Studies Towards \u3cem\u3eAnti\u3c/em\u3e-Bredt Ring Systems of Natural Products

Different ways for the synthesis of anti-Bredt ring systems of natural products have been explored. An intended Favorskii rearrangement-divinylcyclopropane rearrangement to lead to the bicyclo[4.3.1] decadiene ring system was not accomplished. An envisioned tandem cyclopropanation-divinycyclopropane rearrangement of 2,3-divinyhex-2-enol did not furnish the desired bicyclo[4.4.1]undecadiene system, either, because cyclopropane occurred on the exocyclic double bond. In the course of cyclopropanation studies on various cyclohexenols, an α-silyl-α-diazoethyl acetate was employed as tether. It could be removed by protodesilylation or oxidative cleavage to give a 1-(carboxylic ester)-cyclopropane or a 1-(carboxylic easter)-1-hydroxy cyclopropane derivative, respectively. Cyclopropanation general occurred on the less substituted more electron rich double bond. Epoxidation of 2,3-divinylhex-2-enol with subsequent Cope rearrangement furnished the anti-Bredt oxabicyclo[4.4.1]undecadiene system that could be transformed into its regioisomer by Ireland-Claisen rearrangement. Studies of the ring-closing metathesis of a cobalt carbonyl complexed ynediene to give a 10- or 11-membered ring failed. Ring-closing metathesis of a vinylsilane furnished an eight-membered ring

Small Molecules as Probes for Cell Division and Intracellular Transport

Cell-permeable small molecules that can act on their targets on fast time scales are powerful probes of cell division mechanisms and intracellular transport processes. Phenotype-based screens with chemical libraries have been used to identify such inhibitors. However, probes for most proteins are still not available, and the requirements on compound collections to yield such probes are not well understood. Here I present two approaches to find and use such probes. First, in an attempt to find probes for cell division, I have shown that a small collection of 100 diaminopyrimidines yielded a range of cell division phenotypes, including changes in spindle geometry, chromosome positioning and mitotic index. Monopolar mitotic spindles were induced by 4 inhibitors including one that targets Polo-like kinases, evolutionarily conserved serine/threonine kinases. Using chemical inhibitors and high-resolution live-cell microscopy, I found that Polo-like kinase activity is needed for the assembly and maintenance of bipolar mitotic spindles. Inhibition of Polo-like kinase destabilized kinetochore microtubules while stabilizing other spindle microtubules, leading to monopolar spindles. Second, I used pigment organelles in Xenopus melanophore cells, a specialized intracellular transport system for which the motor proteins driving movement, and primary signals regulating movement, are known, to identify inhibitors of intracellular transport. Screening of an unbiased commercial library yielded a compound, 37P11, that could be characterized as possible inhibitor of a yet unknown element in the regulation of organelle movement. From a collection of diaminopyrimidines, one compound, DAP-29, was identified that potentially targets cytoplasmic dynein, an essential motor protein in many transport processes. Both compounds showed activity in assays in a variety of other intracellular transport systems, highlighting their potential use as biological probes. My findings indicate that development of new screening systems and further testing of compounds based on „privileged scaffolds‟, such as diaminopyrimidines, can lead to powerful new probes for cell division and intracellular transport

Intensity and timing of physical activity in relation to postmenopausal breast cancer risk: the prospective NIH-AARP diet and health study.

BACKGROUND: Despite strong evidence of an inverse association of physical activity with postmenopausal breast cancer risk, whether a certain intensity or time of life of physical activity is most effective for lowering breast cancer risk is not known. METHODS: In 118,899 postmenopausal women in the prospective NIH-AARP Diet and Health Study, we examined the relations of light and moderate-to-vigorous intensity physical activity during four periods of life ("historical": ages 15-18, 19-29, 35-39 years; "recent": past 10 years) to postmenopausal breast cancer risk. Physical activity was assessed by self-report at baseline, and 4287 incident breast cancers were identified over 6.6 years of follow-up. RESULTS: In age-adjusted and multivariate Cox regression models, >7 hours/week of moderate-to-vigorous activity during the past 10 years was associated with 16% reduced risk of postmenopausal breast cancer (RR:0.84; 95%CI:0.76,0.93) compared with inactivity. The association remained statistically significant after adjustment for BMI (RR:0.87; 95%CI:0.78,0.96). Neither moderate-to-vigorous activity during other periods of life nor light intensity activity during any period of life was related to breast cancer risk, and associations did not vary by tumor characteristics. CONCLUSION: A high level of recent, but not historical, physical activity of moderate-to-vigorous intensity is associated with reduced postmenopausal breast cancer risk. More precise recall of recent physical activity than activity in the distant past is one possible explanation for our findings.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Hyperglycosylated hCG activates LH/hCG-receptor with lower activity than hCG

While human chorionic gonadotropin (hCG) appears to have an essential role in early pregnancy, it is controversial whether the hyperglycosylated form of hCG (hCG-h), which is the major hCG isoform during the first 4-5 weeks of pregnancy, is able to activate LH/hCG receptor (LHCGR). To address this, we utilized different extensively characterized hCG and hCG beta reference reagents, cell culture- and urine-derived hCG-h preparations, and an in vitro reporter system for LHCGR activation. The WHO hCG reference reagent (99/688) was found to activate LHCGR with an EC50-value of 3.3 +/- 0.6 pmol/L (n = 9). All three studied hCG-h preparations were also able to activate LHCGR, but with a lower potency (EC50-values between 7.1 +/- 0.5 and 14 +/- 3 pmol/L, n = 5-11, for all P <0.05 as compared to the hCG reference). The activities of commercial urinary hCG (Pregnyl) and recombinant hCG (Ovitrelle) preparations were intermediate between those of the hCG reference and the hCG-h. These results strongly suggest that the hCG-h is functionally similar to hCG, although it has lower potency for LHCGR activation. Whether this explains the reduced proportion of hCG-h to hCG reported in patients developing early onset pre-eclampsia or those having early pregnancy loss remains to be determined.Peer reviewe

Long-term follow up of factual knowledge after a single, randomised problem-based learning course

BACKGROUND: The long-term effect of problem-based learning (PBL) on factual knowledge is poorly investigated. We took advantage of a previous randomised comparison between PBL and traditional teaching in a 3(rd )year course to follow up factual knowledge of the students during their 4(th )and 5(th )year of medical school training. METHODS: 3(rd )year medical students were initially randomized to participate in a problem-based (PBL, n = 55), or a lecture-based (LBL, n = 57) course in basic pharmacology. Summative exam results were monitored 18 months later (after finishing a lecture-based course in clinical pharmacology). Additional results of an unscheduled, formative exam were obtained 27 months after completion of the first course. RESULTS: Of the initial sample of 112 students, 90 participated in the second course and exam (n = 45, 45). 32 (n = 17 PBL, n = 15 LBL) could be exposed to the third, formative exam. Mean scores (± SD) were 22.4 ± 6.0, 27.4 ± 4.9 and 20.1 ± 5.0 (PBL), or 22.2 ± 6.0, 28.4 ± 5.1 and 19.0 ± 4.7 (LBL) in the first, second and third test, respectively (maximum score: 40). No significant differences were found between the two groups. CONCLUSION: A small-scale exposure to PBL, applied under randomized conditions but in the context of a traditional curriculum, does not sizeably change long-term presence of factual knowledge within the same discipline

Dilepton Spectra from Decays of Light Unflavored Mesons

The invariant mass spectrum of the $e^{+}e^{-}$ and $\mu ^{+}\mu ^{-}$ pairs from decays of light unflavored mesons with masses below the $\phi (1020)$-meson mass to final states containing along with a dilepton pair one photon, one meson, and two mesons are calculated within the framework of the effective meson theory. The results can be used for simulations of the dilepton spectra in heavy-ion collisions and for experimental searches of dilepton meson decays.Comment: 73 pages, 19 figures, 3 tables, REVTeX, new references adde

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

GrassPlot v. 2.00 – first update on the database of multi-scale plant diversity in Palaearctic grasslands

Abstract: GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). Following a previous Long Database Report (Dengler et al. 2018, Phyto- coenologia 48, 331–347), we provide here the first update on content and functionality of GrassPlot. The current version (GrassPlot v. 2.00) contains a total of 190,673 plots of different grain sizes across 28,171 independent plots, with 4,654 nested-plot series including at least four grain sizes. The database has improved its content as well as its functionality, including addition and harmonization of header data (land use, information on nestedness, structure and ecology) and preparation of species composition data. Currently, GrassPlot data are intensively used for broad-scale analyses of different aspects of alpha and beta diversity in grassland ecosystems

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight