Pharmacokinetics of Py-Im Polyamides Depend on Architecture: Cyclic versus Linear

The pharmacokinetic properties of three pyrrole-imidazole (Py-Im) polyamides of similar size and Py-Im content but different shape were studied in the mouse. Remarkably, hairpin and cyclic oligomers programmed for the same DNA sequence 5′-WGGWWW-3′ displayed distinct pharmacokinetic properties. Furthermore, the hairpin 1 and cycle 2 exhibited vastly different animal toxicities. These data provide a foundation for design of DNA binding Py-Im polyamides to be tested in vivo

Measurement of electron screening in muonic lead

Energies of the transitions between high-lying (n≥6) states of muonic lead were accurately determined. The results are interpreted as a ∼2% test of the electron screening. The agreement between experiment and theory is good if it is assumed that the refilling of the electron K shell is fast. The present results furthermore severely restrict possible ionization of the electron L shell

Gene expression changes in a tumor xenograft by a pyrrole-imidazole polyamide

Gene regulation by DNA binding small molecules could have important therapeutic applications. This study reports the investigation of a DNA-binding pyrrole-imidazole polyamide targeted to bind the DNA sequence 5′-WGGWWW-3′ with reference to its potency in a subcutaneous xenograft tumor model. The molecule is capable of trafficking to the tumor site following subcutaneous injection and modulates transcription of select genes in vivo. An FITC-labeled analogue of this polyamide can be detected in tumor-derived cells by confocal microscopy. RNA deep sequencing (RNA-seq) of tumor tissue allowed the identification of further affected genes, a representative panel of which was interrogated by quantitative reverse transcription-PCR and correlated with cell culture expression levels

Activity of a Py–Im Polyamide Targeted to the Estrogen Response Element

Pyrrole-imidazole (Py–Im) polyamides are a class of programmable DNA minor groove binders capable of modulating the activity of DNA-binding proteins and affecting changes in gene expression. Estrogen receptor alpha (ERα) is a ligand-activated hormone receptor that binds as a homodimer to estrogen response elements (ERE) and is a driving oncogene in a majority of breast cancers. We tested a selection of structurally similar Py–Im polyamides with differing DNA sequence specificity for activity against 17β-estadiol (E2)–induced transcription and cytotoxicity in ERα positive, E2-stimulated T47DKBluc cells, which express luciferase under ERα control. The most active polyamide targeted the sequence 5′-WGGWCW-3′ (W = A or T), which is the canonical ERE half site. Whole transcriptome analysis using RNA-Seq revealed that treatment of E2-stimulated breast cancer cells with this polyamide reduced the effects of E2 on the majority of those most strongly affected by E2 but had much less effect on the majority of E2-induced transcripts. In vivo, this polyamide circulated at detectable levels following subcutaneous injection and reduced levels of ER-driven luciferase expression in xenografted tumors in mice after subcutaneous compound administration without significant host toxicity

Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide

Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress

Rapid Orthotics for Cure Kenya: Mechanical Design and Modeling of 3D Printed Sockets

Rapid Orthotics for Cure Kenya (ROCK) works with CURE, a non-profit orthopedic workshop in Kjabe, Kenya, to implement a 3D printing system for manufacturing custom prosthetics and orthotics. The goal is to reduce the production time and cost for the current transtibial sockets being manufactured in the orthotic clinic to give the patients a way to integrate into society and reduce stigma from their communities. The team has developed a transtibial socket for below-the-knee amputees produced by a 3D printing system that converts a scan of the residual limb to a model that takes a third of the time to print versus the current manufacturing method. The current focus of the team is to develop a rigorous testing procedure adhering to the requirements set by the ISO 10328 Standard, an internationally recognized testing method. In order to ensure the safety of the sockets, tests must be run demonstrating that the product can withstand the different forces experienced during the gait cycle. Due to the complex geometry of the applied forces outlined in the ISO 10328, the team has designed a novel testing rig that interfaces with the MTS machine at Messiah University to apply the necessary forces according to the geometry outlined in the standard. Additionally, computer-based simulations are being developed in SolidWorks, a 3D modeling software, to determine how the components will behave under certain loading conditions. This is done to ensure accordance with the 10328 Standard and will be critical in the future for developing necessary cyclic tests.https://mosaic.messiah.edu/engr2021/1013/thumbnail.jp

The role of ν\nu-induced reactions on lead and iron in neutrino detectors

We have calculated cross sections and branching ratios for neutrino induced reactions on ^{208}Pb and ^{56}Fe for various supernova and accelerator-relevant neutrino spectra. This was motivated by the facts that lead and iron will be used on one hand as target materials in future neutrino detectors, on the other hand have been and are still used as shielding materials in accelerator-based experiments. In particular we study the inclusive ^{56}$Fe(\nu_e,e^-)$^{56}Co and ^{208}$Pb(\nu_e,e^-)$^{208}Bi cross sections and calculate the neutron energy spectra following the decay of the daughter nuclei. These reactions give a potential background signal in the KARMEN and LSND experiment and are discussed as a detection scheme for supernova neutrinos in the proposed OMNIS and LAND detectors. We also study the neutron-emission following the neutrino-induced neutral-current excitation of ^{56}Fe and ^{208}Pb.Comment: 23 pages (including 7 figures

Observation of single collisionally cooled trapped ions in a buffer gas

Individual Ba ions are trapped in a gas-filled linear ion trap and observed with a high signal-to-noise ratio by resonance fluorescence. Single-ion storage times of ~5 min (~1 min) are achieved using He (Ar) as a buffer gas at pressures in the range 8e-5 - 4e-3 torr. Trap dynamics in buffer gases are experimentally studied in the simple case of single ions. In particular, the cooling effects of light gases such as He and Ar and the destabilizing properties of heavier gases such as Xe are studied. A simple model is offered to explain the observed phenomenology.Comment: 5 pages, 4 figures, accepted for publication in Phys. Rev. A. Minor text and figure change

A simple radionuclide-driven single-ion source

We describe a source capable of producing single barium ions through nuclear recoils in radioactive decay. The source is fabricated by electroplating 148Gd onto a silicon {\alpha}-particle detector and vapor depositing a layer of BaF2 over it. 144Sm recoils from the alpha decay of 148Gd are used to dislodge Ba+ ions from the BaF2 layer and emit them in the surrounding environment. The simultaneous detection of an {\alpha} particle in the substrate detector allows for tagging of the nuclear decay and of the Ba+ emission. The source is simple, durable, and can be manipulated and used in different environments. We discuss the fabrication process, which can be easily adapted to emit most other chemical species, and the performance of the source