ALBERT

Description: Identification of drug–target interactions is an important process in drug discovery. Although high-throughput screening and other biological assays are becoming available, experimental methods for drug–target interaction identification remain to be extremely costly, time-consuming and challenging even nowadays. Therefore, various computational models have been developed to predict potential drug–target associations on a large scale. In this review, databases and web servers involved in drug–target identification and drug discovery are summarized. In addition, we mainly introduced some state-of-the-art computational models for drug–target interactions prediction, including network-based method, machine learning-based method and so on. Specially, for the machine learning-based method, much attention was paid to supervised and semi-supervised models, which have essential difference in the adoption of negative samples. Although significant improvements for drug–target interaction prediction have been obtained by many effective computational models, both network-based and machine learning-based methods have their disadvantages, respectively. Furthermore, we discuss the future directions of the network-based drug discovery and network approach for personalized drug discovery based on personalized medicine, genome sequencing, tumor clone-based network and cancer hallmark-based network. Finally, we discussed the new evaluation validation framework and the formulation of drug–target interactions prediction problem by more realistic regression formulation based on quantitative bioactivity data.

Description: Cadmium is a widespread environmental pollutant and poses some potential risks to human health. However, the signaling events controlling cadmium toxicity are not fully understood. In this study, we examined the effect of cadmium chloride on cell viability and the intracellular nitric oxide (NO) level in yeast cells. The results showed that exposure of yeast cells to cadmium (0–100 μM) could induce cell killing with significantly increased intracellular NO levels. Morphological analysis of the nuclei with 4 ' ,6-diamidino-2-phenylindole staining and DNA strand breaks analysis showed that cadmium at 50 μM can induce cell apoptosis in yeast cells. Treatment of yeast cells with cadmium (50 μM) and the nitric oxide scavenger c-PTIO [2-(4-carboxyphenyl)-4,4,5,5-teramethylimidazoline-1-oxyl-3-oxide; 0.2 mM] showed that c-PTIO attenuated the cadmium-induced cell killing. Our findings indicated that cadmium-induced yeast cell killing is mediated by a directly increased intracellular NO level.

Description: SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction of SLX4 with TRF2. Telomeres present an inherent obstacle for DNA replication and repair due to their high propensity to form branched DNA intermediates. Here we provide novel insight into the mechanism and regulation of the SLX4 complex in telomere preservation. SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress. Disruption of SLX4's interaction with TRF2 or SLX1 and SLX1's nuclease activity independently causes telomere fragility, suggesting a requirement of the SLX4 complex for nucleolytic resolution of branched intermediates during telomere replication. Indeed, the SLX1–SLX4 complex processes a variety of telomeric joint molecules in vitro . The nucleolytic activity of SLX1-SLX4 is negatively regulated by telomeric DNA-binding proteins TRF1 and TRF2 and is suppressed by the RecQ helicase BLM in vitro . In vivo , in the presence of functional BLM, telomeric circle formation and telomere sister chromatid exchange, both arising out of nucleolytic processing of telomeric homologous recombination intermediates, are suppressed. We propose that the SLX4-toolkit is a telomere accessory complex that, in conjunction with other telomere maintenance proteins, ensures unhindered, but regulated telomere maintenance.

Description: Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait.

Description: The Fanconi anemia protein SLX4 assembles a genome and telomere maintenance toolkit, consisting of the nucleases SLX1, MUS81 and XPF. Although it is known that SLX4 acts as a scaffold for building this complex, the molecular basis underlying this function of SLX4 remains unclear. Here, we report that functioning of SLX4 is dependent on its dimerization via an oligomerization motif called the BTB domain. We solved the crystal structure of the SLX4 BTB dimer, identifying key contacts (F681 and F708) that mediate dimerization. Disruption of BTB dimerization abrogates nuclear foci formation and telomeric localization of not only SLX4 but also of its associated nucleases. Furthermore, dimerization-deficient SLX4 mutants cause defective cellular response to DNA interstrand crosslinking agent and telomere maintenance, underscoring the contribution of BTB domain-mediated dimerization of SLX4 in genome and telomere maintenance.

Description: Atmospheric optical turbulence seriously limits the performance of high angular resolution instruments. An eight-night campaign of measurements was carried out at the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) site in 2011, to characterize the optical turbulence. Two instruments were set up during the campaign: a differential image motion monitor (DIMM) used to measure the total atmospheric seeing, and a single star Scidar (SSS) to measure the vertical profiles of the turbulence $C_n^2(h)$ and the horizontal wind velocity ${\boldsymbol v}(h)$ . The optical turbulence parameters are also calculated with the Weather Research and Forecasting (WRF) model coupled with the Trinquet–Vernin model, which describes optical effects of atmospheric turbulence by using the local meteorological parameters. This paper presents assessment of the optical parameters involved in high angular resolution astronomy. Its includes seeing, isoplanatic angle, coherence time, coherence étendue, vertical profiles of optical turbulence intensity $C_n^2(h)$ and horizontal wind speed ${\boldsymbol v}(h)$ . The median seeing is respectively 1.01, 1.17 and 1.07 arcsec as measured with the DIMM, the SSS and predicted with WRF model. The history of seeing measurements at the LAMOST site is reviewed, and the turbulence measurements in this campaign are compared with other astronomical observatories in the world.

Description: 〈span〉〈div〉SUMMARY〈/div〉Backprojection (BP) of teleseismic 〈span〉P〈/span〉 waves is a powerful tool to study the evolution of seismic radiation of large earthquakes. The common interpretations on the BP results are qualitative comparisons with earthquake kinematic observations, such as the evolution of slip on the fault and rupture velocity. However, the direct relation between the BP images and physical properties of the earthquake rupture process remains unclear and is needed for further application of this technique. In this study, we start from a theoretical formulation of the BP images, which is linear in the frequency domain, and carry on a synthetic exercise with kinematic source representations and virtual receivers embedded in a homogeneous full-space. We find that the fundamental linear formulation of the BP method is most correlated with the true kinematic source properties: in frequency domain the BP images are proportional to the images of slip motion through a scaling matrix $\mathbf {F}(\omega )$ that accounts for radiation pattern and source–receiver geometry and that acts as a spatial smoothing operator. Overall, the synthetic BP images match relatively well the kinematic models and our exercise validates that the BP image can be directly used to track the spatiotemporal propagation of rupture front. However, because $\mathbf {F}(\omega )$ is not strictly an identity matrix due to limited station coverage in space (azimuth and distance) and to the limited frequency bands of the seismograms, it remains difficult to recover the details in the rupture fronts from BP images. We define a resolvability parameter ε〈sub〉〈span〉I〈/span〉〈/sub〉(ω) built from $\mathbf {F}(\omega )$ that incorporates fault geometry, radiation pattern and wave propagation (source–array geometry) to quantify the ability of the BP method to resolve details of the rupture on the fault. ε〈sub〉〈span〉I〈/span〉〈/sub〉(ω) successfully captures the similarity between BP images and kinematic source. We analyse the resolvability of most tectonically active regions and the most commonly used seismic arrays. Based on this global resolvability analysis, we propose an empirical relation between the seismic frequency, resolvable area and earthquake magnitude. It provides general guidelines to choose the lowest frequency in seismic waveform (e.g. about 0.3 Hz for 〈span〉M〈/span〉〈sub〉w〈/sub〉 8 and 1 Hz for 〈span〉M〈/span〉〈sub〉w〈/sub〉 7 earthquakes) and to interpret the BP image in terms of the source kinematics. In general, this work attempts to provide a clear interpretation of the BP images in light of the real earthquake rupture process and give a systematic evaluation of seismic data limitations.〈/span〉

Description: 〈p〉The massless Dirac electron transport in graphene has led to a variety of unique light-matter interaction phenomena, which promise many novel optoelectronic applications. Most of the effects are only accessible by breaking the spatial symmetry, through introducing edges, p-n junctions, or heterogeneous interfaces. The recent development of direct synthesis of lateral heterostructures offers new opportunities to achieve the desired asymmetry. As a proof of concept, we study the photothermoelectric effect in an asymmetric lateral heterojunction between the Dirac semimetallic monolayer graphene and the parabolic semiconducting monolayer MoS〈sub〉2〈/sub〉. Very different hot-carrier cooling mechanisms on the graphene and the MoS〈sub〉2〈/sub〉 sides allow us to resolve the asymmetric thermalization pathways of photoinduced hot carriers spatially with electrostatic gate tunability. We also demonstrate the potential of graphene-2D semiconductor lateral heterojunctions as broadband infrared photodetectors. The proposed structure shows an extreme in-plane asymmetry and provides a new platform to study light-matter interactions in low-dimensional systems.〈/p〉

Description: Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope ( P omnibus = 6.9 x 10 –135 ). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His 〉 Phe 〉 Arg 〉 Tyr Gly 〉 Ser)—but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional P omnibus = 2.2 x 10 –33 ) and 74 (conditional P omnibus = 1.1 x 10 –8 ). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 x 10 –6 ) and HLA-DPβ1 (Phe9, conditional P = 3.0 x 10 –5 ) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01 ) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.