Exploring the cellular accumulation of metal complexes

Transition metal complexes offer great potential as diagnostic and therapeutic agents, and a growing number of biological applications have been explored. To be effective, these complexes must reach their intended target inside the cell. Here we review the cellular accumulation of metal complexes, including their uptake, localization, and efflux. Metal complexes are taken up inside cells through various mechanisms, including passive diffusion and entry through organic and metal transporters. Emphasis is placed on the methods used to examine cellular accumulation, to identify the mechanism(s) of uptake, and to monitor possible efflux. Conjugation strategies that have been employed to improve the cellular uptake characteristics of metal complexes are also described

Polarization transfer in e⃗+p→e+p⃗\vec{e}^+p \rightarrow e^+ \vec{p} scattering using the Super BigBite Spectrometer

The effects of multi-photon-exchange and other higher-order QED corrections on elastic electron-proton scattering have been a subject of high experimental and theoretical interest since the polarization transfer measurements of the proton electromagnetic form factor ratio $G_E^p/G_M^p$ at large momentum transfer $Q^2$ conclusively established the strong decrease of this ratio with $Q^2$ for $Q^2 \gtrsim 1$ GeV$^2$. This result is incompatible with previous extractions of this quantity from cross section measurements using the Rosenbluth Separation technique. Much experimental attention has been focused on extracting the two-photon exchange (TPE) effect through the unpolarized $e^+p/e^-p$ cross section ratio, but polarization transfer in polarized elastic scattering can also reveal evidence of hard two-photon exchange. Furthermore, it has a different sensitivity to the generalized TPE form factors, meaning that measurements provide new information that cannot be gleaned from unpolarized scattering alone. Both $\epsilon$-dependence of polarization transfer at fixed $Q^2$, and deviations between electron-proton and positron-proton scattering are key signatures of hard TPE. A polarized positron beam at Jefferson Lab would present a unique opportunity to make the first measurement of positron polarization transfer, and comparison with electron-scattering data would place valuable constraints on hard TPE. Here, we propose a measurement program in Hall A that combines the Super BigBite Spectrometer for measuring recoil proton polarization, with a non-magnetic calorimetric detector for triggering on elastically scattered positrons. Though the reduced beam current of the positron beam will restrict the kinematic reach, this measurement will have very small systematic uncertainties, making it a clean probe of TPE.Comment: 6 pages, 3 figures. Contribution to the EPJA topical issue, "An Experimental Program with Positron Beams at Jefferson Lab." arXiv admin note: substantial text overlap with arXiv:2007.15081, arXiv:1906.0941

Prior Authorization Requirements for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Across US Private and Public Payers

A comprehensive review of prior authorization (PA) requirements for a new class of expensive cholesterol-lowering drugs known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has found unusually complex and burdensome demands across public and private insurance plans in the United States. These findings raise concerns that current policies may create undue barriers to care even in medically appropriate patients, particularly since requirements were just as stringent for patients with a genetic condition that creates more clear-cut eligibility for PCSK9 inhibitor treatment

Helium, Oxygen, Proton, and Electron (HOPE) Mass Spectrometer for the Radiation Belt Storm Probes Mission

The HOPE mass spectrometer of the Radiation Belt Storm Probes (RBSP) mission (renamed the Van Allen Probes) is designed to measure the in situ plasma ion and electron fluxes over 4π sr at each RBSP spacecraft within the terrestrial radiation belts. The scientific goal is to understand the underlying physical processes that govern the radiation belt structure and dynamics. Spectral measurements for both ions and electrons are acquired over 1 eV to 50 keV in 36 log-spaced steps at an energy resolution ΔE FWHM/E≈15 %. The dominant ion species (H+, He+, and O+) of the magnetosphere are identified using foil-based time-of-flight (TOF) mass spectrometry with channel electron multiplier (CEM) detectors. Angular measurements are derived using five polar pixels coplanar with the spacecraft spin axis, and up to 16 azimuthal bins are acquired for each polar pixel over time as the spacecraft spins. Ion and electron measurements are acquired on alternate spacecraft spins. HOPE incorporates several new methods to minimize and monitor the background induced by penetrating particles in the harsh environment of the radiation belts. The absolute efficiencies of detection are continuously monitored, enabling precise, quantitative measurements of electron and ion fluxes and ion species abundances throughout the mission. We describe the engineering approaches for plasma measurements in the radiation belts and present summaries of HOPE measurement strategy and performance

Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements

RNA-sequencing (RNA-seq) is commonly used to identify genetic modules that respond to perturbations. In single cells, transcriptomes have been used as phenotypes, but this concept has not been applied to whole-organism RNA-seq. Also, quantifying and interpreting epistatic effects using expression profiles remains a challenge. We developed a single coefficient to quantify transcriptome-wide epistasis that reflects the underlying interactions and which can be interpreted intuitively. To demonstrate our approach, we sequenced four single and two double mutants of Caenorhabditis elegans. From these mutants, we reconstructed the known hypoxia pathway. In addition, we uncovered a class of 56 genes with HIF-1–dependent expression that have opposite changes in expression in mutants of two genes that cooperate to negatively regulate HIF-1 abundance; however, the double mutant of these genes exhibits suppression epistasis. This class violates the classical model of HIF-1 regulation but can be explained by postulating a role of hydroxylated HIF-1 in transcriptional control

Two-dimensional Navier--Stokes simulation of deformation and break up of liquid patches

The large deformations and break up of circular 2D liquid patches in a high Reynolds number (Re=1000) gas flow are investigated numerically. The 2D, plane flow Navier--Stokes equations are directly solved with explicit tracking of the interface between the two phases and a new algorithm for surface tension. The numerical method is able to pursue the simulation beyond the breaking or coalescence of droplets. The simulations are able to unveil the intriguing details of the non-linear interplay between the deforming droplets and the vortical structures in the droplet's wake.Comment: 13 pages including 4 postscript figures; Revised version as resubmitted to PRL. Title has change

Late-Time Spectroscopy of SN 2002cx: The Prototype of a New Subclass of Type Ia Supernovae

We present Keck optical spectra of SN 2002cx, the most peculiar known Type Ia supernova (SN Ia), taken 227 and 277 days past maximum light. Astonishingly, the spectra are not dominated by the forbidden emission lines of iron that are a hallmark of thermonuclear supernovae in the nebular phase. Instead, we identify numerous P-Cygni profiles of Fe II at very low expansion velocities of about 700 km/s, which are without precedent in SNe Ia. We also report the tentative identification of low-velocity O I in these spectra, suggesting the presence of unburned material near the center of the exploding white dwarf. SN 2002cx is the prototype of a new subclass of SNe Ia, with spectral characteristics that may be consistent with recent pure deflagration models of Chandrasekhar-mass thermonuclear supernovae. These are distinct from the majority of SNe Ia, for which an alternative explosion mechanism, such as a delayed detonation, may be required.Comment: 18 pages, 5 figures, to appear in The Astronomical Journal; minor revisions to match accepted versio

Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5′-WGGWWW-3′ and 5′GGGWWW-3′. The compound is capable of binding to κB sites and reducing the expression of various NF-κB–driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α–inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists

Inorganic−Organic Hybrid Luminescent Binary Probe for DNA Detection Based on Spin-Forbidden Resonance Energy Transfer

We describe the design of new fluorescent binary probe sensors for DNA detection based on spin-forbidden resonance energy transfer (SF-RET). Binary probes consist of a donor and acceptor fluorophores that are attached to two different oligonucleotides and serve as a resonance energy transfer (RET) donor−acceptor pair when hybridized to adjacent sites of a target sequence. In the absence of target, excitation of the donor results in fluorescence only from the donor, but when the probes hybridize to the target, the fluorophores are brought into close proximity favoring RET, yielding fluorescence mainly from the acceptor fluorophore. These new binary probes use the metal complex Ru(bpy‘)(DIP)_2^(2+) as the energy donor and an organic fluorophore (Cy5) as the energy acceptor. Energy transfer from the MLCT state of the Ru complex to singlet Cy5 is spin forbidden and produces a delayed fluorescence of Cy5. This paper demonstrates that fluorescence delay of Cy5 can be used to time resolve the emission of the probe from the intense fluorescence background of a model system for cellular background; this provides the reported system to overcome intense autofluorescence, an important and general advantage over “classical” spin-allowed steady-state probes