Design, Synthesis, and Biological Activity of 5\u27-Phenyl-1,2,5,6-tetrahydro-3,3\u27-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (Ki = 123 nM) over the α4β2, and α7 receptors

Econometric Methods for Fractional Response Variables with an Application to 401(k) Plan Participation Rates

We offer simple quasi-likelihood methods for estimating regression models with a fractional dependent variable and for performing asymptotically valid inference. Compared with log-odds type procedures, there is no difficulty in recovering the regression function for the fractional variable, and there is no need to use ad hoc transformations to handle data at the extreme values of zero and one. We also offer some new, simple specification tests by nesting the logit or probit function in a more general functional form. We apply these methods to a data set of employee participation rates in 401(k) pension plans.

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel

Microscopic Model of Charge Carrier Transfer in Complex Media

We present a microscopic model of a charge carrier transfer under an action of a constant electric field in a complex medium. Generalizing previous theoretical approaches, we model the dynamical environment hindering the carrier motion by dynamic percolation, i.e., as a medium comprising particles which move randomly on a simple cubic lattice, constrained by hard-core exclusion, and may spontaneously annihilate and re-appear at some prescribed rates. We determine analytically the density profiles of the "environment" particles, as seen from the stationary moving charge carrier, and calculate its terminal velocity as the function of the applied field and other system parameters. We realize that for sufficiently small external fields the force exerted on the carrier by the "environment" particles shows a viscous-like behavior and define an analog of the Stokes formula for such dynamic percolative environments. The corresponding friction coefficient is also derived.Comment: appearing in Chem. Phys. Special Issue on Molecular Charge Transfer in Condensed Media - from Physics and Chemistry to Biology and Nano-Engineering, edited by A.Kornyshev (Imperial College London), M.Newton (Brookhaven Natl Lab) and J.Ulstrup (Technical University of Denmark

Micro internal combustion swing engine (MICSE) for portable power generation systems

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76989/1/AIAA-2002-722-277.pd

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T\u3eC, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1