Search for the Lepton-Number-Violating Decay Ξ-→pμ-μ-

A sensitive search for the lepton-number-violating decay Ξ-→pμ-μ- has been performed using a sample of ∼109  Ξ- hyperons produced in 800  GeV/c p-Cu collisions. We obtain B(Ξ-→pμ-μ-)\u3c4.0×10-8 at 90% confidence, improving on the best previous limit by 4 orders of magnitude

Integrating single-molecule FRET and biomolecular simulations to study diverse interactions between nucleic acids and proteins

The conformations of biological macromolecules are intimately related to their cellular functions. Conveniently, the well-characterized dipole–dipole distance-dependence of Förster resonance energy transfer (FRET) makes it possible to measure and monitor the nanoscale spatial dimensions of these conformations using fluorescence spectroscopy. For this reason, FRET is often used in conjunction with single-molecule detection to study a wide range of conformationally dynamic biochemical processes. Written for those not yet familiar with the subject, this review aims to introduce biochemists to the methodology associated with single-molecule FRET, with a particular emphasis on how it can be combined with biomolecular simulations to study diverse interactions between nucleic acids and proteins. In the first section, we highlight several conceptual and practical considerations related to this integrative approach. In the second section, we review a few recent research efforts wherein various combinations of single-molecule FRET and biomolecular simulations were used to study the structural and dynamic properties of biochemical systems involving different types of nucleic acids (e.g., DNA and RNA) and proteins (e.g., folded and disordered)

Real-time compaction of nanoconfined DNA by an intrinsically disordered macromolecular counterion

We demonstrate how a recently developed nanofluidic device can be used to study protein-induced compaction of genome-length DNA freely suspended in solution. The protein we use in this study is the hepatitis C virus core protein (HCVcp), which is a positively charged, intrinsically disordered protein. Using nanofluidic devices in combination with fluorescence microscopy, we observe that protein-induced compaction preferentially begins at the ends of linear DNA. This observation would be difficult to make with many other single-molecule techniques, which generally require the DNA ends to be anchored to a substrate. We also demonstrate that this protein-induced compaction is reversible and can be dynamically modulated by exposing the confined DNA molecules to solutions containing either HCVcp (to promote compaction) or Proteinase K (to disassemble the compact nucleo-protein complex). Although the natural binding partner for HCVcp is genomic viral RNA, the general biophysical principles governing protein-induced compaction of DNA are likely relevant for a broad range of nucleic acid-binding proteins and their targets

Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer

Background If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration-resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. Methods The PREVAIL study, which included 1717 chemotherapy-naïve men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). Results Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57–0.81 and HR 0.63, 95% CI 0.52–0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60–0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. Conclusion In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS

Disordered RNA chaperones can enhance nucleic acid folding via local charge screening

This work is licensed under a Creative Commons Attribution 4.0 International License.RNA chaperones are proteins that aid in the folding of nucleic acids, but remarkably, many of these proteins are intrinsically disordered. How can these proteins function without a well-defined three-dimensional structure? Here, we address this question by studying the hepatitis C virus core protein, a chaperone that promotes viral genome dimerization. Using single-molecule fluorescence spectroscopy, we find that this positively charged disordered protein facilitates the formation of compact nucleic acid conformations by acting as a flexible macromolecular counterion that locally screens repulsive electrostatic interactions with an efficiency equivalent to molar salt concentrations. The resulting compaction can bias unfolded nucleic acids towards folding, resulting in faster folding kinetics. This potentially widespread mechanism is supported by molecular simulations that rationalize the experimental findings by describing the chaperone as an unstructured polyelectrolyte.Swiss National Science FoundationEuropean Molecular Biology OrganizationIntramural Research Program of the NIDDK at the National Institutes of Healt

Corporate Hierarchies and the Size of Nations: Theory and Evidence

Corporate organization varies within a country and across countries with country size. The paper starts by establishing some facts about corporate organization based on unique data of 660 Austrian and German corporations. The larger country (Germany) has larger firms with flatter more decentral corporate hierarchies compared to the smaller country (Austria). Firms in the larger country change their organization less fast than firms in the smaller country. Over time firms have been introducing less hierarchical organizations by delegating power to lower levels of the corporation. We develop a theory which explains these facts and which links these features to the trade environment that countries and firms face. We introduce firms with internal hierarchies in a Krugman (1980) model of trade. We show that international trade and the toughness of competition in international markets induce a power struggle in firms which eventually leads to decentralized corporate hierarchies. We offer econometric evidence which is consistent with the models predictions

Ions Accelerated by Sounder-Plasma Interaction as Observed by Mars Express

The ion sensor of the Analyzer of Space Plasmas and Energetic Atoms (ASPERA-3) experiment detects accelerated ions during pulses of radio emissions from the powerful topside sounder: the Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS) onboard Mars Express. Accelerated ions (O+2, O+, and lighter ions) are observed in an energy range up to 800 eV when MARSIS transmits at a frequency close to the plasma frequency. Individual observations consist of almost monoenergetic ion beams aligned with the MARSIS antenna or lying in the plane perpendicular to the antenna. The observed ion beams are often accompanied by a small decrease in the electron flux observed by the electron sensor of Analyzer of Space Plasmas and Energetic Atoms 3. Observations indicate that the voltage applied to the antenna causes charging of the spacecraft to several hundreds of volts by the electrons of the ambient plasma. Positively charged ions are accelerated when the spacecraft discharges

Search for the Lepton-Number-Violating Decay Ξ−→pμ−μ−\Xi^- \to p \mu^- \mu^-

A sensitive search for the lepton-number-violating decay $\Xi^-\to p \mu^-\mu^-$ has been performed using a sample of $\sim10^9$ $\Xi^-$ hyperons produced in 800 GeV/$c$ $p$-Cu collisions. We obtain $\mathcal{B}(\Xi^-\to p \mu^-\mu^-)< 4.0\times 10^{-8}$ at 90% confidence, improving on the best previous limit by four orders of magnitude.Comment: 9 pages, 5 figures, to be published in Phys. Rev. Let