Diethyl N,N-dimethylaminomethylenemalonate in the synthesis of fused heterocyclic systems

The reactions of diethyl N,N-dimethylaminomethylenemalonate ( 3 ) with N- and C- nucleophiles were studied. In the reaction of 3 with heterocyclic amines 4 , with the amino group attached at α-position in respect to the ring nitrogen atom, substitution of the dimethylamino group in 3 with the heterocyclic amino took place to give diethyl heteroarylaminomethylenemalonates 5 , which can cyclize into fused azino- 6 or azolopyrimidinones 7 . In the reaction of 3 with the compound with an active methylene group attached at α-position in regard to the ring nitrogen atom, such as pyridinylacetonitrile ( 8 ), ethyl pyridinyl- ( 9 ), and quinolinylacetate ( 10 ), fused quinolizines 11 and 12 , and benzo[c]quinolizine 13 were formed, respectively. Heterocyclic systems with an active or potentially active methylene group incorporated in the ring system, such as pyrazole 14 , pyrimidine 15 , and pyridine derivative 18 , gave with 3 fused pyranones 16, 17 , and 19 , and dihydroxynaphthalenes 22 and 23 naphtho[2,1-b]pyranones 24 and 25 .     

U6 is unsuitable for normalization of serum miRNA levels in patients with sepsis or liver fibrosis

MicroRNA (miRNA) levels in serum have recently emerged as potential novel biomarkers for various diseases. miRNAs are routinely measured by standard quantitative real-time PCR (qPCR); however, the high sensitivity of qPCR demands appropriate normalization to correct for nonbiological variation. Presently, RNU6B (U6) is used for data normalization of circulating miRNAs in many studies. However, it was suggested that serum levels of U6 themselves might differ between individuals. Therefore, no consensus has been reached on the best normalization strategy in ‘circulating miRNA''. We analyzed U6 levels as well as levels of spiked-in SV40-RNA in sera of 44 healthy volunteers, 203 intensive care unit patients and 64 patients with liver fibrosis. Levels of U6 demonstrated a high variability in sera of healthy donors, patients with critical illness and liver fibrosis. This high variability could also be confirmed in sera of mice after the cecal ligation and puncture procedure. Most importantly, levels of circulating U6 were significantly upregulated in sera of patients with critical illness and sepsis compared with controls and correlated with established markers of inflammation. In patients with liver fibrosis, U6 levels were significantly downregulated. In contrast, levels of spiked-in SV40 displayed a significantly higher stability both in human cohorts (healthy, critical illness, liver fibrosis) and in mice. Thus, we conclude that U6 levels in the serum are dysregulated in a disease-specific manner. Therefore, U6 should not be used for data normalization of circulating miRNAs in inflammatory diseases and previous studies using this approach should be interpreted with caution. Further studies are warranted to identify specific regulatory processes of U6 levels in sepsis and liver fibrosis.     

Identification of sources and production processes of bottled waters by stable hydrogen and oxygen isotope ratios

Bottled water is a food product that considerably depends on the environment from which it originates, not only at the place where it is produced, but predominantly on the conditions in the recharge area of the wells captured for bottling. According to their source and the bottling process, bottled waters can be divided into natural and artificially sparkling waters, still and flavoured waters. These waters originate from various parts of the hydrological cycle and their natural origin is reflected in their hydrogen and oxygen stable isotopic compositions (delta(2)H and delta(18)O). A total of 58 domestic and foreign brands and 16 replicates of bottled waters, randomly collected on the Slovene market in September 2004, were analysed for delta(2)H and delta(18)O. The isotopic composition varied between -83 per thousand and -46 per thousand with an average of -66 per thousand for hydrogen, and between -11.9 per thousand and -7.5 per thousand with an average of -9.6 per thousand for oxygen. This investigation helped (1) to determine and test the classification of bottled waters, (2) to determine the natural origin of bottled water, and (3) to indicate differences between the natural and production processes. The production process may influence the isotopic composition of flavoured waters and artificially sparkling waters. No such modification was observed for still and natural sparkling waters. The methods applied, together with hydrological knowledge, can be used for the authentication of bottled waters for regulatory and consumer control applications.     

Joint characteristic functions construction via copulas

When modelling dependent risks it is important to be able to generate joint distributions with given marginals. One of the ways which may be useful in connection with using the Fast Fourier Transform is to construct joint characteristic functions from marginal characteristic functions. In this paper a class of n-dimensional continuous copulas is presented which in turn lead to a simple construction of joint characteristic functions with given marginal characteristic functions. Bounds on various measures of correlation are also given.     

A Crystallographic Charge Density Study of the Partial Covalent Nature of Strong N⋅⋅⋅Br Halogen Bonds

The covalent nature of strong N?Br???N halogen bonds in a cocrystal ( 2 ) of N‐bromosuccinimide ( NBS ) with 3,5‐dimethylpyridine ( lut ) was determined from X‐ray charge density studies and compared to a weak N?Br???O halogen bond in pure crystalline NBS ( 1 ) and a covalent bond in bis(3‐methylpyridine)bromonium cation (in its perchlorate salt ( 3 ). In 2 , the donor N?Br bond is elongated by 0.0954 Å, while the Br???acceptor distance of 2.3194(4) is 1.08 Å shorter than the sum of the van der Waals radii. A maximum electron density of 0.38 e Å^?3 along the Br???N halogen bond indicates a considerable covalent contribution to the total interaction. This value is intermediate to 0.067 e Å^?3 for the Br???O contact in 1 , and approximately 0.7 e Å^?3 in both N?Br bonds of the bromonium cation in 3 . A calculation of the natural bond order charges of the contact atoms, and the σ*(N1?Br) population of NBS as a function of distance between NBS and lut , have shown that charge transfer becomes significant at a Br???N distance below about 3 Å.     

Comparison of monthly and daily isotopic composition of precipitation in the coastal area of Slovenia

The stable isotopic composition (delta(2)H and delta(18)O) of short-term (daily) precipitation collected from October 2002 to September 2003 at two stations in a coastal, karstic area in south-western Slovenia was investigated. In addition, monthly composite samples were collected and analysed for comparison with amount-weighted monthly means. The delta(2)H and delta(18)O values obtained show a wide range and reflect seasonal climatic variations. Deuterium excess and local meteoric water lines (LMWLs) were determined and cumulative frequency analysis and coincidence tests were performed. The statistical coincidence test showed that the LMWLs calculated from monthly data for Portoroz and Kozina are coincident, but the LMWLs calculated from daily precipitation events are not. This difference could be explained by the greater variance of the isotopic composition of daily precipitation in comparison to monthly composite samples and also to the influence of evaporation during events below<1 mm at Portoroz during the extremely dry and warm spring-summer season of 2003. Finally, synoptic maps and backward trajectories of a selected precipitation event showed that changes of isotopic composition are related to mixing of air masses originating from the continent and Mediterranean cyclogenesis.     

Size-biased sampling of Poisson point processes and excursions

Summary Some general formulae are obtained for size-biased sampling from a Poisson point process in an abstract space where the size of a point is defined by an arbitrary strictly positive function. These formulae explain why in certain cases (gamma and stable) the size-biased permutation of the normalized jumps of a subordinator can be represented by a stickbreaking (residual allocation) scheme defined by independent beta random variables. An application is made to length biased sampling of excursions of a Markov process away from a recurrent point of its statespace, with emphasis on the Brownian and Bessel cases when the associated inverse local time is a stable subordinator. Results in this case are linked to generalizations of the arcsine law for the fraction of time spent positive by Brownian motion.Research supported in part by NSF grant DMS88-01808 and DMS91-07351     

Large deflections of nonlinearly elastic non-prismatic cantilever beams made from materials obeying the generalized Ludwick constitutive law

This paper studies large deflections of nonlinearly elastic cantilever beams made from materials obeying the generalized Ludwick constitutive law. An exact moment-curvature formula which can be applied to study arbitrarily loaded and supported beams of rectangular cross-sections is developed. Several advantages of the generalized Ludwick’s model are illustrated. Numerical examples considered in this materially and geometrically nonlinear analysis clearly indicate rich nonlinear behavior of the beams.     

An excursion approach to maxima of the Brownian bridge

Distributions of functionals of Brownian bridge arise as limiting distributions in non-parametric statistics. In this paper we will give a derivation of distributions of extrema of the Brownian bridge based on excursion theory for Brownian motion. The idea of rescaling and conditioning on the local time has been used widely in the literature. In this paper it is used to give a unified derivation of a number of known distributions, and a few new ones. Particular cases of calculations include the distribution of the Kolmogorov–Smirnov statistic and the Kuiper statistic.     

Perturbed Brownian motions

Summary. We study `perturbed Brownian motions', that can be, loosely speaking, described as follows: they behave exactly as linear Brownian motion except when they hit their past maximum or/and maximum where they get an extra `push'. We define with no restrictions on the perturbation parameters a process which has this property and show that its law is unique within a certain `natural class' of processes. In the case where both perturbations (at the maximum and at the minimum) are self-repelling, we show that in fact, more is true: Such a process can almost surely be constructed from Brownian paths by a one-to-one measurable transformation. This generalizes some results of Carmona-Petit-Yor and Davis. We also derive some fine properties of perturbed Brownian motions (Hausdorff dimension of points of monotonicity for example). Received: 17 May 1996 / In revised form: 21 January 1997