Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file

The screening files of many large companies, including Pfizer, have grown considerably due to internal chemistry efforts, company mergers and acquisitions, external contracted synthesis, or compound purchase schemes. In order to screen the targets of interest in a cost-effective fashion, we devised an easy-to-assemble, plate-based diversity subset (PBDS) that represents almost the entire computed chemical space of the screening file whilst comprising only a fraction of the plates in the collection. In order to create this file, we developed new design principles for the quality assessment of screening plates: the Rule of 40 (Ro40) and a plate selection process that insured excellent coverage of both library chemistry and legacy chemistry space. This paper describes the rationale, design, construction, and performance of the PBDS, that has evolved into the standard paradigm for singleton (one compound per well) high-throughput screening in Pfizer since its introduction in 2006.     

Development of a high-throughput thermoelectric screening tool for combinatorial thin film libraries

We have developed a high-throughput thermoelectric screening tool for the study of combinatorial thin films. This tool consists of a probe to measure resistance and Seebeck coefficient on an automated translation stage. A thin film library of the (Ca_1−x−ySr_xLa_y)₃Co₄O₉ ternary system has been fabricated on a Si (1 0 0) substrate, using combinatorial pulsed laser deposition by the natural-composition-spread method. We have demonstrated successful mapping of the resistance and Seebeck coefficient of this film library. The mapping indicates that the substitution of La for Ca results in an increase of both resistance and Seebeck coefficient, and that of Sr results in a decrease of resistance. The screening tool allows us to measure 1080 data points in 6 h.     

Modulated spin liquid: a new paradigm for URu2Si2

We argue that near a Kondo breakdown critical point, a spin liquid with spatial modulations can form. Unlike its uniform counterpart, we find that this occurs via a second order phase transition. The amount of entropy quenched when ordering is of the same magnitude as for an antiferromagnet. Moreover, the two states are competitive, and at low temperatures are separated by a first order phase transition. The modulated spin liquid we find breaks Z4 symmetry, as recently seen in the hidden order phase of URu2Si2. Based on this, we suggest that the modulated spin liquid is a viable candidate for this unique phase of matter.     

Rapid beat generation of large-scale zonal flows by drift waves: a nonlinear generic paradigm

The generalized Charney-Hasegawa-Mima equation is unstable to a four wave modulational instability whereby a coherent, monochromatic drift wave can drive a band of modes and associated zonal flows unstable. Although initially the fastest growing modes dominate, a secondary nonlinear instability later drives the longest wavelength zonal flow and its associated sidebands at twice the growth rate of the fastest growing modulationally unstable modes. This results in a direct transfer from strongly unstable short wavelength modes to the weakly unstable long wavelength modes, which drains the short wavelength pump energy. A related but less efficient direct enstrophy cascade generates very short wavelength modes lying outside the band of modulationally unstable modes.     

大规模集成电路抗辐射性能无损筛选方法

空间辐射环境会对电子器件产生辐射损伤。由于商用器件性能普遍优于抗辐射加固器件,所以从商用器件中筛选出抗辐射性能优异的器件将在一定程度上提高空间电子系统的可靠性。结合数学回归分析与物理应力实验的方法,研究了集成电路抗辐射性能无损筛选技术。通过不同的外界能量注入及总剂量辐照实验,探究电路典型参数的应变情况与电路耐辐射性能的关系,并确定其辐射敏感参数;建立预测电路抗辐射性能的多元线性回归方程,并对应力条件下的回归方程进行辐照实验验证。结果显示,物理应力实验与数学回归分析结合的筛选方法减小了实验值与预测值的偏差,提高了预估方程的拟合优度和显著程度,使预估方程处于置信区间。     

On the generation of large clusters in forming gas-jet targets for lasers

The problem of increasing the mean size of clusters in gas-jet targets is tackled. Based on a mathematical model of clustering, the dependence of the cluster mean size on the nozzle length and rate of expansion is derived. The nozzle shape providing micrometer-size clusters is found. The parameters of gas-jet targets produced with this nozzle are studied in detail.     

Laser phase control of high-order harmonic generation at large internuclear distance: the H+ -H2+ system

Exact (Born-Oppenheimer) 3-D numerical solutions of the time-dependent Schr?dinger equation are obtained for the one electron linear H+-H2+ atom-molecule system at large internuclear distance R in interaction with two-cycles intense (I>10(14) W cm(-2)) 800 nm laser pulses. High-order harmonic generation (HHG) spectra are obtained with an energy cutoff larger than the atomic maximum of I(p)+3U(p), where I(p) is the ionization potential and U(p) is the ponderomotive energy. At large R, this extended cutoff is shown to be related to the nature of electron transfer, whose direction is shown to depend critically on the carrier-envelope phase (CEP) of the ultrashort pulse. Constructive and destructive interferences in the HHG spectrum resulting from coherent superpositions of electronic states in the H+-H2+ system are interpreted in terms of multiple electron trajectories extracted from a time profile analysis.     

Second harmonic generation: the solution for an amplitude-modulated initial pulse

We address the initial value problem for one-dimensional second harmonic generation starting from a purely amplitude-modulated fundamental wave. A general method to solve the problem in terms of a Schrödinger equation is presented, in which the initial pulse-shape is taken as a potential. Several examples with the complete solution given in analytical form are discussed. A much broader class of solutions can be found with the help of a single numerical integration. In particular, solutions with incident pulses approximating a sech -shape have been obtained.     

大规模集成电路抗辐射性能无损筛选方法

空间辐射环境会对电子器件产生辐射损伤。由于商用器件性能普遍优于抗辐射加固器件,所以从商用器件中筛选出抗辐射性能优异的器件将在一定程度上提高空间电子系统的可靠性。结合数学回归分析与物理应力实验的方法,研究了集成电路抗辐射性能无损筛选技术。通过不同的外界能量注入及总剂量辐照实验,探究电路典型参数的应变情况与电路耐辐射性能的关系,并确定其辐射敏感参数;建立预测电路抗辐射性能的多元线性回归方程,并对应力条件下的回归方程进行辐照实验验证。结果显示,物理应力实验与数学回归分析结合的筛选方法减小了实验值与预测值的偏差,提高了预估方程的拟合优度和显著程度,使预估方程处于置信区间。     

High-power sixth-harmonic generation of an Nd:YAG laser with KBe2BO3F2 prism-coupled devices

High-power sixth harmonic generation from an Nd:YAG laser (10 ns, 10 kHz) has been achieved with a KBe₂BO₃F₂ (KBBF) prism-coupled device (PCD) containing a 1.95 mm thick KBBF crystal. The highest output power reached 120.5 mW at 177.3 nm, and the highest conversion efficiency from 354.7 to 177.3 nm was 1.82%. Moreover, stable sixth harmonic output with an average power of 22.2 mW was produced by another KBBF-PCD, in which the thickness of the KBBF crystal was 1.51 mm. The highest and stable sixth harmonic output powers are improved by about three and six times compared with the previously published results, respectively.     

Docking of a novel DNA methyltransferase inhibitor identified from high-throughput screening: insights to unveil inhibitors in chemical databases

Inhibitors of DNA methyltransferase (DNMT) are attractive compounds not only as potential therapeutic agents for the treatment of cancer and other diseases, but also as research tools to investigate the role of DNMTs in epigenetic events. Recent advances in high-throughput screening (HTS) for epigenetic targets and the availability of the first crystallographic structure of human DNMT1 encourage the integration of research strategies to uncover and optimize the activity of DNMT inhibitors. Herein, we present a binding model of a novel small-molecule DNMT1 inhibitor obtained by HTS, recently released in a public database. The docking model is in agreement with key interactions previously identified for established inhibitors using extensive computational studies including molecular dynamics and structure-based pharmacophore modeling. Based on the chemical structure of the novel inhibitor, a sequential computational screening of five chemical databases was performed to identify candidate compounds for testing. Similarity searching followed by molecular docking of chemical databases such as approved drugs, natural products, a DNMT-focused library, and a general screening collection, identified at least 108 molecules with promising DNMT inhibitory activity. The chemical structures of all hit compounds are disclosed to encourage the research community working on epigenetics to test experimentally the enzymatic and demethylating activity in vivo. Five candidate hits are drugs approved for other indications and represent potential starting points of a drug repurposing strategy.     

改进的二维分形模型在海面电磁散射中的应用

提出了一种改进的二维分形海面模型，其表面谱函数在空间波数小于基波波数及大于基波波数时分别满足正幂率关系和负幂率关系.通过比较可以发现在不同风速时，改进模型的空间自相关函数及表面轮廓谱和有关文献结果有较好的吻合.在满足Kirchhoff近似条件下推导了改进分形模型的散射系数及散射强度系数的计算公式并进行了数值计算，比较了改进模型和经典模型的后向散射强度系数角分布并详细讨论了它们随入射频率、海上风速和风向的变化. 关键词： 改进分形模型 粗糙海面 电磁散射 Kirchhoff近似     

Performance analysis of an improved burst-outputted model for an OBS core router

Differentiated probability outputted scheme (DPOS) is an improved burst-outputted paradigm in optical burst switching (OBS) core routers. In this paper, the blocking performance for multi-priority traffic in a DPOS applied OBS core router with limited buffers has been analyzed and discussed firstly. Several simulation results indicted that DPOS had a better performance in blocking than the outputted model presented in the previous work had. Besides, our proposed scheduling mechanism can supported the quality-of-service (QoS) efficiently for OBS networks.     

A new walk-off compensated multipass scheme for large enhancement of conversion efficiency for fourth harmonic generation

A significant enhancement is treated in the energy of a fourth harmonic generated beam (266 nm) by employing the new technique of walk-off compensated multipass configuration without any change either in the beam parameters or in the intensity of the input fundamental laser radiation. As much as 56% conversion efficiency is obtained in twin lithium tetraborate crystals, even though the effective nonlinear coefficient of the crystal is as low as 1/6th that of KDP. Apart from crystals that have large walk-off angles, low effective nonlinear coefficients, or both, the simple experimental set-up would also be quite suitable for those crystals, especially infrared crystals that have large effective nonlinear coefficients but low laser damage thresholds.     

LBVS: an online platform for ligand-based virtual screening using publicly accessible databases

Abundant data on compound bioactivity and publicly accessible chemical databases increase opportunities for ligand-based drug discovery. In order to make full use of the data, an online platform for ligand-based virtual screening (LBVS) using publicly accessible databases has been developed. LBVS adopts Bayesian learning approach to create virtual screening models because of its noise tolerance, speed, and efficiency in extracting knowledge from data. LBVS currently includes data derived from BindingDB and ChEMBL. Three validation approaches have been employed to evaluate the virtual screening models created from LBVS. The tenfold cross validation results of twenty different LBVS models demonstrate that LBVS achieves an average AUC value of 0.86. Our internal and external testing results indicate that LBVS is predictive for lead identifications. LBVS can be publicly accessed at http://rcdd.sysu.edu.cn/lbvs.     

Design of an improved Offner spectrometer for crop fluorescence detection

To monitor crop growth more efficiently, various kinds of hyperspectral spectrometers have been designed to detect chlorophyll fluorescence. In this paper, the traditional Offner spectrometer system is improved, and a structure with a higher spectral resolution is obtained. The double-reflection telescope system is selected, and the spectrometer adopts a highly dense linear reflective convex grating to achieve higher spectral resolution. On this basis, an amplifying lens is added to meet the need for a long slit. An Offner structure is obtained with a slit and image plane on the same side of the grating. The initial structure of the telescope system and the spectrometer are optimized by codeV software. The results show that the spectral resolution is 0.3 nm in the range of 670 similar to 780 nm, the overall Modulation Transfer Function (MTF) is greater than 0.75 at the cut-off frequency of 17 lp/mm, and the Root Mean Square radius (RMS) of the speckle is less than 15 mu m. The proposed system can meet the requirements of highly precise real-time monitoring in crop growth chlorophyll detection.