Small-sample asymptotic distributions of M-estimators of location

Asymptotic formulae for the distribution of M-estimators, i.e. maximum likelihood type estimators, of location, including the arithmetic mean, are derived which numerical studies show to give relative errors for densities and tail areas of the order of magnitude of 1% down to sample sizes 3 and 4 even in the extreme tails. The paper is the continuation of earlier work by the second author and is also closely related to Daniels's work on the saddlepoint approximation. The method consists in expanding the derivative of the logarithm of the unstandardized density of the estimator in powers of 1/n at each point, using recentring by means of conjugate distributions. This method yields a unified point of view for the comparison of other asymptotic methods, namely saddlepoint method, Edgeworth expansion and large deviations approach, which are also compared numericall

π‐Extended Diaza[7]helicenes by Hybridization of Naphthalene Diimides and Hexa‐peri‐hexabenzocoronenes

The synthesis of an unprecedented, π‐extended hexabenzocorene (HBC)‐based diaza[7]helicene is presented. The target compound was synthesized by an ortho‐fusion of two naphthalene diimide (NDI) units to a HBC‐skeleton. A combination of Diels–Alder and Scholl‐type oxidation reactions involving a symmetric di‐NDI‐tolane precursor were crucial for the very selective formation of the helical superstructure via a hexaphenyl‐benzene (HPB) derivative. The formation of the diaza[7]helicene moiety in the final Scholl oxidation is favoured, affording the symmetric π‐extended helicene as the major product as a pair of enantiomers. The separation of the enantiomers was successfully accomplished by HPLC involving a chiral stationary phase. The absolute configuration of the enantiomers was assigned by comparison of circular dichroism spectra with quantum mechanical calculations

Four-Step Domino Reaction Enables Fully Controlled Non-Statistical Synthesis of Hexaarylbenzene with Six Different Aryl Groups*

Hexaarylbenzene (HAB) derivatives are versatile aromatic systems playing a significant role as chromophores, liquid crystalline materials, molecular receptors, molecular-scale devices, organic light-emitting diodes and candidates for organic electronics. Statistical synthesis of simple symmetrical HABs is known via cyclotrimerization or Diels–Alder reactions. By contrast, the synthesis of more complex, asymmetrical systems, and without involvement of statistical steps, remains an unsolved problem. Here we present a generally applicable synthetic strategy to access asymmetrical HAB via an atom-economical and high-yielding metal-free four-step domino reaction using nitrostyrenes and α,α-dicyanoolefins as easily available starting materials. Resulting domino product—functionalized triarylbenzene (TAB)—can be used as a key starting compound to furnish asymmetrically substituted hexaarylbenzenes in high overall yield and without involvement of statistical steps. This straightforward domino process represents a distinct approach to create diverse and still unexplored HAB scaffolds, containing six different aromatic rings around central benzene core. © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmb

Amphiphilic Perylene-Calix[4]arene hybrids:synthesis and tunable self-assembly

The first highly water-soluble perylene–calix[4]­arene hybrid with the calixarene scaffold acting as a structure-determining central platform is presented. In this tetrahedrally shaped amphiphilic architecture the hydrophilic and hydrophobic subunits are oriented at the opposite side of the calixarene platform. The hydrophobic part contains the two perylene diimide moieties, which enable strong π–π interactions in self-assembly processes. Two hydrophilic Newkome-type dendrons provide sufficient water solubility at slightly basic conditions. The tetrahedrally shaped amphiphile displays an unprecedented aggregation behavior down to concentrations as low as 10^–7 mol L^–1. The intriguing self-assembly process of the compound in water as well as under changed polarity conditions, achieved by addition of THF, could be monitored by the complemented use of cryogenic transmission electron microscopy (cryo-TEM), UV–vis spectroscopy, and fluorescence spectroscopy. Molecular-dynamics and molecular modeling simulations helped in understanding the interplay of supramolecular and optical behavior

Mutations of the ret protooncogene in German multiple endocrine neoplasia families: Relation between genotype and phenotype.

It has been suggested that not only the position but also the nature of the mutations of the ret protooncogene strongly correlate with the clinical manifestation of the multiple endocrine neoplasm type 2 (MEN 2) syndrome. In particular, individuals with a Cys634-Arg substitution should have a greater risk of developing parathyroid disease. We, therefore, analyzed 94 unrelated families from Germany with inherited medullary thyroid carcinoma (MTC) for mutation of the ret protooncogene. In all but 1 of 59 families with MEN 2A, germline mutations in the extracellular domain of the ret protein were found. Some 81% of the MEN 2A mutations affected codon 634. Phenotype-genotype correlations suggested that the prevalence of pheochromocytoma and hyperparathyroidism is significantly higher in families with codon 634 mutations, but there was no correlation with the nature of the mutation. In all but 1 of 27 familial MTC (FMTC) families, mutations were detected in 1 of 4 cysteines in the extracellular domain of the ret protooncogene. Half of the FMTC mutations affected codon 634. Mutations outside of codon 634 occurred more often in FMTC families than in MEN 2A families. In all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were found. These data confirm the preferential localization of MEN 2-associated mutations and the correlation between disease phenotype and the position of the ret mutation, but there was no correlation between the occurrence of hyperparathyroidism or pheochromocytoma and the nature of the mutation

Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction

Aza‐ and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six‐step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult‐to‐access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X‐ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 μm for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 μm).Six steps in one go! An unprecedented two component six‐step domino reaction, providing a straightforward and atom economical route to bioactive azabicycles and carbobicycles is presented. DFT calculations accounting for dispersion interactions revealed that chemoselectivity might result from small differences in transition state and reaction energies of the branching step. This reaction opens up a new vista of generating, in a single operation, new antivirals outperforming clinically used drugs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/1/chem201504798.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/2/chem201504798_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/3/chem201504798-sup-0001-misc_information.pd

CFD-modeling and Experiments of insulation debris transport phenomena in water flow

The investigation of insulation debris generation, transport and sedimentation becomes important with regard to reactor safety research for PWR and BWR, when considering the long-term behavior of emergency core cooling systems during all types of loss of coolant accidents (LOCA). The insulation debris released near the break during a LOCA incident consists of a mixture of disparate particle population that varies with size, shape, consistency and other properties. Some fractions of the released insulation debris can be transported into the reactor sump, where it may perturb/impinge on the emergency core cooling systems. Open questions of generic interest are the sedimentation of the insulation debris in a water pool, its possible re-suspension and transport in the sump water flow and the particle load on strainers and corresponding pressure drop. A joint research project on such questions is being performed in cooperation between the University of Applied Sciences Zittau/Görlitz and the Forschungszentrum Dresden-Rossendorf. The project deals with the experimental investigation of particle transport phenomena in coolant flow and the development of CFD models for its description. While the experiments are performed at the University at Zittau/Görlitz, the theoretical modeling efforts are concentrated at Forschungszentrum Dresden-Rossendorf. In the current paper the basic concepts for CFD modeling are described and feasibility studies including the conceptual design of the experiments are presented

Early and Differential Diagnosis of Dementia and Mild Cognitive Impairment Design and Cohort Baseline Characteristics of the German Dementia Competence Network

Background: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. Methods: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. Results: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. Conclusion: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD. Copyright (C) 2009 S. Karger AG, Base