Search

In this study we evaluate how far the scope of similarity searching can be extended to identify not only ligands binding to the same target as the reference ligand(s) but also ligands of other homologous targets without initially known ligands. This "homology-based similarity searching" requires molecular representations reflecting the ability of a molecule to interact with target proteins. The Similog keys, which are introduced here as a new molecular representation, were designed to fulfill such requirements. They are based only on the molecular constitution and are counts of atom triplets. Each triplet is characterized by the graph distances and the types of its atoms. The atom-typing scheme classifies each atom by its function as H-bond donor or acceptor and by its electronegativity and bulkiness. In this study the Similog keys are investigated in retrospective in silico screening experiments and compared with other conformation independent molecular representations. Studied were molecules of the MDDR database for which the activity data was augmented by standardized target classification information from public protein classification databases. The MDDR molecule set was split randomly into two halves. The first half formed the candidate set. Ligands of four targets (dopamine D2 receptor, opioid delta-receptor, factor Xa serine protease, and progesterone receptor) were taken from the second half to form the respective reference sets. Different similarity calculation methods are used to rank the molecules of the candidate set by their similarity to each of the four reference sets. The accumulated counts of molecules binding to the reference target and groups of targets with decreasing homology to it were examined as a function of the similarity rank for each reference set and similarity method. In summary, similarity searching based on Unity 2D-fingerprints or Similog keys are found to be equally effective in the identification of molecules binding to the same target as the reference set. However, the application of the Similog keys is more effective in comparison with the other investigated methods in the identification of ligands binding to any target belonging to the same family as the reference target. We attribute this superiority to the fact that the Similog keys provide a generalization of the chemical elements and that the keys are counted instead of merely noting their presence or absence in a binary form. The second most effective molecular representation are the occurrence counts of the public ISIS key fragments, which like the Similog method, incorporates key counting as well as a generalization of the chemical elements. The results obtained suggest that ligands for a new target can be identified by the following three-step procedure: 1. Select at least one target with known ligands which is homologous to the new target. 2. Combine the known ligands of the selected target(s) to a reference set. 3. Search candidate ligands for the new targets by their similarity to the reference set using the Similog method. This clearly enlarges the scope of similarity searching from the classical application for a single target to the identification of candidate ligands for whole target families and is expected to be of key utility for further systematic chemogenomics exploration of previously well explored target families.

Annotation efforts in biosciences have focused in past years mainly on the annotation of genomic sequences. Only very limited effort has been put into annotation schemes for pharmaceutical ligands. Here we propose annotation schemes for the ligands of four major target classes, enzymes, G protein-coupled receptors (GPCRs), nuclear receptors (NRs), and ligand-gated ion channels (LGICs), and outline their usage for in silico screening and combinatorial library design. The proposed schemes cover ligand functionality and hierarchical levels of target classification. The classification schemes are based on those established by the EC, GPCRDB, NuclearDB, and LGICDB. The ligands of the MDL Drug Data Report (MDDR) database serve as a reference data set of known pharmacologically active compounds. All ligands were annotated according to the schemes when attribution was possible based on the activity classification provided by the reference database. The purpose of the ligand-target classification schemes is to allow annotation-based searching of the ligand database. In addition, the biological sequence information of the target is directly linkable to the ligand, hereby allowing sequence similarity-based identification of ligands of next homologous receptors. Ligands of specified levels can easily be retrieved to serve as comprehensive reference sets for cheminformatics-based similarity searches and for design of target class focused compound libraries. Retrospective in silico screening experiments within the MDDR01.1 database, searching for structures binding to dopamine D2, all dopamine receptors and all amine-binding class A GPCRs using known dopamine D2 binding compounds as a reference set, have shown that such reference sets are in particular useful for the identification of ligands binding to receptors closely related to the reference system. The potential for ligand identification drops with increasing phylogenetic distance. The analysis of the focus of a tertiary amine based combinatorial library compared to known amine binding class A GPCRs, peptide binding class A GPCRs, and LGIC ligands constitutes a second application scenario which illustrates how the focus of a combinatorial library can be treated quantitatively. The provided annotation schemes, which bridge chem- and bioinformatics by linking ligands to sequences, are expected to be of key utility for further systematic chemogenomics exploration of previously well explored target families.

NbS2 nanoparticles with a closed cage structure (inorganic fullerene-like phase—IF) were synthesized by reaction between NbCl5 vapor and H2S gas in a reducing atmosphere at 400 °C, and subsequent annealing under a H2S/H2 atmosphere at 550 °C. Following the synthesis, the nanoparticles were found to have a large excess of Nb; they were agglomerated; highly dislocated and enfolded by amorphous material. After annealing, most of the amorphous material crystallized into closed NbS2 shells, and the nanoparticles appeared to be much more faceted. Transmission electron microscopy revealed that the interlayer spacing (c/n) of the annealed particles had decreased. They were also agglomerated, being connected to neighboring nanoparticles through their outer NbS2 layers after annealing. In related experiments Nb2O3 nanofibers, which organize into a nanoflower superstructure, and also NbS2 nanofibers were synthesized under somewhat different growth conditions.

Neue elektrische Antriebskonzepte ermöglichen es, eine hohe Funktionalität in einem eingeschränkten Bauraum unterzubringen. Damit steigt auch in der Landwirtschaft das Interesse an elektrischen Antrieben. Die Projektgruppe Elektrische Maschinen und Antriebe der HTW Dresden beteiligt sich mit der TU Dresden an einem Projekt, bei dem beginnend mit der elektrisch angetriebenen Dreschtrommel umfassend an einem Mähdrescher untersucht wird, wie diese Antriebe in einzelne Funktionselemente integriert werden können. Neben der Auslegung der Antriebe werden Verfahren erarbeitet, die Verluste im Motor mit hoher Genauigkeit zu berechnen. So können in Zukunft passgenaue Kühlkonzepte für diese Antriebstechnik entwickelt werden. Anforderungen gerade im Bereich der Elektromobilität fordern den Blick für neue Materialien, deren elektromagnetisches und thermisches Verhalten werden in ihrem Einfluss auf die Erwärmung untersucht. Analytische und kombinierte Berechnungsmethoden in 2D-FEM gestatten die vereinfachte Rechnung unter Berücksichtigung von Grundwelle und entstehenden Harmonischen zu qualifizieren. Verlustberechnungen aus der transienten FEM-Rechnung ermöglichen diese Verbesserung. Die Methode wird am Beispiel der elektrischen Dreschtrommel mit den berechneten Verlustverteilungen beschrieben. Neue Methoden der 3D-FEM, wie sie die Software Ansys bietet, werden für die Nutzung von Einflüssen der Wirbelstromeffekte und in Auswertung für die Segmentierung von Permanentmagneten dargestellt. Die exemplarisch gewonnenen Erkenntnisse liefern einen Beitrag für weitere Schneidwerksantriebe am Mähdrescher, aber auch darüber hinaus in Projekten mit Herstellern elektrischer Maschinen. New concepts for electrical drives make it possible to put a high functionality into a restricted structural form. Thereby the interest in electrical drives increases also in the farming. The project team Electrical machines and drives of the HTW Dresden participates together with the TU Dresden in a project, where starting with the electrically driven threshing cylinder is comprehensively examined at a combine harvester, how these drives can be integrated into single function elements. Besides the dimensioning of the drives are developed methods to calculate losses in the engine with high precision. So custom-fit cooling concepts can be developed for this drive technology in future. Requirements just in the area of the electric mobility call looking for new materials, whose electromagnetic and thermic behavior are examined in her influence on the warming. Analytical and combined computation methods in 2D-FEM allow the simplified calculation under consideration of the fundamental wave and the arising harmonic ones. Loss calculations by means of the transient FEM calculation make possible this improvement. The method is described at the example of the electrical threshing cylinder with the calculated loss distributions. New methods of the 3D-FEM, as the software of Ansys offers, are presented for the use of influences of the eddy current effects and in evaluation for the segmentation of permanent magnets. The exemplarily got knowledge provides a contribution for further cut header drives at the combine but also furthermore in projects together with manufacturers of electrical machines.

The Black Sea is the largest anoxic basin on earth and provides unique conditions for the study of key processes controlling the biology and biogeochemistry at pelagic redoxclines. By identifying microbiological/biogeochemical agents and assessing rates of the coupled cycles of carbon, nitrogen, phosphorus, sulfur, manganese and iron at the redox boundary the functional response of this specific environment upon the change of external conditions will be visible. Geochemical and textural investigation of authigenic mineral phases at the redoxcline will be also important to assess the importance of the so-called "Mn-Fe-P shuttle" for the phosphorus cycle and primary productivity, and to clarify the trapping function of trace-metals in anoxic systems. To meet the various water column sampling demands, on more than 40 stations CTD and P-CTD profiles as well as multi-nets and in-situ pumps were deployed along several slope transects in the northwestern and northeastern Black Sea. Additionally, a permanent sediment trap mooring has been deployed in the central western basin. The sedimentary archive has been extensively sampled during the cruise by means of multicorer, gravity corer and piston corer. The upper parts of the cores consists of finely laminated late Holocene units providing excellent records of the Black Sea environmental history, of past changes in redoxcline dynamics, and of climate signals transported by rivers from the northern drainage basins of the Black Sea. Presite multibeam and Parasound surveys of about 400 nm were concluded. The research cruise was integral part of the implementation plan of the bilateral scientific cooperation between Germany and Ukraine in the field of marine sciences supported by the German and Ukrainian Ministries of Education and Science., MARIA S. MERIAN-Berichte

The weight reduction has become a key driver in the automotive design. The study and the simulations of non-conventional materials has become very important. This work is focused on the numerical crashworthiness design of carbon fibres reinforced plastics (CFRP) structures. After a literature research on the currently numerical models specifically used for CFRP, two different numerical models were developed in order to reproduce experimental crush test on CFRP tube previously made. The influence of several different parameters on the final results was analysed. The work put in evidence the advantages of crushing zone modelling compared to a stacked shell one.

The breakpoints of deletions and translocations in the proximal chromosome 14q region were defined in nine patients, four of whom have not been reported previously. The aberrant chromosomes were isolated by flow cytometry and used to map the chromosome 14 deletion or translocation breakpoints. The parental origins of deletions were ascertained as paternal in five cases and maternal in one. With the draft genomic sequence for human chromosome 14 available, gene searches were performed on selected intervals of the 14q11.2-q21 region to identify candidate genes for the observed phenotype in some of those affected. Gain of function of the gene PAX9 on chromosome 14 is a possible candidate for a t(14;18) patient affected with mesomelic bone dysplasia. Furthermore, a compilation of other human chromosome 14q proximal deletion and translocation cases was obtained from a search on cytogenetic databases. These findings suggest a locus for myelofibrosis at chromosome 14q13. This study contributes to useful information for identifying disease genes in this region.

Editor—Hypomelanosis of Ito (HI) (MIM 146150) is an aetiologically heterogeneous physical finding characterised by a swirling pattern of hypopigmentation of the skin, typically distributed along the lines of Blaschko, reflecting pigmentary mosaicism. Chromosomal abnormalities are common and very heterogeneous. They include X;autosomal translocations and mosaicism of aneuploidy, segmental trisomies, or monosomies.1-5 As HI is not a specific disorder, it has also been referred to as pigmentary mosaicism.6 This report adds a further chromosomal anomaly which has not been described in pigmentary mosaicism previously. The proband was the first son born to a 29 year old mother and a 30 year old father. There was no family history of recurrent abortions, consanguinity, or mental retardation. He was born by caesarian section at term after an uncomplicated pregnancy with a weight of 3560 g (50th centile), a length of 50 cm (50th centile), and an occipitofrontal circumference (OFC) of 32 cm (

Using morpholine as sole source of carbon, nitrogen and energy, strain HE5 (DSM 44238) was isolated from forest soil. The isolated strain was identified as a member of the subgroup of fast-growing Mycobacterium species as revealed by 16S rDNA analysis. An identity of 99.4% was obtained to Mycobacterium gilvum; however, the type strain was unable to utilize morpholine. A maximal growth rate of 0.17 h(-1) was observed at a morpholine concentration of 30 mM, 30 degrees C and pH 7.2. The substrate was tolerated at concentrations up to 100 mM. Besides morpholine, the strain utilized pyrrolidine, piperidine and proposed intermediates in morpholine metabolism such as glycolate, glyoxylate and ethanolamine. Degradation of morpholine, piperidine and pyrrolidine by resting or permeabilized cells was strictly dependent on the presence of oxygen. Addition of the cytochrome-P450-specific inhibitor metyrapone to the growth medium resulted in a significantly decreased growth rate if these cyclic amines were used as a substrate. Carbon monoxide difference spectra of crude extracts from cells grown on these substrates compared to spectra obtained for extracts of succinate-grown cells indicated that cytochrome P450 is specifically expressed during growth on the cyclic amines. These data indicated that a cytochrome-P450-dependent monooxygenase is involved in the degradation of the three cyclic amines.

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in approximately 2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader-Willi syndrome patients. Such a difference cannot be easily accounted for if 'gamete complementation' is the main mechanism leading to UPD. If we assume that non-disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post-zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non-random X-chromosome inactivation (XCI) observed in maternal UPD15 patients (p < 0.001) provides indirect evidence that a post-zygotic error is also typically involved in loss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as compared with normal controls. This may be simply the consequence of an age association with maternal non-disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.

Intramolecular oxa-conjugate addition has been employed in a stereoselective synthesis of enantiopure polyalkyl-substituted tetrahydropyrans, which are frequently found as substructures in many natural products. The requisite cyclization precursors, 7-hydroxy-2-enimides 3 and 7-hydroxy-2-enoates 6 were easily accessible by silyloxy Cope rearrangements of the appropriate chiral syn-aldols. It was found that the stereoselectivity of the cyclization could be controlled by judicious choice of the carboxylic acid derivative, resulting in a kinetically controlled reaction for the imides and a thermodynamically controlled process for the esters. Mechanistic considerations that could account for the stereocontrol of the process are outlined.

This paper compares the effectiveness of similarity measures based on two-dimensional fingerprints and on molecular fields for identifying pairs of bioisosteric molecules in the BIOSTER database. The results suggest that the two types of descriptor are complementary in nature, each finding some bioisosteric pairs that are not found by the other. This conclusion is confirmed by studies of groups of BIOSTER molecules that share the same activity characteristics, and by experiments that involve combining the two types of similarity measure.

Enantiopure piperidines 4 may be accessed in very good overall yields and high stereoselectivity from the bifunctional products 2 of the silyloxy Cope rearrangement of chiral aldol products 1 by sequential nucleophilic addition of primary amines and subsequent hydrogenation. The reaction is proposed to proceed by initial imine formation followed by an intramolecular aza-conjugate addition to the α,β-unsaturated imide. The stereoselectivity is controlled by A(1.2) strain between the imine N-alkyl group and the conjugate double bond. In an alternate approach, polyalkyl-substituted piperidines were prepared by the addition of organozinc reagents to cyanopiperidines readily obtained from the Cope products in the presence of a silver salt.

Several new approaches for the enantioselective synthesis of the chromane moiety of vitamin E are described. Sonogashira coupling of 3a with the alkyne 4 and subsequent elimination gave 6, which was bis(hydroxylated) in 93% yield and with 85% ee. Recrystallization gave enantiopure 7a, which was hydrogenated and transformed into the vitamin E precursor 11. The bis(hydroxylation) of 18 and 21 to give 9 and 22, respectively, was less than satisfactory, proceeding with ee values of 28% and 18%. In contrast, stereoselective allylation of ketone 15 followed by removal of the protecting group or ozonolysis of the allyl moiety furnished the allyl alcohol 26 and the aldehyde 27, respectively, in almost enantiopure form, which again could be used as precursors for vitamin E. Partial hydrogenation of 5a gave the alkene 32a and that of 28 the alkene 30b, both of which show interesting atropisomerism.

Ein 29jahriger Patient stellte sich in unserer Ambulanz mit einer beidseitigen Gynakomastie und einem beidseits verringertem Hodenvolumen vor. Die Hormonbestimmungen ergaben die Diagnose eines primaren Hypogonadismus. Wegen des Verdachts auf ein Klinefelter-Syndrom wurde eine Chromosomenanalyse durchgefuhrt. Es fand sich eine XX-Konstellation bei fehlendem Y-Chromosom (46,XX-Karyotyp). Manner mit 46,XX-Karyotyp tragen meist eine Translokation des geschlechtsdeterminierenden Gens (SRY-Gen=sex determining region of Y) vom Y- auf ein X-Chromosom, die auch bei unserem Patienten nachgewiesen wurde.

The 4-benzylidene-3-oxo[1,3]oxathiolan-5-ones 13–15, which were derived from the 3-oxo[1,3]oxathiolan-5-ones 9–11 by Knoevenagel condensation with the aldehydes 12, cyclize in an intramolecular hetero Diels–Alder reaction with high yield and excellent endo/exo as well as induced diastereoselectivity to give the hetero Diels–Alder adducts 16–18. The preferred formation of the Knoevenagel products 13–15 with a (Z) configuration was predicted with DFT calculations (B3LYP-6-311+G*) using the model systems 28 and 29. In addition B3LYP-6-31G*/sB3LYP/3-21G(*) calculations on transition structures for the hetero Diels–Alder reaction of 29 and 30 allowed a good correlation with the experimental results, which show that an endo attack of the dienophile syn to the S–O group in 13–15 leads to the main products.

Intermolecular hetero Diels-Alder reactions of the enantiopure sulfinimine 11 with the enol ethers 12-16 at 20 °C and 11 kbar lead to the tetrahydropyridines 18-22 in high yield, with very good to good endo/exo selectivities, and with an induced diastereoselectivity of up to 2.1:1. The sulfinyl group in the adducts can be removed with MeLi followed by treatment with acetyl chloride or dimethyl sulfate. According to this procedure, 21 gives either N-acetyltetrahydropyridine 29 or the N-methyldihydropyridine 32. The intramolecular Diels-Alder reaction of 26 yields 27, which is transformed into 33 and 34, respectively.

The rotational potential energy surface (PES) of methyl vinyl sulfoxide (1) was calculated at MP2/6-31+G*, B3LYP/6-311+G*, B3LYP/3-21G(*), MP2/3-21G(*), PM3, and AM1. All ab initio methods gave two conformations: one with the S−O bond (a) syncoplanar to the carbon−carbon double bond and one with the lone pair in plane (b); the first one is preferred by 1.7 kcal mol-1. The energy difference is strongly basis set dependent: B3LYP/6-311+G* offers the best compromise. Semiempirical methods give a qualitatively different rotational PES. Whereas the effect methyl group in the E-position is small, Z-substitution leads to destabilization of conformation a through sterical interaction, so that conformation b is preferred by 0.4 kcal mol-1. Electron-withdrawing substituents such as ester or keto groups in the α-position destabilize conformations c and d where the lone pair is syncoplanar to the CC double bond, so that the syncoplanar orientation of the S−O bond is favored by ca. 5 kcal mol-1, depending on the sub...

DiGeorge syndrome (DGS) is a developmental field defect, characterised by absent/hypoplastic thymus and parathyroid, and conotruncal heart defects, with haploinsufficiency loci at 22q (DGS1) and 10p (DGS2). We performed fluorescence in situ hybridisations (FISH) and polymerase chain reaction (PCR) analyses in 12 patients with 10p deletions, nine of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region is defined by two DGS patients, and maps within a 1 cM interval including D10S547 and D10S585. The other seven DGS patients are hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q maps at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described are in the range of 10-50 cM and enable the tentative mapping of loci for ptosis and hearing loss, features which are not part of the DGS clinical spectrum.

A common mechanism for chromosomal fragile site genesis is not yet apparent. Folate-sensitive fragile sites are expanded p(CCG)n repeats that arise from longer normal alleles. Distamycin A or bromodeoxyuridine-inducible fragile site FRA16B is an expanded AT-rich approximately 33 bp repeat; however, the relationship between normal and fragile site alleles is not known. Here, we report that bromodeoxyuridine-inducible, distamycin A-insensitive fragile site FRA10B is composed of expanded approximately 42 bp repeats. Differences in repeat motif length or composition between different FRA10B families indicate multiple independent expansion events. Some FRA10B alleles comprise a mixture of different expanded repeat motifs. FRA10B fragile site and long normal alleles share flanking polymorphisms. Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports dynamic mutation as a common mechanism for repeat expansion.

Reaction of aliphatic aldehydes 1 and allylsilane 3 at −78 °C in the presence of the norpseudoephedrine derivative 2a and catalytic amounts of trifluoromethanesulfonic acid trimethylsilyl ester gives the homoallylic ethers 4 with >98% diastereoselectivity. The ethers 4 can be transformed into the corresponding homoallylic alcohols 5 having an enantiomeric excess >98% using sodium in liquid ammonia. On-line NMR spectroscopy indicates that the mixed acetal 7 and the oxazolidinium ion 12 are intermediates in the formation of 4. At higher temperature proton transfer occurs to give the oxazolidinium ion 18, which does not react with allylsilane, but gives the oxazolidine 17 on aqueous workup. Protonation of 17 with trifluoromethanesulfonic acid leads to 18 but not to the oxazolidinium ion 12. Thus, an allylation starting from 17 is not possible.

Many biologically active and widely distributed natural products contain a dihydro- or a tetrahydropyran moiety. One of the best methods for the synthesis of these compounds is the hetero Diels-Aider reaction of 1-0Xia-1,3-butadienes which leads to substituted and annulated 3,4-dihydro-2H-pyrans usually in excellent yields and high selectivity. Further transformations of these substances e.g. by hydrogenation yield the tetrahydropyrans with the basic skeleton of the carbohydrates. In this article at first theoretical aspects of the cycloaddition are discussed which include ab initio calculations of the energies and the coefficients of 1-oxa-1,3-butadienes and different dienophiles. In addition, calculations of the transition structure of the cycloaddition of acrolein and ethene are presented. In the second chapter general considerations on the regia- and stereoselectivity of the cycloadditions are presented. In the following parts different hetero Diels-Aider reactions with activated and non-activated 1-oxa-1,3-butadiens and their use in diastereoselective transformations and the synthesis of natural products as carbohydrates, alkaloids, terpenes, steroids, cannabinoids, mycotoxins, ionophores and antibiotics are described. A point of emphasis is the domino Knoevenagel hetero Diels-Aider reaction in which the oxabutadienes are formed in situ and which allows the highly efficient synthesis of complex dihydropyrans starting from simple substrates. In the final chapters enantioselective cycloadditions, reactions on solid support and cycloadditions under high pressure are discussed.

Cyclic nucleotide-gated (CNG) ion channels serve as final targets of signal transduction in vertebrate photoreceptors. While the basic mechanisms of phototransduction are similar in rod and cone photoreceptors, both cell types express distinct sets of components of the transduction pathway. We report here the cloning of the cDNA encoding the alpha-subunit of the cGMP-gated channel of human cone photoreceptors. The open reading frame predicts a polypeptide of 694 amino acid residues with conserved functional parts and amino acid positions typical for the alpha-subunit of CNG-channels. Heterologous expression of the cDNA in Xenopus oocytes gave rise to cGMP-gated channel activity. Antiserum directed against the C-terminus of the bovine cone CNG channel alpha-subunit crossreacted specifically with the heterologously expressed polypeptide and stained cone photoreceptors and weakly also the outer plexiform layer in human retinal sections. Northern blot analysis detected a prominent mRNA species of approximately 3.8 kb in human retina. The entire gene spans approximately 30 kb of genomic sequence and is located on the pericentric band q11.2 of human chromosome 2. The gene is composed of seven exons, with introns located at positions which are preserved with respect to the human rod gene, indicating a common ancestral gene structure. RT-PCR analysis gave no evidence for alternatively spliced transcripts.

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P

Karyotypes with an interstitial deletion and a marker chromosome formed from the deleted segment are rare. We identified such a rearrangement in a newborn infant, who presented with macrocephaly, asymmetric square skull, minor facial anomalies, omphalocele, inguinal hernias, hypospadias, and club feet. The karyotype 46,XY,del(5) (pter --> p13::cen --> qter)/47,XY,+dicr(5)(:p13 --> cen::p13 --> cen), del(5)(pter --> p13::cen --> qter) was identified by banding studies and FISH analysis in the peripheral lymphocytes. One breakpoint on the del(5) maps distal to GDNF, and FISH analysis using an alpha-satellite probe suggests that the proximal breakpoint maps within the centromere. The dicentric r(5) consists of two copies of the segment deleted in the del(5), resulting in trisomy of proximal 5p (5p13-cen). The phenotype of the propositus is compared with other trisomy 5p cases and possible mechanisms for the generation of this unique chromosomal rearrangement are discussed.

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) of chromosome 15. Including the present and published cases, more than 120 patients with maternal UPD of human chromosome 15 have been ascertained. Investigation of chromosome 15 markers indicates that approximately 71 per cent of the additional maternal chromosomes were the result of meiosis I segregation errors, 13 per cent were the result of meiosis II errors, and 16 per cent resulted from post-zygotic duplication of one chromosome 15. An increase in maternal age is associated with UPD cases due to meiotic errors. The age-specific risk for UPD(15) is analysed and shows an exponential increase with maternal age which is similar to that observed for trisomy 21. For women greater than or equal to 40 years of age, the risk for UPD(15) is approximately 1/3400 livebirths. The frequency of chromosome aberrations associated with UPD(15) is also discussed. Two types of aberrations are at significantly increased risk of fetal UPD(15): de novo (or inherited) isochromosome 15 and confined placental mosaicism for trisomy 15. Two additional abnormalities, de novo small marker chromosomes derived from 15, e.g., idic15(pter-q11:q11-pter), and familial Robertsonian translocations involving chromosome 15, appear to have a mildly increased risk of UPD(15).

About 70% of patients with Prader-Willi syndrome (PWS) and Angelman syndrome (AS) have a common interstitial de novo microdeletion encompassing paternal (PWS) or maternal (AS) loci D15S9 to D15S12. Most of the non-deletion PWS patients and a small number of non-deletion AS patients have a maternal or paternal uniparental disomy (UPD)15, respectively. Other chromosome 15 rearrangements and a few smaller atypical deletions, some of the latter being associated with an abnormal methylation pattern, are rarely found. Molecular and fluorescence in situ hybridization (FISH) analysis have both been used to diagnose PWS and AS. Here, we have evaluated, in a typical routine cytogenetic laboratory setting, the efficiency of a diagnostic strategy that starts with a FISH deletion assay using Alu-PCR (polymerase chain reaction)-amplified 1315S10-positive yeast artificial chromosome (YAC) 273A2. We performed FISH in 77 patients suspected of having PWS (n = 66) or AS (n = 11) and compared the results with those from classical cytogenetics and wherever possible with those from DNA analysis. A FISH deletion was found in 16/66 patients from the PWS group and in 3/11 patients from the AS group. One example of a centromere 15 co-hybridization performed in order to exclude cryptic translocations or inversions is given. Of the PWS patients, 14 fulfilled Holm's criteria, but two did not. DNA analysis confirmed the commmon deletion in all patients screened by the D15S63 methylation test and in restriction fragment length polymorphism dosage blots. In 3/58 non-deletion patients, other chromosomal aberrations were found. Of the non-deleted group, 27 subjects (24 PWS, 3 AS) were tested molecularly, and three patients with an uniparental methylation pattern were found in the PWS group. The other 24/27 subjects had neither a FISH deletion nor uniparental methylation, but two had other cytogenetic aberrations. Given that cytogenetic analysis is indispensable in most patients, we find that the FISH deletion assay with YAC 273A2 is an efficient first step for stepwise diagnostic testing and mutation-type analysis of patients suspected of having PWS or AS.

We describe the clinical manifestations of an autosomal dominant form of craniosynostosis in a large family with eight affected relatives. Unilateral or bilateral coronal synostosis, low frontal hair line, strabismus, ptosis, and partial cutaneous syndactyly of fingers and toes are findings suggestive of the diagnosis of Saethre-Chotzen syndrome. The disease locus was excluded from the two adjacent Saethre-Chotzen candidate regions on 7p by linkage analysis with markers D7S664 and D7S507. This indicates heterogeneity of Saethre-Chotzen syndrome with a locus outside the candidate regions on 7p.

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (

Die pharmazeutische Forschung setzt computergestutzte Methoden zur Toxizitatsvorhersage seit Jahren mit Erfolg ein.1) Bei Novartis wurde jetzt dazu ein Web-basiertes System entwickelt.

ICF syndrome (ICFS) is a rare immunodeficiency disorder characterized by instability of the pericentromeric heterochromatin predominantly of chromosomes 1 and 16. DNA methylation studies in two unrelated ICFS patients provide further evidence for a marked hypomethylation of satellite 2 DNA. The ICFS-specific disturbances of chromatin structure take place within the satellite 2 DNA regions, as demonstrated by fluorescence in situ hybridization analysis. Moreover, methylation studies of genomic imprinted loci D15S63, D15S9, and H19 have revealed hypomethylation to different degrees in both patients; this provides evidence for hypomethylation at autosomal single copy loci in ICFS. Cell fusion experiments have revealed a distinct reduction of chromosomal abnormalities in ICFS cells after fusion with normal cells, suggesting that the abnormalities are caused by the loss of function of an as yet unknown trans acting factor. Although it is now clear that wide-spread DNA hypomethylation is a characteristic feature of ICFS, neither the cause and mechanism of hypomethylation nor their relationship to the clinical symptoms is known. We speculate that a phenotypic effect might result from tissue-dependent abnormal gene expression and/or from a possible structural disturbance of DNA domains, which, with respect to the immunodeficiency, partially prevents the normal somatic recombinations in immunologically active cells.

Down syndrome is usually caused by complete trisomy 21. Rarely, it is due to partial trisomy of the segment 21q22. We report on a 33-month-old girl with tetrasomy 21 pter {yields} q22.1 resulting from an extra chromosome idic(21)(q22.1). She has craniofacial traits typical of Down syndrome, including brachycephaly, third fontanel, upward slanting palpebral fissures, round face, and protruding tongue. Speech development is quite delayed whereas motor development is only mildly retarded. The molecular content of the extra isodicentric chromosome was defined by molecular genetic investigations using 13 single copy probes unique to chromosome 21, and SOD1 expression studies. The child was found to have 4 copies of the region defined by D21S16 (21cen) through D21S93 on 21q22.1 and two copies of the remaining region defined by SOD1 {yields} D21S55 {yields} D21S123. In view of the recent assignment of Down syndrome facial characters to the 21q22 region, defined in part by D21S55, it is significant that this child shows a subset of Down syndrome facial manifestations, without duplication of this region. These results suggest that genes contributing to the facial and some of the hand manifestations of Down syndrome also exist in the chromosomal region proximal to D21S55 in band 21q22.1.more » 34 refs., 6 figs., 3 tabs.« less

In many fields of the chemical industry the moisture content in the gaseous initial, intermediate and end products as well as in the vehicle gases play an important role. It is therefore necessary to measure the moisture concentration online and to use it for control purposes. The monitoring of the moisture as a quality parameter for the end product is likewise important. A new two-cell measuring equipement is presented which is maintenance-free and can operate over a very long period without ever interrupting gas moisture measurement.

Recently a novel method termed compound set enrichment (CSE) has been described that uses the activity distribution of a structural class of compounds to identify hit series from primary screening data. This report describes how this method can be used to identify such hit series, even when no hits according to conventional hit-calling methods for a given structural class are present in the data set. Such series, which were called latent hit series, were identified prospectively in a cell-based screening campaign and also in a series of retrospective analyses of publicly available data sets from PubChem. The assay used for the prospective case study was developed to identify compounds modulating protein translation directed from the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV) genomic RNA. The assay was designed with the ability to detect two assay readouts. The first assay readout monitors compound effects on IRES-directed translation, and the second readout monitors the cell viability and general effect on protein expression. By applying CSE separately to both of them, six validated latent hit series with apparently no effects on cell viability were identified. For each of these series, further testing of new compounds enabled identification of additional hits, also apparently with no effect on cell viability. These validated latent hit series would have been missed by a conventional cutoff-based hit-calling approach. This prospective study further supports CSE as a method for the analysis of high-throughput screening experiments.

is an often-quoted catchphrase in the information management field. Few industries can, however,claim this notion to be more pertinent to their current state than can thepharmaceutical industry. While the “omics” revolution (e.g., genomics,proteomics, metabolomics) is most frequently cited for its massive

The Scaffold Tree algorithm (J Chem Inf Model 47:47-58, 2007) allows to organize large molecular data sets by arranging sets of molecules into a unique tree hierarchy based on their scaffolds, with scaffolds forming leaf nodes of such tree. The hierarchy is created by iterative removal of rings from more complex scaffolds using chemically meaningful set of rules, until a single, root ring is obtained. The classification is deterministic, data set independent, and scales linearly with the number of compounds included in the data set. In this review we summarize the basic principles of the Scaffold Tree methodology and review its applications, which appeared in recent medicinal chemistry literature, including the use of Scaffold Trees for visualization of large chemical data sets, compound clustering, and the identification of novel bioactive molecules. References to several computer programs, including also free tools available on the Internet, allowing to perform classification and visualization of molecules based on their scaffolds are also provided.

Der Kostendruck in der Landwirtschaft zwingt dazu, die Produktivität und Effizienz der Agrartechnik in Mähdreschern weiter zu steigern. Die Notwendigkeit, wesentlich größere Maschinenleistungen in einem eingeschränkten Bauraum unterzubringen, erfordert neue Antriebskonzepte. Am Beispiel einer elektrisch direkt angetriebenen Dreschtrommel wird die Möglichkeit der Integration elektrischer Antriebe in die Funktionselemente gezeigt., LANDTECHNIK, Bd. 65 Nr. 3 (2010)

Reaction of aliphatic aldehydes 1 and allylsilane 3 at −78 °C in the presence of the norpseudoephedrine derivative 2a and catalytic amounts of trifluoromethanesulfonic acid trimethylsilyl ester gives the homoallylic ethers 4 with >98% diastereoselectivity. The ethers 4 can be transformed into the corresponding homoallylic alcohols 5 having an enantiomeric excess >98% using sodium in liquid ammonia. On-line NMR spectroscopy indicates that the mixed acetal 7 and the oxazolidinium ion 12 are intermediates in the formation of 4. At higher temperature proton transfer occurs to give the oxazolidinium ion 18, which does not react with allylsilane, but gives the oxazolidine 17 on aqueous workup. Protonation of 17 with trifluoromethanesulfonic acid leads to 18 but not to the oxazolidinium ion 12. Thus, an allylation starting from 17 is not possible.

Intermolecular hetero Diels-Alder reactions of the enantiopure sulfinimine 11 with the enol ethers 12-16 at 20 °C and 11 kbar lead to the tetrahydropyridines 18-22 in high yield, with very good to good endo/exo selectivities, and with an induced diastereoselectivity of up to 2.1:1. The sulfinyl group in the adducts can be removed with MeLi followed by treatment with acetyl chloride or dimethyl sulfate. According to this procedure, 21 gives either N-acetyltetrahydropyridine 29 or the N-methyldihydropyridine 32. The intramolecular Diels-Alder reaction of 26 yields 27, which is transformed into 33 and 34, respectively.

The 4-benzylidene-3-oxo[1,3]oxathiolan-5-ones 13–15, which were derived from the 3-oxo[1,3]oxathiolan-5-ones 9–11 by Knoevenagel condensation with the aldehydes 12, cyclize in an intramolecular hetero Diels–Alder reaction with high yield and excellent endo/exo as well as induced diastereoselectivity to give the hetero Diels–Alder adducts 16–18. The preferred formation of the Knoevenagel products 13–15 with a (Z) configuration was predicted with DFT calculations (B3LYP-6-311+G*) using the model systems 28 and 29. In addition B3LYP-6-31G*/sB3LYP/3-21G(*) calculations on transition structures for the hetero Diels–Alder reaction of 29 and 30 allowed a good correlation with the experimental results, which show that an endo attack of the dienophile syn to the S–O group in 13–15 leads to the main products.

Intramolecular oxa-conjugate addition has been employed in a stereoselective synthesis of enantiopure polyalkyl-substituted tetrahydropyrans, which are frequently found as substructures in many natural products. The requisite cyclization precursors, 7-hydroxy-2-enimides 3 and 7-hydroxy-2-enoates 6 were easily accessible by silyloxy Cope rearrangements of the appropriate chiral syn-aldols. It was found that the stereoselectivity of the cyclization could be controlled by judicious choice of the carboxylic acid derivative, resulting in a kinetically controlled reaction for the imides and a thermodynamically controlled process for the esters. Mechanistic considerations that could account for the stereocontrol of the process are outlined.