in OMD (47-59%) and CP (7.8-23.5%). High-protein forage or coconut cake or both were also included as a supplement in 92% of the rations. Both M- and W- farmers had larger (p < 0.001) herds (mean 1.8 animal units (AU) per household) than their counterparts with off-farm income (mean 1.44 AU/household), but only the male farmers without off-farm income achieved higher feeding levels (84.4 vs 65.6 72.1 g digestible organic matter (DOM)/kg0.75 per day) and milk production (6.4 vs 5.3-5.7 L/lactating cow). The lower production of animals kept by female and M+ farmers was related to lower feeding levels. M- farmers realized higher feeding levels than their M+ counterparts. W- farmers did not collect extra feed in response to higher levels of production. It was concluded that dairy farming in the mid-country of Sri Lanka is particularly important for poorer households without income from off-farm employment.

Agriculture↗
PubMed2001

A theoretical approach to the influence of the macrocycle conformation on the molecular electronic structure in Mg-porphyrins.

Nonplanar saddled (sad) ruffled (ruf) and domed (dom) conformations of the Mg-porphyrin (MgP) macrocycle in several degrees of deformation have been computed. These symmetrical distortion modes were induced in unsubstituted macrocycle using molecular definitions for calculations which permits us to achieve a systematical variation of the nonplanarity varying only a convenient geometrical parameter of the molecule. Series of nonplanar macrocycles like those synthesized in previous works employing peripheral substitutions are obtained. The procedure here used to induce deformations gives the possibility of investigating the modulator role of the out-of-plane distortions on the geometry and electronic properties of the porphyrin avoiding additional influences due to the substituents or the surrounding protein scaffolding.

Chlorophyll↗
PubMed2003

Replacement value of undecorticated sunflower meal as a supplement for milk production by crossbred cows and buffaloes in the northern plains of India.

The replacement value of undecorticated sunflower meal (SFM) in the diets of dairy animals was assessed on-station and on-farm. Eighteen primiparous crossbred (Bos taurus x Bos indicus) cows (350.4 +/- 8.84 kg), randomly allocated to three groups, were used in the on-station study. The animals were fed on either a conventional concentrate supplement (control) or on an experimental concentrate, in which SFM replaced 25% (SFM-25) or 50% (SFM-50) of the CP in the control supplement. Green oats (Avena sativa) were supplied ad libitum. A metabolism trial conducted following 60 days of experimental feeding revealed that the intakes of DM, DCP and TDN were similar among the groups. The digestibilities of OM, CP, EE, NDF and ADF were also without significant differences. All the groups were in positive nitrogen balance. Inclusion of SFM at either level had no effect on the intake, excretion or retention of nitrogen. The daily milk yield and its composition did not differ among the dietary treatments. Moreover, the efficiency of utilization of DOM and TDN for FCM production tended to reflect, although non-significantly, increasing levels of SFM inclusion. In the on-farm study, seven multiparous milking buffaloes belonging to six farmers were used to assess the effect of replacing 20% of the CP of the conventional supplement with SFM, in a predominantly crop residue-based diet. The study continued for 4 months and revealed that the average daily feed intake and milk production was similar in the control and SFM-fed groups. It was concluded that SFM can be effectively utilized as a cheaper replacement for costly oil cakes and wheat bran for economic milk production by smallholder farmers.

Animals↗
PubMed2003

Rapid N-acetyltransferase 2 imputed phenotype and smoking may increase risk of colorectal cancer in women (Netherlands).

OBJECTIVE: The relationship between smoking and colorectal cancer risk and whether such effect is modified by variations in the NAT2 genotype is investigated. METHODS: In the prospective DOM (Diagnostisch Onderzoek Mammacarcinoom; 27,722 women) cohort follow-up from 1976 until 1987 revealed 54 deaths due to colon or rectal cancer, and follow-up from 1987 to 01-01-1996 revealed 204 incident colorectal cancer cases. A random sample (n = 857) from the baseline cohort was used as controls. Four NAT2 restriction fragment length polymorphisms (RFLPs) were analysed using DNA extracted from urine samples. Rapid or slow acetylator phenotype status was attributed to individuals. RESULTS: Smoking may increase the risk for colon cancer (RR = 1.36, 95% CI 0.97-1.92) as well as for rectal cancer (RR = 1.31, 95% CI 0.76-2.25), although not statistically significant. Rapid NAT2 acetylation did not increase colorectal cancer risk, but in combination with smoking the risk was statistically significant increased, compared to women who had a slow NAT2 imputed phenotype and never smoked (RR = 1.56, 95% CI 1.03-2.37). For colon cancer, but not for rectal cancer the increased risk was statistically significant (RR = 1.67, 95% CI, 1.05-2.67 versus RR = 1.30 95% CI 0.63-2.68). CONCLUSIONS: Our study points to smoking as a risk factor for colon and rectal cancer and, in addition, especially in women with rapid NAT2 imputed phenotype.

Arylamine N-Acetyltransferase↗
PubMed2004

Heritable aspects of dysplastic breast glandular tissue (DY).

Breast parenchymal patterns, as visible on mammograms, are determined by the relative amount of radio-dense, glandular dysplastic tissue DY). High percentages of DY are related to higher breast cancer risk. Previous studies reported heritable influences on DY of 32-67%, depending on the family relationship that was studied. depending on the family relationship that was studied. We assessed heritability in 466 sister-, 25 dizygotic twin- and 26 monozygotic twin-pairs participating in a population-based breast cancer screening program; the DOM project (Diagnostic Investigation Mamma Carcinoma). The heritability was estimated for non-twin sisters, dizygotic and monozygotic twins seperately by computing correlations between siblings from the dichotomous DY-score (high risk versus low risk). This was done using methods based on the number of shared genes per sibtype. Heritability estimates were 38, 34 and 88% for sisters, dizygotic twins and monozygotic twins respectively. Heritability estimates from models that combine monozygotic twins with dizygotic twins or sisters indicated that combine monozygotic twins with dizygotic twins or sisters indicated that dominant gene effects, genetic interactions or gene-environment effects could be involved. Parity appeared to have an effect on the heritabile influence with estimates ranging from 90% in sisters that were both nulliparous, to 2% in sisterpairs discordant for nulliparity. These result indicate a substantial genetic influence on DY, but with a possible modifying ability of other factors, such as parity.

Adult↗
PubMed2003

Normal coordinate structural decomposition of the heme distortions of hemoglobin in various quaternary states and bound to allosteric effectors.

The distortions of the alpha1, alpha2, beta1, and beta2 hemes of human hemoglobin (HbA) in various quaternary states and as affected by the presence of allosteric effectors was investigated by subjecting CHARMM energy-minimized models to normal coordinate structural decomposition (NSD) analysis. NSD was applied to the individual hemes extracted from the R, T, and R2-state models of HbA and to HbA bound to DPG and to IHP. Overall, NSD results are indicative of characteristic distortions, not only for the hemes of the different HbA quaternary states, but also for the hemes of the HbA models bound to allosteric effectors. Comparing the distortions of the inequivalent alpha and beta hemes in T-state HbA, we show good correlation between NSD and the experimentally observed low-frequency nu52 (Eg) and gamma7 (A2u) modes reported in the literature for alpha and beta HbA hemes while noting substantial differences between these types for B2u and B1u distortions. For the R2 hemes, NSD yields heme distortions that are more comparable to those of the R-state, especially in magnitude. However, the R2 hemes do not exhibit inequivalence of alpha and beta heme distortions, a result that may contribute to an understanding of the functional importance of this state. Relative to T-state heme distortions, NSD results on the effector-bound hemes show that tertiary changes induced in T-state HbA as a result of binding DPG and IHP drastically affect heme distortions. In the alpha hemes extracted from the HbA-DPG model, most noteworthy are the increased wav(x) and wav(y) distortions and enhancement of ruf and dom deformations. In the beta hemes, the wav(y) is the most affected distortion with increase in sad. The NSD results are also different for the hemes of the HbA-IHP model, in that the beta sad and ruf deformations are more enhanced with increase of doming in the alpha hemes. Our results describe the effect of the subtle protein-induced changes on the nonplanarity of the HbA hemes that may play a role in the regulation of their oxygen affinity.

Allosteric Site↗
PubMed2003

Mouse models for four types of Waardenburg syndrome.

Waardenburg syndrome (WS) is an auditory-pigmentary syndrome caused by a deficiency of melanocytes and other neural crest-derived cells. Depending on a variety of symptoms associated with the auditory-pigmentary symptoms, WS is classified into four types: WS type 1 (WS1), WS2, WS3, and WS4. Six genes contributing to this syndrome--PAX3, SOX10, MITF, SLUG, EDN3 and EDNRB--have been cloned so far, all of them necessary for normal development of melanocytes. Mutant mice with coat color anomalies were helpful in identifying these genes, although the phenotypes of these mice did not necessarily perfectly match those of the four types of WS. Here we describe mice with mutations of murine homologs of WS genes and verify their suitability as models for WS with special interest in the cochlear disorder. The mice include splotch (Sp), microphthalmia (mi), Slugh-/-, WS4, JF1, lethal-spotting (ls), and Dominant megacolon (Dom). The influence of genetic background on the phenotypes of mice mutated in homologs of WS genes is also addressed. Finally, possible interactions among the six WS gene products are discussed.

Animals↗
PubMed2000

Uptake of dissolved organic carbon and trace elements by zebra mussels.

Zebra mussels (Dreissena polymorpha) are widespread and abundant in major freshwater ecosystems in North America, even though the phytoplankton food resources in some of these systems seem to be too low to sustain them. Because phytoplankton biomass is greatly depleted in ecosystems with large D. polymorpha populations and bacteria do not seem to be an important food source for this species, exploitation of alternative carbon sources may explain the unexpected success of D. polymorpha in such environments. Here we examine the possibility that absorption of dissolved organic carbon (DOC) from water could provide a nutritional supplement to zebra mussels. We find that mussels absorb 14C-labelled DOC produced by cultured diatoms with an efficiency of 0.23%; this indicates that DOC in natural waters could contribute up to 50% of the carbon demand of zebra mussels. We also find that zebra mussels absorb some dissolved metals that have been complexed by the DOM; although absorption of dissolved selenium was unaffected by DOC, absorption of dissolved cadmium, silver and mercury by the mussels increased 32-, 8.7- and 3.6-fold, respectively, in the presence of high-molecular-weight DOC.

Animals↗
PubMed1990

Breast cancer screening: its impact on clinical medicine.

Breast cancer screening is generally accepted as an effective means of reducing breast cancer mortality in post-menopausal women. In this analysis the impact of nationwide screening on clinical medicine and the effects for the women involved are quantified. Effect estimates are based on results from screening trials in Utrecht (DOM-project) and Nijmegen, and on bi-annual screening of women aged 50-70. The consequences for health care are based on generally accepted assessment and treatment policies. The number of assessment procedures for non-palpable lesions will increase by 12% per year in the build-up period, and will remain slightly higher. The total number of biopsies in a real population is expected to decrease. Screening will lead to a shift in primary treatment modalities, as 15% of mastectomies will be replaced by breast conserving therapy. The temporary increase in the demand for primary treatment in the first years will be followed by a decrease in the demand for treating women with advanced disease. Favourable effects outweigh the inevitable unfavourable effects, with high quality screening and an appropriate invitation system. Breast cancer screening can also be recommended after considering other consequences than mortality reduction.

Aged↗