Bielefeld University

About: Bielefeld University is a education organization based out in Bielefeld, Nordrhein-Westfalen, Germany. It is known for research contribution in the topics: Population & Quantum chromodynamics. The organization has 10123 authors who have published 26576 publications receiving 728250 citations. The organization is also known as: University of Bielefeld & UNIVERSITAET BIELEFELD.

Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion

Abstract: Mammalian and prokaryotic high-temperature requirement A (HtrA) proteins are chaperones and serine proteases with important roles in protein quality control. Here, we describe an entirely new function of HtrA and identify it as a new secreted virulence factor from Helicobacter pylori, which cleaves the ectodomain of the cell-adhesion protein E-cadherin. E-cadherin shedding disrupts epithelial barrier functions allowing H. pylori designed to access the intercellular space. We then designed a small-molecule inhibitor that efficiently blocks HtrA activity, E-cadherin cleavage and intercellular entry of H. pylori.

Measuring underreporting and under-ascertainment in infectious disease datasets: a comparison of methods

Abstract: Background: Efficient and reliable surveillance and notification systems are vital for monitoring public health and disease outbreaks. However, most surveillance and notification systems are affected by a degree of underestimation (UE) and therefore uncertainty surrounds the ‘true’ incidence of disease affecting morbidity and mortality rates. Surveillance systems fail to capture cases at two distinct levels of the surveillance pyramid: from the community since not all cases seek healthcare (under-ascertainment), and at the healthcare-level, representing a failure to adequately report symptomatic cases that have sought medical advice (underreporting). There are several methods to estimate the extent of under-ascertainment and underreporting. Methods: Within the context of the ECDC-funded Burden of Communicable Diseases in Europe (BCoDE)-project, an extensive literature review was conducted to identify studies that estimate ascertainment or reporting rates for salmonellosis and campylobacteriosis in European Union Member States (MS) plus European Free Trade Area (EFTA) countries Iceland, Norway and Switzerland and four other OECD countries (USA, Canada, Australia and Japan). Multiplication factors (MFs), a measure of the magnitude of underestimation, were taken directly from the literature or derived (where the proportion of underestimated, under-ascertained, or underreported cases was known) and compared for the two pathogens. Results: MFs varied between and within diseases and countries, representing a need to carefully select the most appropriate MFs and methods for calculating them. The most appropriate MFs are often disease-, country-, age-, and sex-specific. Conclusions: When routine data are used to make decisions on resource allocation or to estimate epidemiological parameters in populations, it becomes important to understand when, where and to what extent these data represent the true picture of disease, and in some instances (such as priority setting) it is necessary to adjust for underestimation. MFs can be used to adjust notification and surveillance data to provide more realistic estimates of incidence.

Physiological aspects of raffinose family oligosaccharides in plants: protection against abiotic stress.

Abstract: Abiotic stresses resulting from water deficit, high salinity or periods of drought adversely affect plant growth and development and represent major selective forces during plant evolution. The raffinose family oligosaccharides (RFOs) are synthesised from sucrose by the subsequent addition of activated galactinol moieties donated by galactinol. RFOs are characterised as compatible solutes involved in stress tolerance defence mechanisms, although evidence also suggests that they act as antioxidants, are part of carbon partitioning strategies and may serve as signals in response to stress. The key enzyme and regulatory point in RFO biosynthesis is galactinol synthase (GolS), and an increase of GolS in expression and activity is often associated with abiotic stress. It has also been shown that different GolS isoforms are expressed in response to different types of abiotic stress, suggesting that the timing and accumulation of RFOs are controlled for each abiotic stress. However, the accumulation of RFOs in response to stress is not universal and other functional roles have been suggested for RFOs, such as being part of a carbon storage mechanism. Transgenic Arabidopsis plants with increased galactinol and raffinose concentrations had better ROS scavenging capacity, while many sugars have been shown in vitro to have antioxidant activity, suggesting that RFOs may also act as antioxidants. The RFO pathway also interacts with other carbohydrate pathways, such as that of O-methyl inositol (OMI), which shows that the functional relevance of RFOs must not be seen in isolation to overall carbon re-allocation during stress responses.

CO Fixation to Stable Acyclic and Cyclic Alkyl Amino Carbenes: Stable Amino Ketenes with a Small HOMO–LUMO Gap

Abstract: Reactive intermediates play a central role in modern chemistry.[1] Since 1900, and the discovery by Gomberg of a stable radical,[2] many species that were thought to be too short-lived for observation have been isolated. The availability of stable versions of reactive intermediates has allowed for a superior control of their reactivity and a better understanding of the mechanism of chemical reactions. Even more importantly, new applications of these species have been found, for example, the successful use of stable carbenes as ligands for transition-metal catalysts,[3] and even as organic catalysts.[4] There are still several families of synthetically important reactive intermediates, the preparation of which has been impeded by the belief that they are incapable of existence, or has eluded the synthetic skills of investigators. Because of their very high reactivity, ketenes are key intermediates in synthetic organic chemistry, and have even found industrial applications.[5–7] Despite the isolation of diphenylketene as early as the beginning of the 20th century,[8] most ketenes are intrinsically unstable and cannot be isolated.[5] Calculations have predicted that σ-electron-withdrawing substituents, as well as π-donor groups destabilize ketenes.[9] Accordingly, alkoxy ketenes have only been characterized at low temperature or by fast-spectroscopic methods,[10] whereas amino ketenes have never been observed.[11] Transient triplet carbenes, such as methylene, react with CO to give the corresponding ketenes.[12] In contrast, although the carbonylation of singlet carbenes is spin-allowed, there are very few examples of ketene formation using this route.[13] In 1994 it was claimed that the imidazol-2-ylidene 1a reacts with carbon monoxide to give the stable diamino ketene 2a (Scheme 1).[14] However, a year later Arduengo et al.[15] were not able to duplicate these experimental results. They demonstrated computationally that the parent compound 2b is not even a transition state, and found that there is no stable structure associated with the combination of 1b and CO, other than “a non-bonded weakly interacting (van der Waals) complex” 3b (scheme 1). Moreover, the calculations showed that the CO addition leading to 2b is not favored thermodynamically [ΔH(298 K) =+15.9 kcalmol−1].[15] Scheme 1 N-heterocyclic carbenes (NHCs) do not react with CO; the structure of van der Waals complex 3 b. Herein we report that, in marked contrast with cyclic diamino carbenes 1, stable acyclic 4a[16] and 4b, and cyclic alkyl amino carbenes (CAACs) 6[17] react with CO to afford amino ketenes 5a,b and 7, respectively (see Scheme 2), which are indefinitely stable at room temperature both in solution and in the solid state. We show that the ring structure forces the planarization of the amino fragment of 7, and therefore causes the destabilizing n–π donation from the amino group. Consequently, the HOMO of the ketene 7 is raised and the singlet–triplet gap considerably reduced, which induces unusual optical and NMR spectroscopic properties. Scheme 2 Addition of CO to carbenes 4 a,b and 6. According to calculations,[16] the singlet–triplet gap (26.7 kcalmol−1) and the HOMO (−4.3 eV) for acyclic alkyl amino carbenes 4 are much smaller and higher in energy, respectively, than for NHCs 1 (79.6 kcalmol−1 and −5.4 eV).[18] Consequently, carbenes 4 are more nucleophilic but also more electrophilic than NHCs 1, and are therefore better candidates for a carbonylation reaction. Indeed, when carbon monoxide was bubbled at room temperature through a THF solution of acyclic carbene 4a, a clean reaction occurred, and after evaporation of the solvent under vacuum, ketene 5a was obtained in good yield as a pale yellow oil (Scheme 2). The IR spectrum of 5a shows a very strong C=C=O stretching vibration at 2066 cm−1, and the 13C NMR signals for the ketene group appear at δ =213.95 (CCO) and 60.90 (CCO) ppm; all these values are expected for a ketene bearing a σ-electron-withdrawing group.[9] Only one set of NMR signals was observed for the isopropyl substituents, which suggests free rotation around the N–CCO bond. Starting from carbene 4b, which has cyclohexyl instead of isopropyl groups, ketene 5b was isolated as pale yellow crystals (m.p.: <20°C) suitable for X-ray diffraction (Figure 1).[19] Interestingly, the N–C1 bond (ca. 1.43 A) is much longer than in carbene 4a (1.30 A), suggesting again the absence of interaction between the nitrogen lone pair and the CCO fragment. Indeed, molecule 5b escapes the destabilizing n–π donation, by pyramidalization of the amino group (sum of the angles: 347.7°), and by directing the nitrogen lone pair 180°away from the CCO moiety. Consequently, the observed geometric parameters of the CCO fragment of 5b are very similar to those calculated for the parent ketene H2CCO (Table 1).[20] Figure 1 Molecular view of the crystal structure of 5 b. Selected bond lengths [A] and angles [°]: N–C1 1.426(4), C1–C2 1.310(5), C2–O 1.174(4), C1–C3 1.517(4), N–C6a 1.417(7); N-C1-C3 122.6(3), C3-C1-C2 ... Table 1 Comparison of the spectroscopic data, geometric parameters, and singlet–triplet (S/T) energy gap for ketenes. The next challenge was to synthesize an amino ketene in which the nitrogen lone pair would be forced to stay parallel to the C=C π system. We have recently shown that despite the reluctance of phosphorus to be planar (inversion barrier 35 kcalmol−1 for PH3 compared to 5 kcalmol−1 for NH3), its incorporation into a ring, in addition to the use of bulky substituents, allowed us to force its planarization.[21,22] Applying the same concept, the CAAC 6 (Scheme 2)appeared to be the ideal precursor. As soon as carbon monoxide was bubbled at room temperature through a THF solution of CAAC 6, a very deep blue color appeared. After evaporation of the solvent under vacuum, ketene 7 crystallizes from hexane at −20°C as blue crystals (65%, m.p.: 95–97°C) suitable for X-ray diffraction (Figure 2).[19] As expected, the nitrogen atom is in a planar environment (sum of the angles: 357.3°), and the lone pair is coplanar with the C=C π system. Although the N1a–C1 bond (ca. 1.40 A) is much longer than that of carbene 6(1.31 A), it is similar to that observed for ketene 5b. Similarly, in the IR spectrum, the C=C=O stretching vibration for 7 is at 2073 cm−1, very close to that observed for 5 (Δν =7 cm−1). These results suggest only a weak interaction between the nitrogen lone pair and the CCO fragment. However, compared to other ketenes, a dramatic red-shifted UV absorption is observed (very intense band from 500 to 700 nm, λmax 598 nm), as well as a spectacular downfield shift of the 13C NMR signal of the CCO carbon of 7 (δ ≈ 278 ppm; Table 1). Figure 2 Molecular view of the crystal structure of 7. Selected bond lengths [A] and angles [°]: N1a–C1a 1.405(2), C1a–C2aa 1.334(5), C2aa–O1aa 1.186(5) C1a–C5a 1.524(2), N1a–C11a 1.437(2); N1a-C1a-C5a 110.80(14), ... To gain further insight into the electronic structure of amino ketenes 5 and 7, density functional theory (DFT) calculations at triple-zeta basis set quality[20] were performed on the parent acyclic amino ketenes 5cpyr and 5cpla (Scheme 3), which feature a nitrogen atom in a pyramidal (pyr) and planar (pla) environment, respectively. The calculated geometry and NMR chemical shifts for 5cpyr are similar to those observed experimentally for 5a,b (Table 1). Of particular interest, the lone pair of 5cpyr is also directed 180° away from the CCO fragment. Forcing the nitrogen to be in a planar geometry, with the lone pair parallel to the C=C π system, costs 6.8 kcalmol−1, and 5cpla is not even an energy minimum on the electronic hypersurface. In 5cpla the π-conjugation of the amino group with the adjacent C=C π bond has a drastic effect on the frontier orbitals. It raises the HOMO (π-C=C) while the LUMO (π*-C=O), is not affected. The resulting smaller HOMO–LUMO gap is in line with the smaller value of the adiabatic singlet–triplet energy separation, which decreases from 23.9 for 5cpyr to 17.0 kcalmol−1 for 5cpla. In other words, forcing the π-conjugation with the adjacent amino substituent, as in the calculated 5cpla and observed ketenes 7, induces a biradical character. The reduction of the HOMO–LUMO energy gap readily explains the red-shift of the π(C=C)-→ π*(C=O) optical transition. The small singlet–triplet energy gap leads to the enhancement of the paramagnetic term, and therefore the downfield shift of the 13C NMR signal of the CO carbon of 5cpla and 7. Scheme 3 Schematic representations of the calculated parent amino ketenes 5 cpyr and 5 cpla. In conclusion, cumulenes 5 and 7 are the first ketenes prepared from CO fixation to stable carbenes. When compared to the parent ketene (H2CCO), the presence of a pyramidal amino group as in 5 reduces the singlet–triplet energy gap by about 50%, and the planarization of the amino group as in 7 induces another 30% reduction to reach 17 kcalmol−1. The small HOMO–LUMO energy gap induces unusual optical and NMR spectroscopic properties.[26] The design of ketenes featuring an even more pronounced diradical character is under active investigation.