Synthesis of 4-Thiazolidinone Small Molecules as Potential Inhibitors of the Arp2/3 Complex

Life-essential cellular processes such as endocytosis, motility, and division rely on a cell’s ability to precisely regulate construction of actin filaments in response to external factors and signals. Intrinsically involved in this process is the Actin Related Protein 2/3 (Arp2/3) Complex, a seven-subunit ATPase that functions by nucleating a daughter branch of actin from the side of a pre-existing microfilament. Active Arp2/3 complex is necessary for the proliferation of certain metastatic cancers, and inhibition of Arp2/3 complex is emerging as a potentially useful treatment strategy for such cancers. We describe synthesis and in vitro assays of 4-thiazolidinones predicted by computational methods to inhibit of Arp2/3 Complex strongly, and therefore serve as potential lead compounds for drug development. Known Arp2/3 inhibitor CK-869 serves as the starting point for derivative synthesis. We discuss the efforts towards the synthesis of new compounds and the biochemical data collected about their potency

Synthesis of Small Molecule Derivatives of CK-666 as Potential Inhibitors of the Arp2/3 Complex

The Actin-Related Protein (Arp) 2/3 Complex is an actin nucleating factor intrinsically involved in cellular regulation of actin networks during life-essential processes such as motility. Overexpression of the Arp2/3 complex has indicated as a factor allowing the proliferation of certain metastatic cancers. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. The molecules are designed based off of the structure of known Arp2/3 inhibitor CK-666, which was discovered via high-throughput screening. Details of the synthesis of the tryptamine derivatives are discussed, and the bulk actin polymerization assay used to determine potency of the new compounds is discussed

Report on Comprehensive City Plan for Sarasota, Florida

Sarasota, Florida Report on comprehensive city plan for Sarasota, Florida. John Nolen, City Planner. Philip W. Foster, Associate. Cambridge, Mass. : John Nolen, 1925

Multiple Charge State Beam Acceleration at Atlas

A test of the acceleration of multiple charge-state uranium beams was performed at the ATLAS accelerator. A 238U+26 beam was accelerated in the ATLAS PII linac to 286 MeV (~1.2 MeV/u) and stripped in a carbon foil located 0.5 m from the entrance of the ATLAS Booster section. A 58Ni9+ 'guide' beam from the tandem injector was used to tune the Booster for 238U+38. All charge states from the stripping were injected into the booster and accelerated. Up to 94% of the beam was accelerated through the Booster linac, with losses mostly in the lower charge states. The measured beam properties of each charge state and a comparison to numerical simulations are reported in this paper.Comment: LINAC2000, MOD0

Multiple-Charge Beam Dynamics in an Ion Linac

There is demand for the construction of a medium-energy ion linear accelerator based on superconducting rf (SRF) technology. It must be capable of producing several hundred kilowatts of CW beams ranging from protons to uranium. A considerable amount of power is required in order to generate intense beams of rare isotopes for subsequent acceleration. At present, however, the beam power available for the heavier ions would be limited by ion source performance. To overcome this limit, we have studied the possibility of accelerating multiple-charge-state (multi-Q) beams through a linac. We show that such operation is made feasible by the large transverse and longitudinal acceptance which can be obtained in a linac using superconducting cavities. Multi-Q operation provides not only a substantial increase in beam current, but also enables the use of two strippers, thus reducing the size of linac required. Since the superconducting (SC) linac operates in CW mode, space charge effects are essentially eliminated except in the ECR/RFQ region. Therefore an effective emittance growth due to the multi-charge beam acceleration can be minimized

\u3cem\u3eIn Vitro\u3c/em\u3e Determination of Potency of Small Molecule Inhibitors of Arp2/3 Complex

Actin is a key protein building block of actin microfilaments, which are constructed and deconstructed in response to cellular signaling pathways to regulate cellular processes such as motility, division, and endocytosis. Arp2/3 Complex is a 7-subunit protein complex that is in involved in cellular construction of branched actin networks, functioning by attaching to the side of a pre-existing actin filament and nucleating a daughter branch. Overexpression of Arp2/3 complex has been linked to the ability of certain metastatic cancers to proliferate. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. A bulk actin polymerization assay is used as the key method to determine the potency of inhibitor candidates. Structure-activity relationships derived from these results are also discussed

Isospin splitting of the nucleon mean field

The isospin splitting of the nucleon mean field is derived from the Brueckner theory extended to asymmetric nuclear matter. The Argonne V18 has been adopted as bare interaction in combination with a microscopic three body force. The isospin splitting of the effective mass is determined from the Brueckner-Hartree-Fock self-energy: It is linear acording to the Lane ansatz and such that $m^*_n > m^*_p$ for neutron-rich matter. The symmetry potential is also determined and a comparison is made with the predictions of the Dirac-Brueckner approach and the phenomenological interactions. The theoretical predictions are also compared with the empirical parametrizations of neutron and proton optical-model potentials based on the experimental nucleon-nucleus scattering and the phenomenological ones adopted in transport-model simulations of heavy-ion collisions. The direct contribution of the rearrangement term due to three-body forces to the single particle potential and symmetry potential is discussed.Comment: 8 pages, 10 figure

Probing hyperbolic polaritons using infrared attenuated total reflectance micro-spectroscopy

Hyperbolic polariton modes are highly appealing for a broad range of applications in nanophotonics, including surfaced enhanced sensing, sub-diffractional imaging and reconfigurable metasurfaces. Here we show that attenuated total reflectance micro-spectroscopy (ATR) using standard spectroscopic tools can launch hyperbolic polaritons in a Kretschmann-Raether configuration. We measure multiple hyperbolic and dielectric modes within the naturally hyperbolic material hexagonal boron nitride as a function of different isotopic enrichments and flake thickness. This overcomes the technical challenges of measurement approaches based on nanostructuring, or scattering scanning nearfield optical microscopy. Ultimately, our ATR approach allows us to compare the optical properties of small-scale materials prepared by different techniques systematicallyComment: 13 pages 4 figure

A nationwide study on concordance with multimodal treatment guidelines in bipolar disorder

Background: Most previous studies on concordance with treatment guidelines for bipolar disorder focused on pharmacotherapy. Few studies have included other treatment modalities. Aims: To study concordance with the Dutch guideline of various treatment modalities in outpatient treatment settings for patients with bipolar disorder and to identity factors associated with concordance. Methods: A nationwide non-interventional study using psychiatrists’ and patients’ surveys. Results: 839 patients with bipolar or schizoaffective disorder bipolar type were included. Concordance with the guideline was highest for participation of a psychiatrist in the treatment (98%) and for maintenance pharmacotherapy (96%), but lower for supportive treatment (73.5%), use of an emergency plan (70.6%), psychotherapy (52.2%), group psychoeducation (47.2%), and mood monitoring (47%). Presence of a written treatment plan, a more specialized treatment setting, more years of education, and diagnosis of bipolar I disorder versus bipolar II, bipolar NOS, or schizoaffective disorder were significantly associated with better concordance. Conclusion: In contrast to pharmacotherapy, psychosocial treatments are only implemented to a limited extend in everyday clinical practice in bipolar disorder. More effort is needed to implement non-pharmacological guideline recommendations for bipolar disorder

Permeation of Several Gases through Elastomers, with Emphasis on the Deuterium/hydrogen Pair

The Diffusion and Permeation Coefficients for He, H2, D2, O2, and N2 in a Variety of Elastomers Were Measured by Simple Manometric Methods. the Elastomers Studied Were Butyl Rubber; Hypalon® 40 and 45; Viton® E60 and GF; Hydrin® 100 and Filled Hydrin® 100; Kraton® G, FG, and KG VTEOS; EPDM; Epoxidized Natural Rubber; and Neoprene. Consistent with Earlier Studies, Elastomers with Higher Glass Transition Temperatures Exhibited Lower Diffusion Coefficients. the Ratio of Diffusion Coefficients of the Hydrogen Isotope Pair Differed from the Purely Molecular‐weight‐based Prediction. Deuterium\u27s Slightly Smaller Size Relative to Hydrogen is Consistent with Observed Deviations from the Molecular‐weight‐based Diffusion Coefficient Ratio. © 1993 John Wiley & Sons, Inc. Copyright © 1993 John Wiley & Sons, Inc