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During αβ T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional αβ T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3δ, we reexamined the block in positive selection observed in CD3δ(0) mice. We found that CD3δ(0) thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αβ T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αβ T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

Summary.: The retrosynthetic analysis of Ibogamine, a natural psychotropic alkaloid with exceptional anti-addictive properties found in both enantiomeric forms, requires an efficient access to a racemic cyclohexene. This cyclohexene can be obtained via the sequence Diels-Alder/[3,3] sigmatropic rearrangement reaction starting from substituted 1-thiocyanatobutadienes. An efficient synthesis of the enone, a stable precursor of 1-thiocyanatobutadienes, is reported. Enolisation of this enone was studied to find the optimal conditions to get the desired 1-thiocyanatobutadienes with good Z-selectivity

Public pronouncements on human rights by American officials and by nongovernmental rights advocates often include references to dignity. Yet the term does not appear in the fundamental texts that shaped the American commitment to rights—the Declaration of Independence, the Bill of Rights, and the post-Civil War amendments to the United States Constitution. Many of those using the word may not recognize that Europeans (and others, too) who speak of dignity often mean something that does not accord with the central value given to liberty in the traditional American approach to rights. Though liberty and dignity can be complementary values, there are circumstances in which they can come into conflict. Yet references to dignity have become prominent in American discussions of rights, perhaps because the term is used so frequently in other parts of the world. Another factor may be recognition that, in some important areas, commitment to the concept of dignity, as it is understood in Europe, provides greater protection for rights than is available in the United States.

Aus alt mach neu: Calixpyrrole sind bekannte Anionenbinder und konnen nur schwer in Ubergangsmetallkomplexe uberfuhrt werden. Die vollstandige Hydrierung eines Calixpyrrols ergab nun einen Liganden, der leicht klassische Kupfer-, Nickel- und Palladiumkomplexe bilden kann. Die Metallkomplexe enthalten ein Netzwerk von vier ausgerichteten Wasserstoffbrucken, die spezifisch Gegenionen binden (siehe Bild; blau N, weis H, grun Cl, rot Cu, Ni oder Pd).

Porphobilinogen synthase (PBGS) synthesizes porphobilinogen 2 (PBG), the common precursor of all natural tetrapyrroles, through an asymmetric condensation of two molecules of 5-aminolevulinic acid 1 (ALA). Symmetrically linked dimers 7-11 derived from levulinic acid 3 (gamma-oxovaleric acid) have been synthesized to mimic the assumed bisubstrate bound to the active site of the enzyme. Their inhibition potential was characterized by determination of the IC(50) and K(i) values using PBGS from Pseudomonas aeruginosa. The polarity and the size of the functional group linking the two levulinic acid 3 units have a strong influence on the inhibition behavior.

Studies on the preparation of pyrrolinone-based analogs of rhazinilam (VII) are presented, using suitably functionalized pyrrolinones, e.g. (VI), as key building blocks.

The X-ray structure of the enzyme 5-aminolaevulinic acid dehydratase (ALAD) from yeast complexed with the competitive inhibitor 5-hydroxylaevulinic acid has been determined at a resolution of 1.9 A. The structure shows that the inhibitor is bound by a Schiff-base link to one of the invariant active-site lysine residues (Lys263). The inhibitor appears to bind in two well defined conformations and the interactions made by it suggest that it is a very close analogue of the substrate 5-aminolaevulinic acid (ALA).

Development of better therapies for the T cell–mediated autoimmune disease alopecia areata (AA) could be expedited by an improved understanding of the immunologic signals underlying its pathogenesis. To approach this, our group is mounting a new technological and analytical platform, multiplex immunoprecipitation detected by flow cytometry (MIF). MIF is designed to allow analysis of collections of protein–protein interactions that participate in T cell signaling webs. Early experiments suggest that MIF can detect the increased protein–protein interaction network activity that occurs under conditions of T cell antigenic stimulation. Future experiments will focus on application of MIF to T cells isolated from AA or control patient samples, to identify critical T cell signaling complexes associated with the disorder.

Background: Porphobilinogen synthase is the second enzyme involved in the biosynthesis of natural tetrapyrrolic compounds, and condenses two molecules of 5-aminolevulinic acid (ALA) through a nonsymmetrical pathway to form porphobilinogen. Each substrate is recognized individually at two different active site positions to be regioselectively introduced into the product. According to pulse-labeling experiments, the substrate forming the propionic acid sidechain of porphobilinogen is recognized first. Two different mechanisms for the first bond-forming step between the two substrates have been proposed. The first involves carbon–carbon bond formation (an aldol-type reaction) and the second carbon–nitrogen bond formation, leading to an iminium ion. Results: With the help of kinetic studies, we determined the Michaelis constants for each substrate recognition site. These results explain the Michaelis–Menten behavior of substrate analog inhibitors — they act as competitive inhibitors. Under standard conditions, however, another set of inhibitors demonstrates uncompetitive, mixed, pure irreversible, slow-binding or even quasi-irreversible inhibition behavior. Conclusions: Analysis of the different classes of inhibition behavior allowed us to make a correlation between the type of inhibition and a specific site of interaction. Analyzing the inhibition behavior of analogs of postulated intermediates strongly suggests that carbon–nitrogen bond formation occurs first.

In the title compound, C9H12Br2O3, a (tetra­hydro­furan-2-yl­idene)acetate, the double bond has the Z form. In the tetra­hydro­furan group, the relative configuration of the Br atom in the 3-position and the methyl group in the 5-position is anti. The compound crystallizes with two independent mol­ecules per asymmetric unit and, in the crystal structure, the individual mol­ecules are linked to their symmetry-equivalent mol­ecules by C—H⋯O hydrogen bonds, so forming centrosymmetric hydrogen-bonded dimers.

Background There is significant interest in the generation of improved assays to clearly identify experimental mice possessing functional vision, a property that could qualify mice for inclusion in behavioral and neuroscience studies. Widely employed current methods rely on mouse responses to visual cues in assays of reflexes, depth perception, or cognitive memory. However, commonly assessed mouse reflexes can sometimes be ambiguous in their expression, while depth perception assays are sometimes confounded by variation in anxiety responses and exploratory conduct. Furthermore, in situations where experimental groups vary in their cognitive memory capacity, memory assays may not be ideal for assessing differences in vision. Results We have optimized a non-invasive behavioral assay that relies on an untrained, innate response to identify individual experimental mice possessing functional vision: slow angled-descent forepaw grasping (SLAG). First, we verified that SLAG performance depends on vision and not olfaction. Next, all members of an age-ranged cohort of 158 C57BL/6 mice (57 wild-type, 101 knockout, age range 44–241 days) were assessed for functional vision using the SLAG test without training or conditioning. Subjecting the population to a second innate behavioral test, Dark Chamber preference, corroborated that the functional vision assessment of SLAG was valid. Conclusions We propose that the SLAG assay is immediately useful to quickly and clearly identify experimental mice possessing functional vision. SLAG is based on a behavioral readout with a significant innate component with no requirement for training. This will facilitate the selection of mice of known sighted status in vision-dependent experiments that focus on other types of behavior, neuroscience, and/or cognitive memory.

In the title compounds, C11H18N2, (II), and C13H20N2O, (III), the pyrrolidine rings have twist conformations. Compound (II) crystallizes with two independent molecules (AandB) in the asymmetric unit. The mean planes of the pyrrole and pyrrolidine rings are inclined to one another by 89.99 (11) and 89.35 (10)° in moleculesAandB, respectively. In (III), the amide derivative of (II), the same dihedral angle is much smaller, at only 13.42 (10)°. In the crystal structure of (II), the individual molecules are linkedviaN—H...N hydrogen bonds to form inversion dimers, each with anR22(12) graph-set motif. In the crystal structure of (III), the molecules are linkedviaN—H...O hydrogen bonds to form inversion dimers with anR22(16) graph-set motif.

The elimination of thiocyanic acid from the stereoisomers of the hex-3-ene-2,5-diyl dithiocyanates, 4a, 4b, 6a and 6b, in the presence of a strong neutral base in an organic solvent, yields mixtures of the hex-2,4-dien-2-yl thiocyanates 9, 10 and 11via a preferentially syn process.

While attempting to synthesize a potential inhibitor of the biosynthetic step of formation of PBG, a novel catalytic system inducing the Prins reaction was discovered. Treatment of epoxy geranial with Zn and trimethylsilyl chloride gave (1S,2S,3R,6S) 3-Chloro-3-methyl-6-isopropenyl-1,2-cyclohexanediol in high diastereoselectivity.

The title compounds, rac-(1′R,2R)-tert-butyl 2-(1′-hydroxy­ethyl)-3-(2-nitro­phen­yl)-5-oxo-2,5-dihydro-1H-pyrrole-1-car­box­yl­ate, C17H20N2O6, (I), rac-(1′S,2R)-tert-butyl 2-[1′-hy­droxy-3′-(methoxy­carbon­yl)prop­yl]-3-(2-nitro­phen­yl)-5-oxo-2,5-di­hydro-1H-pyrrole-1-carboxyl­ate, C20H24N2O8, (II), and rac-(1′S,2R)-tert-butyl 2-(4′-bromo-1′-hydroxy­butyl)-5-oxo-2,5-di­hydro-1H-pyrrole-1-carboxyl­ate, C13H20BrNO4, (III), are 5-hy­droxy­alkyl derivatives of tert-butyl 2-oxo-2,5-dihydro­pyrrole-1-carboxyl­ate. In all three compounds, the tert-butoxy­carbonyl (Boc) unit is orientated in the same manner with respect to the mean plane through the 2-oxo-2,5-dihydro-1H-pyrrole ring. The hydroxyl substituent at one of the newly created chiral centres, which have relative R,R stereochemistry, is trans with respect to the oxo group of the pyrrole ring in (I), synthesized using acetaldehyde. When a larger aldehyde was used, as in compounds (II) and (III), the hydroxyl substituent was found to be cis with respect to the oxo group of the pyrrole ring. Here, the relative stereochemistry of the newly created chiral centres is R,S. In compound (I), O—H⋯O hydrogen bonding leads to an inter­esting hexa­gonal arrangement of symmetry-related mol­ecules. In (II) and (III), the hydroxyl groups are involved in bifurcated O—H⋯O hydrogen bonds, and centrosymmetric hydrogen-bonded dimers are formed. The Mukaiyama crossed-aldol-type reaction was successful when using the 2-nitro­phenyl-substituted hydroxy­pyrrole, or the unsubstituted hydroxy­pyrrole, and boron trifluoride diethyl ether as catalyst. The synthetic procedure leads to a syn configuration of the two newly created chiral centres in all three compounds.

— Dihydropyridinones (DHP) react photochemically with olefins to form cycloaddition products. The reactions proceed through the lowest excited state T1 of the DHPs, with rate constants which depend on the olefin and can approach the diffusional limit in the most favourable cases. Intra-and inter-molecular sensitization and quenching have been investigated, as well as spectroscopic properties such as absorption and luminescence spectra, and in particular electron energy loss spectra which have established the energy of the reactive T1, state as 295 kj mol-1 (3.07 eV).

A new tandem reaction leads to bicyclic cyclohexene derivatives with complete control of the relative configuration of the four chiral centers formed. The high diastereoselectivity is the consequence of an endo-selective Diels-Alder reaction followed by an Ireland-Claisen rearrangement that proceeds via a boat-like transition state. © Georg Thieme Verlag Stuttgart.

The synthesis of a pyrazol analogon of porphobilinogen is described. The Mukaiyama crossed aldol reaction is the key step of our approach. The retrosynthetic analysis follows the mechanism for the biosynthesis of porphobilinogen initially proposed by Shemin.

The initial steps in the biosynthesis of the tetrapyrrolic dyes, called the 'pigments of life', are highly convergent. The formation of porphobilinogen, the pyrrolic precursor of the tetrapyrrolic skeleton, uses δ-aminolevulinate as the starting material. This amino acid is dedicated to the biosynthesis of tetrapyrroles. However, the chemical condensation of δ-aminolevulinate leads to a symmetric pyrazine. Attempts to imitate the biosynthesis using one of the proposed pathways for the biosynthesis of porphobilinogen as a guideline has allowed us to synthesize a protected precursor of porphobilinogen in an efficient way. Based on the two major proposals for the biosynthesis, a series of specifically synthesized inhibitors was also tested. The inhibition behavior and the potency of the inhibitors expressed as their Ki value has unraveled an interesting relationship between the structure of the inhibitor and the strength of its interaction with the active site. The concerted use of mechanistic analysis, synthesis and kinetic studies of inhibitors has increased our knowledge about the enzyme porphobilinogen synthase. Structural studies of enzyme-inhibitor complexes will hopefully complement the kinetic results accumulated so far.

This paper describes a heterogeneous DNA-hybridization assay based on electrochemiluminescence (ECL) detection on gold electrodes. Short, 15-mer oligonucleotides were conjugated with a synthesized electrochemiluminescent label, bis(2,2′-bipyridine)-5-isothiocyanato-1,10-phenanthroline ruthenium(II) at the amino-modified 5′-end. Gold electrodes were derivatized with 15-mer oligonucleotide probes via 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) cross-linking reaction and hybridized with Ru-labeled strands. Two types of self-assembled-monolayers have been utilized for the immobilization reaction, 3-mercaptopropanoic acid (3-MHA) and 16-mercaptohexadecanoic acid (16-MHA). Longer thiols were more stable at high electrode potentials needed for the ECL generation. The system was sensitive down to 1 fmol of labeled complementary strand, detected in 30 μL of buffer. Mismatch discrimination was achieved both passively by washing and actively by application of negative electrode potential on electrodes prior to detection, but active denaturing lead to better results. Two base-pair mismatches were discriminated at room temperature. © 2006 Elsevier B.V. All rights reserved.

Understanding the health risk posed by endocrine disrupting chemicals (EDCs) is a challenge that is receiving intense attention. The following study criteria should be considered to facilitate risk assessment for exposure to EDCs: 1) characterization of target health outcomes and their mediators, 2) study of exposures in the context of critical periods of development, 3) accurate estimates of human exposures and use of human-relevant exposures in animal studies, and 4) cross-species comparisons. In this commentary, we discuss the importance and relevance of each of these criteria in studying the effects of prenatal exposure to EDCs. Our discussion focuses on oxidative stress as a mediator of EDC-related health effects due to its association with both EDC exposure and health outcomes. Our recent study (Veiga-Lopez et al. 2015)1 addressed each of the four outlined criteria and demonstrated that prenatal bisphenol-A exposure is associated with oxidative stress, a risk factor for developing diabetes and cardiovascular diseases in adulthood.

The Swiss Chemical Society together with the Foundation 'Schweizer Jugend forscht (SJf)' organised an afternoon session for the high school classes of the Regio Basiliensis. The Swiss Academy of Technical Sciences and the five big chemical companies Clariant, Ciba SC, Novartis, Roche, and Syngenta helped to finance this event. Professors Süss-Fink and Pfaltz presented two talks under the title 'Catalysis, a well-known phenomenon, but with a modern touch'. Between the two scientific talks, Mrs. Noel Gmür Brianza presented the activities and aims of the SJf Foundation with the help of an attractive video.

A graphical representation of the number of people employed by the chemical industry in Switzerland is presented. The number of production sites and the number of persons employed by the chemical industry is relatively small compared to the total number of people in paid employment in Switzerland, however the importance of chemical industry for the Swiss economy is extremely large. Two additional maps show the trends in these figures for 1985–1991 and 1991–1998. To obtain these data the Swiss Federal Statistical Office has included people working part-time and calculated the full-time equivalents based on the figures obtained by evaluating the number of production sites. This procedure allows numbers to be obtained that are reliable and significant. The geographical distribution is no surprise and shows that the major center of activity is the region of Basel, which is responsible for almost one third of the work places. In addition to the 'Regio Basiliensis' the central part of Switzerland between the Lake Constance and Lake Geneva has a relatively high density of chemical industry that is almost evenly distributed. A concentration of chemical industry is also found around the big cities Geneva, Lausanne, and Zürich. In the alpine region there are several major centers of chemical production especially in the cantons Valais and Grisons. The development of the figures of the number of fulltime equivalents between 1985 and 1991 shows some increase in the numbers, whereas between 1991 and 1998 a decrease has occurred. The changes in the chemical industry are in accordance with the general observation of the employment figures for the whole of Switzerland, which reflects the development of the economy during this period. The largest fluctuations are clearly seen in the region of Basel. However one has to take into account that the procedure of counting of production sites attributes one major activity to each independent site and all the employees of one site are then counted as employees of this category. Outsourcing and splitting of activities into different societies may have influenced the results of this evaluation.

The novel tandem process Diels-Alder reaction/Ireland-Claisen rearrangement shows a high diastereoselectivity for the Ireland-Claisen rearrangement starting from the endo-product of the Diels-Alder reaction. Based on this mechanistic knowledge, the novel tandem process could be applied to the synthesis of rac-juvabione.

Starting from the N-butadienyl-N-alkylpropionamides 1a-1c the corresponding N,O-trimethylsilylacetals could be obtained using the mixture of LDA and trimethylsilyl chloride in THF. The unexpected reaction sequence Diels-Alder reaction/acylation between the N-butadienyl-N-alkylketene N,O-trimethylsilylacetal of propionamide (2a-2b) and N-phenylmaleimide produced tricyclic products rac-5a-rac-5b and bicyclic products rac-6a–rac-6b with high diastereoselectivity. The reaction of the N,O-trimethylsilylacetals 2a and 2c with acryloyl chloride in a similar sequence gave the bicyclic products rac-8a and rac-8c. The stepwise synthesis of bicyclic systems of this general structure could only be successfully executed in 26% yield treating the Diels-Alder product rac-10 with LDA.

Calix[4]pyrrol ein leicht zuganglicher Makrocyclus, der seit uber 120 Jahren dank der Arbeiten von Adolf von Baeyer bekannt ist, andert seine Eigenschaften vollstandig bei einer Reduktion. Der reduzierte Makrocyclus wird in der Zuschrift von H. Stoeckli-Evans, R. Neier et al. auf S. 1716 ff. zum ersten Mal beschrieben. Metallkomplexe konnen leicht synthetisiert werden, wobei eine fixierte Anordnung von vier gerichteten Wasserstoffbruckendonoren gebildet wird.

The N-methoxycarbonyl-5,6-dihydro-4-pyridone (1) undergoes photochemical [2 + 2] cycloaddition with a series of differently substituted alkenes in high yield and with extremely high regioselectivity.

The project Pharmasquare (Pharma2) is based on the regular course 'Pharmaceutical Chemistry: Drug Effects on the Molecular Level' alternately presented in Zürich and Basel using the videoconferencing system Telepoly. The course is part of an open learning environment, which is currently complemented by distant learning facilities including a virtual learning environment. Pharma2 receives financial support from the Swiss Virtual Campus, the ETHZ, and matching funds by the Universities of Basel and Neuchâtel. In its final form, the virtual learning environment will offer web-based training modules, a virtual laboratory, the adaptive self-assessment system PharmAskYou, scripts of the Telepoly lectures including learning objectives, a glossary in pharmaceutical sciences, a news-platform, a discussion forum and the 'Question of the Week'.