Expedient organocatalytic syntheses of 4-substituted pyrazolidines and isoxazolidines

The efficient organocatalytic synthesis of heterocyclic systems of biological relevance is a subject of growing interest. We have found that the pyrrolidine/benzoic acid-catalyzed reaction of α-substituted propenals such as methacrolein, 2-benzylpropenal and 2-(n-hexyl)propenal with activated hydrazines takes place in very good yields (83%-99.6%) under very mild conditions to afford 4-substituted pyrazolidin-3-ols (as diastereomer mixtures); subsequent oxidation with PCC affords the corresponding-4-substituted-3-pyrazolidinones in essentially quantitative yields. In a similar way, 4-substituted isoxazolidinones are obtained with N-Cbz-hydroxylamine as a reagent. The use of chiral diarylprolinol trimethylsilyl ethers as catalysts allows the synthesis of several of these compounds in optically active form, in some cases with excellent enantioselectivity (up to 96:4 er). A preliminary evaluation of the biological activity shows that some of these compounds exhibit interesting antibacterial and antifungal activities

Stability of gene rankings from RNAi screens

Motivation: Genome-wide RNA interference (RNAi) experiments are becoming a widely used approach for identifying intracellular molecular pathways of specific functions. However, detecting all relevant genes involved in a biological process is challenging, because typically only few samples per gene knock-down are available and readouts tend to be very noisy. We investigate the reliability of top scoring hit lists obtained from RNAi screens, compare the performance of different ranking methods, and propose a new ranking method to improve the reproducibility of gene selection. Results: The performance of different ranking methods is assessed by the size of the stable sets they produce, i.e. the subsets of genes which are estimated to be re-selected with high probability in independent validation experiments. Using stability selection, we also define a new ranking method, called stability ranking, to improve the stability of any given base ranking method. Ranking methods based on mean, median, t-test and rank-sum test, and their stability-augmented counterparts are compared in simulation studies and on three microscopy image RNAi datasets. We find that the rank-sum test offers the most favorable trade-off between ranking stability and accuracy and that stability ranking improves the reproducibility of all and the accuracy of several ranking methods. Availability: Stability ranking is freely available as the R/Bioconductor package staRank at http://www.cbg.ethz.ch/software/staRank. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Limitations of Near Edge X Ray Absorption Fine Structure as a tool for observing conduction bands in chalcopyrite solar cell heterojunctions

A non optimized interface band alignment in a heterojunctionbased solar cell can have negative eff ects on the current and voltage characteristics of the resulting device. To evaluate the use of Near Edge X ray Absorption Fine Structure spectroscopy NEXAFS as a means to measure the conduction band position, Cu In,Ga S2 chalcopyrite thin film surfaces were investigated as these form the absorber layer in solar cells with the structure ZnO Buffer Cu In,Ga S2 Mo Glass. The composition dependence of the structure of the conduction bands of CuInxGa1 xS2 has been revealed for x 0, 0.67 and 1 with both hard and soft NEXAFS and the resulting changes in conduction band off set at the junction with the bu ffer layer discussed. A comprehensive study of the positions of the absorption edges of all elements was carried out and the development of the conduction band with Ga content was observed, also with respect to calculated densities of state

CdS/Cu(In,Ga)S2 based solar cells with efficiencies reaching 12.9% prepared by a rapid thermal process

In this letter, we report externally confirmed total area efficiencies reaching up to 12.9% for CdS/Cu(In,Ga)S2 based solar cells. These are the highest externally confirmed efficiencies for such cells. The absorbers were prepared from sputtered metals subsequently sulfurized using rapid thermal processing in sulfur vapor. Structural, compositional, and electrical properties of one of these champion cells are presented. The correlation between the Ga distribution profile and solar cell properties is discussed

Dishonest testimony and the virtue of testimonial justice : a naive Bayesian analysis

Testimonial justice is the virtue guiding our assignment of credibility to a speaker. In the debate on testimonial injustice, it is often understood primarily as a tool to prevent discrimination and generally the unfounded discounting of the credibility of certain speakers and groups. But the function of the virtue extends far beyond the purpose of countering prejudice: It also serves as a safeguard against dishonest agents of various kinds. Such agents threaten the integrity of socio-epistemic processes, including the institutions of science and their communication with policymakers and the general public. We offer a classification of dishonest agents and translate them into a simple agent-based model inhabited by naive Bayesian agents. In this formal framework, we investigate the differential impact of varieties of dishonesty and the utility of testimonial justice in preventing or mitigating distortions as well as reliably identifying dishonest agents, given mildly benign conditions

Tau protein, A beta 42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid((1-42)) (Abeta42), promising results for the diagnosis of Alzheimer's disease ( AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases. Copyright (C) 2005 S. Karger AG, Basel

The centrosome and cell proliferation

Centrosomes are frequently amplified in cancer cells. Increased numbers of centrosomes can give rise to multipolar spindles in mitosis, and thereby lead to the formation of aneuploid daughter cells. However, whether centrosome amplification is a cause or a consequence of cancer is unclear. In contrast, loss of a functional centrosome has been shown to lead to cell cycle arrest. In this review, the potential mechanisms underlying centrosome amplification and centrosome-dependent cell cycle regulation are discussed

CENP-E Is a Plus End–Directed Kinetochore Motor Required for Metaphase Chromosome Alignment

AbstractMitosis requires dynamic attachment of chromosomes to spindle microtubules. This interaction is mediated largely by kinetochores. During prometaphase, forces exerted at kinetochores, in combination with polar ejection forces, drive congression of chromosomes to the metaphase plate. A major question has been whether kinetochore-associated microtubule motors play an important role in congression. Using immunodepletion from and antibody addition to Xenopus egg extracts, we show that the kinetochore-associated kinesin-like motor protein CENP-E is essential for positioning chromosomes at the metaphase plate. We further demonstrate that CENP-E powers movement toward microtubule plus ends in vitro. These findings support a model in which CENP-E functions in congression to tether kinetochores to dynamic microtubule plus ends

Assembly of centrosomal proteins and microtubule organization depends on PCM-1

The protein PCM-1 localizes to cytoplasmic granules known as “centriolar satellites” that are partly enriched around the centrosome. We inhibited PCM-1 function using a variety of approaches: microinjection of antibodies into cultured cells, overexpression of a PCM-1 deletion mutant, and specific depletion of PCM-1 by siRNA. All approaches led to reduced targeting of centrin, pericentrin, and ninein to the centrosome. Similar effects were seen upon inhibition of dynactin by dynamitin, and after prolonged treatment of cells with the microtubule inhibitor nocodazole. Inhibition or depletion of PCM-1 function further disrupted the radial organization of microtubules without affecting microtubule nucleation. Loss of microtubule organization was also observed after centrin or ninein depletion. Our data suggest that PCM-1–containing centriolar satellites are involved in the microtubule- and dynactin-dependent recruitment of proteins to the centrosome, of which centrin and ninein are required for interphase microtubule organization