Cell-Based Assays in High-Throughput Screening for Drug Discovery

Drug screening is a long and costly process confronted with low productivity and challenges in using animals, which limit the discovery of new drugs.  To improve drug screening efficacy and minimize animal testing, recent efforts have been dedicated to developing cell-based high throughput screening (HTS) platforms that can provide more relevant in vivo biological information than biochemical assays and thus reduce the number of animal tests and accelerate the drug discovery process. Today, cell-based assays are used in more than half of all high-throughput drug screenings for target validation and ADMET (absorption, distribution, metabolism, elimination and toxicity) in the early stage of drug discovery. In this review, we discuss the uses of different types of cells and cell culture systems, including 2D, 3D and perfusion cell cultures, in cell-based HTS for drug discovery. Optical and electrochemical methods for online, non-invasive detection and quantification of cells or cellular activities are discussed. Recent progresses and applications of 3D cultures and microfluidic systems for cell-based HTS are also discussed, followed with several successful examples of using cell-based HTS in commercial development of new drugs. Finally, a brief discussion on potential applications of cell-based HTS for screening phytochemicals and herbal medicines is provided in this review

Rapid identification of time-frequency domain gravitational wave signals from binary black holes using deep learning

Recent developments in deep learning techniques have offered an alternative and complementary approach to traditional matched filtering methods for the identification of gravitational wave (GW) signals. The rapid and accurate identification of GW signals is crucial for the progress of GW physics and multi-messenger astronomy, particularly in light of the upcoming fourth and fifth observing runs of LIGO-Virgo-KAGRA. In this work, we use the 2D U-Net algorithm to identify the time-frequency domain GW signals from stellar-mass binary black hole (BBH) mergers. We simulate BBH mergers with component masses from 5 to 80 $M_{\odot}$ and account for the LIGO detector noise. We find that the GW events in the first and second observation runs could all be clearly and rapidly identified. For the third observation run, about $80\%$ GW events could be identified and GW190814 is inferred to be a BBH merger event. Moreover, since the U-Net algorithm has advantages in image processing, the time-frequency domain signals obtained through U-Net can preliminarily determine the masses of GW sources, which could help provide the mass priors for future parameter inferences. We conclude that the U-Net algorithm could rapidly identify the time-frequency domain GW signals from BBH mergers and provide great help for future parameter inferences.Comment: 11 pages, 9 figure

Analysis of the clinicopathological characteristics and prognosis of triple-positive breast cancer and HER2-positive breast cancer—A retrospective study

BackgroundAdjuvant chemotherapy and targeted therapy have become standard postoperative therapeutic modalities for human epidermal growth factor receptor 2 (HER2)-positive breast cancer(HER2-positive,HR-negative), including triple-positive breast cancer(HER2-positive,HR-positive). However, these two types of breast cancer differ in terms of pathogenesis. This article analyzes these two types of breast cancer by comparing their prognoses.MethodsThe clinicopathological characteristics of 135 patients, including 60 patients with triple-positive breast cancer and 75 patients with HER2-positive breast cancer, were analyzed to compare the disease-free survival (DFS) and overall survival (OS) of the two groups over a 5-year period. A multifactorial Cox risk model was constructed by grouping age, menstrual status, maximum tumor diameter, number of lymph node metastases, pathological staging, and Ki-67 staining results. All statistical data were analyzed in detail using SPSS25.0 statistical software.ResultsThe 5-year OS rates of patients with breast cancer in the triple-positive and HER2-positive groups were 96.7% and 82.7%, respectively, and the 5-year DFS rates were 90% and 73.3%, respectively. The Cox results revealed that molecular staging was an independent factor affecting recurrent metastasis and survival of breast cancer patients (hazard ratio [HR] =2.199, 95% confidence interval [CI], 1.296-8.266; HR = 9.994, 95% CI, 2.019-49.465).ConclusionThe 5-year DFS and OS rates were significantly better in the triple-positive group than in the HER2-positive group. Subgroups received different prognosis for different chemotherapy regimens. Breast cancer patients should be treated according to the risk of recurrence with symptomatic treatment and precise regulation

The Photometric System of Tsinghua-NAOC 80-cm Telescope at NAOC Xinglong Observatory

Tsinghua-NAOC (National Astronomical Observatories of China) Telescope (hereafter, TNT) is an 80-cm Cassegrain reflecting telescope located at Xinglong bservatory of NAOC, with main scientific goals of monitoring various transients in the universe such as supernovae, gamma-ray bursts, novae, variable stars, and active galactic nuclei. We present in this paper a systematic test and analysis of the photometric performance of this telescope. Based on the calibration observations on twelve photometric nights, spanning the period from year 2004 to year 2012, we derived an accurate transformation relationship between the instrumental $ubvri$ magnitudes and standard Johnson $UBV$ and Cousins $RI$ magnitudes. In particular, the color terms and the extinction coefficients of different passbands are well determined. With these data, we also obtained the limiting magnitudes and the photometric precision of TNT. It is worthwhile to point out that the sky background at Xinglong Observatory may become gradually worse over the period from year 2005 to year 2012 (e.g., $\sim$21.4 mag vs. $\sim$20.1 mag in the V band).Comment: 12 pages,9 figures, accepted by RA

Effect of carbon-coated Al2O3 powder on structure and properties of low-carbon MgO-C refractory composites

In this study, low-carbon MgO-C refractory composites with addition of uncoated (UA) and carbon-coated Al2O3 (CCA) powders were prepared. The effect of heat-treatment temperature on apparent porosity, cold modulus of rupture and thermal expansion was investigated. The results indicated that the CCA was present in the form of porous agglomerates of 400–800 µm in diameter in MgO-C matrix. The formation of spinel started at 1100 °C and 1250 °C in UA-MgO-C and CCA-MgO-C specimens, respectively. In the specimen CCA-MgOC, cyclic spinel was formed on the outer layer of CCA agglomerates, and the dense spinel layer hindered the diffusion of Mg(g) to the interior of the agglomerates, resulting in alumina residues at 1550 °C. The specimen CCA-MgO-C showed better mechanical properties and reduced porosity. Additionally, the average coefficient of thermal expansion of CCA-MgO-C was significantly lower than that of UA-MgO-C. Thus, CCA powder could improve the volume stability of the low-carbon MgO-C refractory composites

Absence of topological Hall effect in Fex_xRh100−x_{100-x} epitaxial films: revisiting their phase diagram

A series of Fe$_x$Rh$_{100-x}$ ($30 \leq x \leq 57$) films were epitaxially grown using magnetron sputtering, and were systematically studied by magnetization-, electrical resistivity-, and Hall resistivity measurements. After optimizing the growth conditions, phase-pure Fe$_{x}$Rh$_{100-x}$ films were obtained, and their magnetic phase diagram was revisited. The ferromagnetic (FM) to antiferromagnetic (AFM) transition is limited at narrow Fe-contents with $48 \leq x \leq 54$ in the bulk Fe$_x$Rh$_{100-x}$ alloys. By contrast, the FM-AFM transition in the Fe$_x$Rh$_{100-x}$ films is extended to cover a much wider $x$ range between 33 % and 53 %, whose critical temperature slightly decreases as increasing the Fe-content. The resistivity jump and magnetization drop at the FM-AFM transition are much more significant in the Fe$_x$Rh$_{100-x}$ films with $\sim$50 % Fe-content than in the Fe-deficient films, the latter have a large amount of paramagnetic phase. The magnetoresistivity (MR) is rather weak and positive in the AFM state, while it becomes negative when the FM phase shows up, and a giant MR appears in the mixed FM- and AFM states. The Hall resistivity is dominated by the ordinary Hall effect in the AFM state, while in the mixed state or high-temperature FM state, the anomalous Hall effect takes over. The absence of topological Hall resistivity in Fe$_{x}$Rh$_{100-x}$ films with various Fe-contents implies that the previously observed topological Hall effect is most likely extrinsic. We propose that the anomalous Hall effect caused by the FM iron moments at the interfaces nicely explains the hump-like anomaly in the Hall resistivity. Our systematic investigations may offer valuable insights into the spintronics based on iron-rhodium alloys.Comment: 9 pages, 10 figures; accepted by Phys. Rev.

Gate-tunable negative differential conductance in hybrid semiconductor-superconductor devices

Negative differential conductance (NDC) manifests as a significant characteristic of various underlying physics and transport processes in hybrid superconducting devices. In this work, we report the observation of gate-tunable NDC outside the superconducting energy gap on two types of hybrid semiconductor-superconductor devices, i.e., normal metal-superconducting nanowire-normal metal and normal metal-superconducting nanowire-superconductor devices. Specifically, we study the dependence of the NDCs on back-gate voltage and magnetic field. When the back-gate voltage decreases, these NDCs weaken and evolve into positive differential conductance dips; and meanwhile they move away from the superconducting gap towards high bias voltage, and disappear eventually. In addition, with the increase of magnetic field, the NDCs/dips follow the evolution of the superconducting gap, and disappear when the gap closes. We interpret these observations and reach a good agreement by combining the Blonder-Tinkham-Klapwijk (BTK) model and the critical supercurrent effect in the nanowire, which we call the BTK-supercurrent model. Our results provide an in-depth understanding of the tunneling transport in hybrid semiconductor-superconductor devices.Comment: 15+6 pages, 4+6 figure

Origin of two types of rhyolites in the Tarim Large Igneous Province: Consequences of incubation and melting of a mantle plume

The Early Permian Tarim Large Igneous Province (LIP) in northwestern China contains a large area of silicic volcanics (similar to 48,000 km(2)) which are spatially and temporally associated with mafic-ultramafic rocks. In order to understand the behavior of crust above a mantle plume, selected rhyolitic samples are investigated in terms of U-Pb zircon dating, geochemical and isotopic analyses. The Tarim rhyolites have high A/CNK ratios (= molar Al2O3/CaO + Na2O + K2O), Fe#, Ga/Al ratios, concentrations of high field strength elements (HFSEs) such as Zr and Nb, and rare earth elements (REEs), along with high zircon saturation temperatures (872-940 degrees C), typical of aluminous A-type granitoids. Two contrasting rock types have been recognized. The low Nb-Ta type rhyolites are mainly associated with the first phase of the Tarim flood basalt magmatism at similar to 290 Ma. They are characterized by negative Nb-Ta anomalies, low epsilon(Nd)(t) and epsilon(Hf)(t) values, and high Sr-87/Sr-88(t) and delta(18) O-zircon values, consistent with a derivation from continental crustal source. The high Nb-Ta type rhyolites and their plutonic equivalents are associated with the second episode of Tarim magmatism (283-272 Ma). They are characterized by small negative to positive Nb-Ta anomalies, oceanic island basalt (0113)-like trace element ratios, low Sr-87/Sr-88(t) and high epsilon(Nd)(t) and epsilon(Hf)(t) values. These high Nb-Ta rhyolites are best interpreted as hybrid products of crystal fractionation of mafic magmas, coupled with crustal assimilation. The temporal and compositional evolution of the Tarim rhyolites reflects various extents of thermal and mass exchange between mantle-derived basaltic magma and crustal material above a mantle plume. When the plume head rises to the base of the Tarim craton, it first melts enriched components in the lithospheric mantle (similar to 290 Ma), part of which may have ponded near the crust-mantle boundary and induced crustal anatexis leading to the formation of the low Nb-Ta type rhyolites. At similar to 280 Ma, large magma chambers and plumbing systems were formed due to increasing magma supply rate during decompression melting of the mantle plume. This led to the formation of a mafic-ultramafic and felsic association of which the high Nb-Ta type rhyolites are a part. (C) 2014 Elsevier B.V. All right reservedGeochemistry & GeophysicsMineralogySCI(E)[email protected],SI59-7220