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Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in‐silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK‐MEL‐28, A431, and SCC‐12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC‐12 squamous carcinoma cell lines. The most active compounds11(A431: IC₅₀ = 5.0 μM, SCC‐12: IC₅₀ = 2.9 μM, SKMEL‐28: IC₅₀ = 4.9 μM, A375: IC₅₀ = 6.7 μM) and13(A431: IC₅₀ = 5.0 μM, SCC‐12: IC₅₀ = 3.3 μM, SKMEL‐28: IC₅₀ = 13.8 μM, A375: IC₅₀ = 17.1 μM), significantly and dose‐dependently induced apoptosis of SCC‐12 and SK‐MEL‐28 cells, as evidenced by the suppression of Bcl‐2 and upregulation of Bax, cleaved caspase‐3, caspase‐9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web‐based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein‐kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure–activity relationship through the preparation and biological evaluation of analogs.

 

The evolution of accreting X-ray binary systems is closely coupled to the properties of their donor stars. Consequently, we can constrain the evolutionary track a system is by establishing the nature of its donor. Here, we present far-ultraviolet (far-UV) spectroscopy of the transient neutron-star low-mass X-ray binary J1858 in different accretion states (low-hard, high-hard, and soft). All of these spectra exhibit anomalous N v, C iv, Si iv, and He ii lines, suggesting that its donor star has undergone CNO processing. We also determine the donor’s effective temperature, Td ≃ 5700 K, and radius, Rd ≃ 1.7 R⊙, based on photometric observations obtained during quiescence. Lastly, we leverage the transient nature of the system to set an upper limit of $\dot{M}_{\rm acc} \lesssim 10^{-8.5}~{\rm M}_{\odot }~\mathrm{ yr}^{-1}$ on the present-day mass-transfer rate. Combining these with the orbital period of the system, Porb = 21.3 h, we search for viable evolution paths. The initial donor masses in the allowed solutions span the range 1 M⊙ ≲ Md,i ≲ 3.5 M⊙. All but the lowest masses in this range are consistent with the strong CNO-processing signature in the UV line ratios. The present-day donor mass in the permitted tracks are 0.5 M⊙ ≲ Md,obs ≲ 1.3 M⊙, higher than suggested by eclipse modelling. Since Porb is close to the so-called bifurcation period, both converging and diverging binary tracks are permitted. If the former is confirmed, J1858 will end its life as an ultracompact system with a substellar donor.

 

Abstract The relationship between extreme precipitation intensity and temperature has been comprehensively studied over different regions worldwide. However, the effect of temperature on the spatiotemporal organization of precipitation, which can have a significant impact on precipitation intensity, has not been adequately studied or understood. In this study, we propose a novel approach to quantifying the spatial and temporal concentration of precipitation at the event level and study how the concentration varies with temperature. The results based on rain gauge data from 843 stations in the Ganzhou county, a humid region in south China, show that rain events tend to be more concentrated both temporally and spatially at higher temperature, and this increase in concentration qualitatively holds for events of different precipitation amounts and durations. The effects of temperature on precipitation organization in space and in time differ at high temperatures. The temporal concentration increases with temperature up to a threshold (approximately 24°C) beyond which it plateaus, whereas the spatial concentration keeps rising with temperature. More concentrated precipitation, in addition to a projected increase of extreme precipitation, would intensify flooding in a warming world, causing more detrimental effects. 

Abstract Soft-elasticity in monodomain liquid crystal elastomers (LCEs) is promising for impact-absorbing applications where strain energy is ideally absorbed at constant stress. Conventionally, compressive and impact studies on LCEs have not been performed given the notorious difficulty synthesizing sufficiently large monodomain devices. Here, we use direct-ink writing 3D printing to fabricate bulk (>cm 3 ) monodomain LCE devices and study their compressive soft-elasticity over 8 decades of strain rate. At quasi-static rates, the monodomain soft-elastic LCE dissipated 45% of strain energy while comparator materials dissipated less than 20%. At strain rates up to 3000 s −1 , our soft-elastic monodomain LCE consistently performed closest to an ideal-impact absorber. Drop testing reveals soft-elasticity as a likely mechanism for effectively reducing the severity of impacts – with soft elastic LCEs offering a Gadd Severity Index 40% lower than a comparable isotropic elastomer. Lastly, we demonstrate tailoring deformation and buckling behavior in monodomain LCEs via the printed director orientation. 

Despite being bright (V ≃ 11.8) and nearby (d = 212 pc) ASAS J071404+7004.3 has only recently been identified as a nova-like cataclysmic variable. We present time-resolved optical spectroscopy obtained at the Isaac Newton and the Hiltner and McGraw-Hill Telescopes, together with Swift X-ray and ultraviolet observations. We combined these with TESS photometry and find a period of 3.28 h and a mass transfer rate of $4\!-\!9\times 10^{-9}\, {\mathrm{M_{\odot }\, yr}^{-1}}$. Historical photometry shows at least one low state establishing the system as a VY Scl star. Our high-cadence spectroscopy also revealed rapidly changing winds emanating from the accretion disc. We have modelled these using the Monte Carlo python code and shown that all the emission lines could emanate from the wind – which would explain the lack of double-peaked lines in such systems. In passing, we discuss the effect of variability on the position of cataclysmic variables in the Gaia Hertzsprung–Russell diagram.

 

The international collaboration designing and constructing the Deep Underground Neutrino Experiment (DUNE) at the Long-Baseline Neutrino Facility (LBNF) has developed a two-phase strategy toward the implementation of this leading-edge, large-scale science project. The 2023 report of the US Particle Physics Project Prioritization Panel (P5) reaffirmed this vision and strongly endorsed DUNE Phase I and Phase II, as did the European Strategy for Particle Physics. While the construction of the DUNE Phase I is well underway, this White Paper focuses on DUNE Phase II planning. DUNE Phase-II consists of a third and fourth far detector (FD) module, an upgraded near detector complex, and an enhanced 2.1 MW beam. The fourth FD module is conceived as a "Module of Opportunity", aimed at expanding the physics opportunities, in addition to supporting the core DUNE science program, with more advanced technologies. This document highlights the increased science opportunities offered by the DUNE Phase II near and far detectors, including long-baseline neutrino oscillation physics, neutrino astrophysics, and physics beyond the standard model. It describes the DUNE Phase II near and far detector technologies and detector design concepts that are currently under consideration. A summary of key R&D goals and prototyping phases needed to realize the Phase II detector technical designs is also provided. DUNE's Phase II detectors, along with the increased beam power, will complete the full scope of DUNE, enabling a multi-decadal program of groundbreaking science with neutrinos. 

Computing demands for large scientific experiments, such as the CMS experiment at the CERN LHC, will increase dramatically in the next decades. To complement the future performance increases of software running on central processing units (CPUs), explorations of coprocessor usage in data processing hold great potential and interest. Coprocessors are a class of computer processors that supplement CPUs, often improving the execution of certain functions due to architectural design choices. We explore the approach of Services for Optimized Network Inference on Coprocessors (SONIC) and study the deployment of this as-a-service approach in large-scale data processing. In the studies, we take a data processing workflow of the CMS experiment and run the main workflow on CPUs, while offloading several machine learning (ML) inference tasks onto either remote or local coprocessors, specifically graphics processing units (GPUs). With experiments performed at Google Cloud, the Purdue Tier-2 computing center, and combinations of the two, we demonstrate the acceleration of these ML algorithms individually on coprocessors and the corresponding throughput improvement for the entire workflow. This approach can be easily generalized to different types of coprocessors and deployed on local CPUs without decreasing the throughput performance. We emphasize that the SONIC approach enables high coprocessor usage and enables the portability to run workflows on different types of coprocessors.