•High potencies and prolonged effects achievable with covalent drugs may result in less frequent dosing and improved therapeutic margins for patients.•Covalent inhibition can dissociate drug ...pharmacodynamics from pharmacokinetics.•Covalent drugs may have reduced risk of developing drug resistance.•Approvals in recent years suggest that covalent drugs are continuing to make impacts on human health.
Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.
Covalent inhibition has a rich history in drug discovery and continues to be a highly successful strategy for addressing diverse targets and disease areas.
We report simultaneous measurements of the magnetization and the ac susceptibility across the magnetic phase diagram of single-crystal MnSi. In our study we explore the importance of the excitation ...frequency, excitation amplitude, sample shape, and crystallographic orientation. The susceptibility, mu sub(0)dM/dB , calculated from the magnetization, is dominated by pronounced maxima at the transition from the helical to the conical and the conical to the skyrmion lattice phase. The maxima in mu sub(0)dM/dB are not tracked by the ac susceptibility, which in addition varies sensitively with the excitation amplitude and frequency at the transition from the conical to the skyrmion lattice phase. The same differences between mu sub(0)dM/dB and the ac susceptibility exist for Mn sub(1-x)Fe sub(x)Si (x = 0.04) and Fe sub(1-x)Co sub(x)Si (x = 0.20). Taken together our study establishes consistently for all major crystallographic directions the existence of a single pocket of the skyrmion lattice phase in MnSi, suggestive of a universal characteristic of all B20 transition metal compounds with helimagnetic order.
We report high-precision measurements of the temperature and magnetic field dependence of the specific heat, C(T,H), across the magnetic phase diagram of MnSi. Clear anomalies establish the Skyrmion ...lattice unambiguously as a thermodynamic phase. The evolution of the specific heat anomalies, the field dependence of the entropy released at the phase transitions, and the temperature versus field dependence of crossover lines provide striking evidence of a tricritical point at μ0H(TCP)(int) = 340 mT and T(TCP) = 28.5 K. The existence of this tricritical point represents strong support of a helimagnetic Brazovskii transition, i.e., a fluctuation-induced first-order transition at H = 0.
This essay reviews two new books examining different aspects of right-wing humor, “The Souls of White Jokes” (Stanford University Press, 2022) by Raúl Pérez and “That’s Not Funny” (University of ...California Press, 2022) by Matt Sienkiewicz and Nick Marx. It puts these works into conversation with a longer tendency within right-wing studies to focus on media content and motivations within a negative affective range. By focusing on the positive emotions associated with white supremacy and right-wing media, these books mark an important turning point away from reductionist accounts of the “reactionary mind” and toward a fuller understanding of the complex and contingent motivations of conservatives.
Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, ...nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer. Here, we discuss nutritional and other possible routes to counteract the age-mediated decline of spermidine levels.
Signal‐detection algorithms (SDAs) are recognized as vital tools in pharmacovigilance. However, their performance characteristics are generally unknown. By leveraging a unique gold standard recently ...made public by the Observational Medical Outcomes Partnership (OMOP) and by conducting a unique systematic evaluation, we provide new insights into the diagnostic potential and characteristics of SDAs that are routinely applied to the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We find that SDAs can attain reasonable predictive accuracy in signaling adverse events. Two performance classes emerge, indicating that the class of approaches that address confounding and masking effects benefits safety surveillance. Our study shows that not all events are equally detectable, suggesting that specific events might be monitored more effectively using other data sources. We provide performance guidelines for several operating scenarios to inform the trade‐off between sensitivity and specificity for specific use cases. We also propose an approach and demonstrate its application in identifying optimal signaling thresholds, given specific misclassification tolerances.
Clinical Pharmacology & Therapeutics (2013); 93 6, 539–546. doi:10.1038/clpt.2013.24
We present the Lambda Adaptive Multi-Band Deblending Algorithm in R (lambdar), a novel code for calculating matched aperture photometry across images that are neither pixel- nor PSF-matched, using ...prior aperture definitions derived from high-resolution optical imaging. The development of this program is motivated by the desire for consistent photometry and uncertainties across large ranges of photometric imaging, for use in calculating spectral energy distributions. We describe the program, specifically key features required for robust determination of panchromatic photometry: propagation of apertures to images with arbitrary resolution, local background estimation, aperture normalization, uncertainty determination and propagation, and object deblending. Using simulated images, we demonstrate that the program is able to recover accurate photometric measurements in both high-resolution, low-confusion, and low-resolution, high-confusion, regimes. We apply the program to the 21-band photometric data set from the Galaxy And Mass Assembly (GAMA) Panchromatic Data Release (PDR; Driver et al. 2016), which contains imaging spanning the far-UV to the far-IR. We compare photometry derived from lambdar with that presented in Driver et al. (2016), finding broad agreement between the data sets. None the less, we demonstrate that the photometry from lambdar is superior to that from the GAMA PDR, as determined by a reduction in the outlier rate and intrinsic scatter of colours in the lambdar data set. We similarly find a decrease in the outlier rate of stellar masses and star formation rates using lambdar photometry. Finally, we note an exceptional increase in the number of UV and mid-IR sources able to be constrained, which is accompanied by a significant increase in the mid-IR colour–colour parameter-space able to be explored.
Abstract
An evolutionary perspective on gecko adhesion was previously hampered by a lack of an explicit phylogeny for the group and of robust comparative methods to study trait evolution, an ...underappreciation for the taxonomic and structural diversity of geckos, and a dearth of fossil evidence bearing directly on the origin of the scansorial apparatus. With a multigene dataset as the basis for a comprehensive gekkotan phylogeny, model-based methods have recently been employed to estimate the number of unique derivations of the adhesive system and its role in lineage diversification. Evidence points to a single basal origin of the spinulate oberhautchen layer of the epidermis, which is a necessary precursor for the subsequent elaboration of a functional adhesive mechanism in geckos. However, multiple gains and losses are implicated for the elaborated setae that are necessary for adhesion via van der Waals forces. The well-supported phylogeny of gekkotans has demonstrated that convergence and parallelism in digital design are even more prevalent than previously believed. It also permits the reexamination of previously collected morphological data in an explicitly evolutionary context. Both time-calibrated trees and recently discovered amber fossils that preserve gecko toepads suggest that a fully-functional adhesive apparatus was not only present, but also represented by diverse architectures, by the mid-Cretaceous. Further characterization and phylogenetically-informed analyses of the other components of the adhesive system (muscles, tendons, blood sinuses, etc.) will permit a more comprehensive reconstruction of the evolutionary pathway(s) by which geckos have achieved their structural and taxonomic diversity. A phylogenetic perspective can meaningfully inform functional and performance studies of gecko adhesion and locomotion and can contribute to advances in bioinspired materials.
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