A Bioequivalence Test by the Direct Comparison of Concentration-versus-Time Curves Using Local Polynomial Smoothers

In order to test if two chemically or pharmaceutically equivalent products have the same efficacy and/or toxicity, a bioequivalence (BE) study is conducted. The 80%/125% rule is the most commonly used criteria for BE and states that BE cannot be claimed unless the 90% CIs for the ratio of selected pharmacokinetics (PK) parameters of the tested to the reference drug are within 0.8 to 1.25. Considering that estimates of these PK parameters are derived from the concentration-versus-time curves, a direct comparison between these curves motivates an alternative and more flexible approach to test BE. Here, we propose to frame the BE test in terms of an equivalence of concentration-versus-time curves which are constructed using local polynomial smoother (LPS). A metric is presented to quantify the distance between the curves and its 90% CIs are calculated via bootstrapping. Then, we applied the proposed procedures to data from an animal study and found that BE between a generic drug and its brand name cannot be concluded, which was consistent with the results by applying the 80%/125% rule. However, the proposed procedure has the advantage of testing only on a single metric, instead of all PK parameters

A Mutation in Intracellular Loop 4 Affects the Drug-Efflux Activity of the Yeast Multidrug Resistance ABC Transporter Pdr5p

Multidrug resistance protein Pdr5p is a yeast ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance by active efflux of intracellular drugs. However, the highly polymorphic Pdr5p from clinical strain YJM789 loses its ability to expel azole and cyclohexmide. To investigate the role of amino acid changes in this functional change, PDR5 chimeras were constructed by segmental replacement of homologous BY4741 PDR5 fragments. Functions of PDR5 chimeras were evaluated by fluconazole and cycloheximide resistance assays. Their expression, ATPase activity, and efflux efficiency for other substrates were also analyzed. Using multiple lines of evidence, we show that an alanine-to-methionine mutation at position 1352 located in the predicted short intracellular loop 4 significantly contributes to the observed transport deficiency. The degree of impairment is likely correlated to the size of the mutant residue

Search for light dark matter from atmosphere in PandaX-4T

We report a search for light dark matter produced through the cascading decay of $\eta$ mesons, which are created as a result of inelastic collisions between cosmic rays and Earth's atmosphere. We introduce a new and general framework, publicly accessible, designed to address boosted dark matter specifically, with which a full and dedicated simulation including both elastic and quasi-elastic processes of Earth attenuation effect on the dark matter particles arriving at the detector is performed. In the PandaX-4T commissioning data of 0.63 tonne$\cdot$year exposure, no significant excess over background is observed. The first constraints on the interaction between light dark matter generated in the atmosphere and nucleus through a light scalar mediator are obtained. The lowest excluded cross-section is set at $5.9 \times 10^{-37}{\rm cm^2}$ for dark matter mass of $0.1$ MeV$/c^2$ and mediator mass of 300 MeV$/c^2$. The lowest upper limit of $\eta$ to dark matter decay branching ratio is $1.6 \times 10^{-7}$