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This study presents observations of coherent modes (CMs) in a spherical tokamak using a microwave interferometer near the midplane. The CMs within the 30–60 kHz frequency range were observed during electron cyclotron resonance heating only, and the frequency of the CMs increased proportionally with the square root of the electron temperature near $R = 0.7m$. Generally, these modes displayed bursting and chirping signatures with strong density rise and fall. Their appearance indicated an increase in the intensity of hard x rays, suggesting a deterioration in energetic electron confinement. Furthermore, the effect of CMs on the intensity of energetic electron-driven whistler waves was observed. They decreased when CMs were present and gradually increased with the decrease in CM intensity. The CMs may influence the intensity of whistler waves by affecting the energetic electron confinement.
Female crabs enter a stage of rapid ovarian development after mating, and cholesterol is a substrate for steroid hormone synthesis. Therefore, in this experiment, an 8-week feeding trial was conducted to investigate the effects of mating treatments (mated crab and unmated crab) and three dietary cholesterol levels (0·09 %, 0·79 % and 1·40 %) on ovarian development, cholesterol metabolism and steroid hormones metabolism of adult female swimming crab (Portunus trituberculatus). The results indicated that crabs fed the diet with 0·79 % cholesterol significantly increased gonadosomatic index (GSI) and vitellogenin (VTG) content than other treatments in the same mating status. Moreover, mated crabs had markedly increased GSI and VTG content in the ovary and hepatopancreas than unmated crabs. The histological observation found that exogenous vitellogenic oocytes appeared in the mated crabs, while previtellogenic oocytes and endogenous vitellogenic oocytes were the primary oocytes in unmated crabs. The transmission electron microscopy analysis showed that when fed diet with 0·79 % cholesterol, the unmated crabs contained more rough endoplasmic reticulum and mated crabs had higher yolk content than other treatments. Furthermore, mating treatment and dietary 0·79 % cholesterol level both promoted cholesterol deposition by up-regulation of the mRNA and protein expression levels of class B scavenger receptors 1 (Srb1), while stimulating the secretion of steroid hormones by up-regulation of the mRNA and protein expression of steroidogenic acute regulatory protein (Star). Overall, the present results indicated that mating behaviour plays a leading role in promoting ovarian development, and dietary 0·79 % cholesterol level can further promote ovarian development after mating.
Carboxylesterases (CarEs) is an important detoxification enzyme system in phase Ⅰ participating in insecticides resistance. In our previous study, SlCarE054, a CarEs gene from lepidoptera class, was screened out to be upregulated in a pyrethroids and organophosphates resistant population. Its overexpression was verified in two field-collected populations of Spodoptera litura (Lepidoptera: Noctuidae) resistant to pyrethroids and organophosphates by qRT-PCR. Spatiotemporal expression results showed that SlCarE054 was highly expressed in the pupae stage and the digestive tissue midgut. To further explore its role in pyrethroids and organophosphates resistance, its metabolism activity to insecticides was determined by UPLC. Its recombinant protein showed significant metabolism activity to cyhalothrin and fenvalerate, but not to phoxim or chlorpyrifos. The metabolic activity of SlCarE054 to β-cypermethrin showed stereoselectivity, with higher metabolic activity to θ-cypermethrin than the enantiomer α-cypermethrin. The metabolite of β-cypermethrin was identified as 3-phenoxybenzaldehyde. Further modelling and docking analysis indicated that β-cypermethrin, cyhalothrin and fenvalerate could bind with the catalytic triad of the 3D structure of SlCarE054. The interaction of β-cypermethrin with SlCarE054 also showed the lowest binding energy. Our work provides evidence that SlCarE054 play roles in β-cypermethrin resistance in S. litura.
The current epidemic of type 2 diabetes mellitus (T2DM) significantly affects human health worldwide. Activation of brown adipocytes and browning of white adipocytes are considered as a promising molecular target for T2DM treatment. Mulberry leaf, a traditional Chinese medicine, has been demonstrated to have multi-biological activities, including anti-diabetic and anti-inflammatory effects. Our experimental results showed that mulberry leaf significantly alleviated the disorder of glucose and lipid metabolism in T2DM rats. In addition, mulberry leaf induced browning of inguinal white adipose tissue (IWAT) by enhancing the expressions of brown-mark genes as well as beige-specific genes, including uncoupling protein-1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), PRD1-BF-1-RIZ1 homologous domain containing protein 16 (PRDM16), cell death inducing DFFA-like effector A (Cidea), CD137 and transmembrane protein 26 (TMEM26). Mulberry leaf also activated brown adipose tissue (BAT) by increasing the expressions of brown-mark genes including UCP1, PGC-1α, PPARα, PRDM16 and Cidea. Moreover, mulberry leaf enhanced the expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) genes that are responsible for mitochondrial biogenesis in IWAT and BAT. Importantly, mulberry leaf also increased the expression of UCP1 and carnitine palmitoyl transferase 1 (CPT-1) proteins in both IWAT and BAT via a mechanism involving AMP-activated protein kinase (AMPK) and PGC-1α pathway. In conclusion, our findings identify the role of mulberry leaf in inducing adipose browning, indicating that mulberry leaf may be used as a candidate browning agent for the treatment of T2DM.
Thrombocytopenia occasionally occurs following the closure of some giant patent ductus arteriosus cases. Unfortunately, there is no associated research describing the associated risk factors for thrombocytopenia post-procedure.
Methods:
We reviewed all patients who received occluders with sizes ≥10/12 mm between January 2013 and June 2019. All the data and information on the characteristics of the patients and their follow-up were recorded. Univariate analysis, receiver operating characteristic curves, and linear regression were used to analyse the risk factors for thrombocytopenia and the predictors of hospitalisation stay.
Results:
Finally, 32 patients (17.5%) suffered from thrombocytopenia. Univariate analysis revealed the ratio between occluder disc size (mm) and body weight (kg) (1.71 ± 0.51 versus 1.35 ± 0.53) as an independent predictive factor for thrombocytopenia, and the area under the curve of the ratio of occluder size and body weight for predicting thrombocytopenia post-closure was 0.691 (95% confidence interval: 0.589–0.792, p = 0.001). The best cut-off value for the ratio of occluder size and weight was 1.5895, with a sensitivity and specificity of 68.8 and 66.9%, respectively. Each unit of the ratio of occluder size and body weight predicted an average hospitalisation stay of 2.856 days (95% confidence interval: 1.380–4.332). Treatment with medication did not reduce the hospitalisation stay or benefit platelet restoration.
Conclusion:
Once the ratio of occluder size and body weight is greater than 1.6, thrombocytopenia always exists. Every unit of the ratio of occluder size and body weight represents an additional 3 days of hospitalisation. Treatment does not reduce the duration of hospitalisation.
To overcome the steric effect of norbornene (NB), first-generation Grubbs’ catalyst (GC1) was used as the catalyst to graft NB onto the polypropylene (PP) chain by reactive extrusion. Instead of harsh reaction conditions, such as anhydrous, which was the general method to synthesize NB polymers, this convenient method would be easier to industrialize. The mechanism of grafting was studied by using Fourier Transform InfraRed spectra and differential scanning calorimetry. It was found that GC1 could initiate the ring-opening metathesis polymerization of NB to obtain short NB chain-grafted PP-g-NB. The rheological behavior showed that the grafted NB short chains on PP-g-NB increase the shear thinning of the polymers and decrease the system viscosity.
A tunable ultrafast intensity-rotating optical field is generated by overlapping a pair of 20 Hz, 800 nm chirped pulses with a Michelson interferometer (MI). Its rotating rate can be up to 10 trillion radians per second ($\text{Trad}/\text{s}$), which can be flexibly tuned with a mirror in the MI. Besides, its fold rotational symmetry structure is also changeable by controlling the difference from the topological charges of the pulse pair. Experimentally, we have successfully developed a two-petal lattice with a tunable rotating speed from $3.9~\text{Trad}/\text{s}$ up to $11.9~\text{Trad}/\text{s}$, which is confirmed by our single-shot ultrafast frame imager based on noncollinear optical-parametric amplification with its highest frame rate of 15 trillion frames per second (Tfps). This work is carried out at a low repetition rate. Therefore, it can be applied at relativistic, even ultrarelativistic, intensities, which usually operate in low repetition rate ultrashort and ultraintense laser systems. We believe that it may have application in laser-plasma-based accelerators, strong terahertz radiations and celestial phenomena.
Triticum monococcum ssp. monococcum has useful traits for bread wheat improvement. The synthesis of Triticum turgidum–T. monococcum amphiploids is an essential step for transferring genes from T. monococcum into bread wheat. In this study, 264 wide hybridization combinations were done by crossing 60 T. turgidum lines belonging to five subspecies with 83 T. monococcum accessions. Without embryo rescue and hormone treatment, from the 10,810 florets pollinated, 1983 seeds were obtained, with a mean crossability of 18.34% (range 0–89.29%). Many hybrid seeds (90.73%, 923/1017) could germinate and produce plants. A total of 56 new amphiploids (AABBAmAm) were produced by colchicine treatment of T. turgidum × T. monococcum F1 hybrids. The chromosome constitution of amphiploids was characterized by fluorescence in situ hybridization using oligonucleotides probes with different chromosome and sub-chromosome specificities. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis indicated that the Glu-A1m-b, Glu-A1m-c, Glu-A1m-d and Glu-A1m-h proteins of T. monococcum were expressed in some amphiploids. Despite resistance reduction in several cases, 45 out of 56 amphiploids exhibited resistance to the current predominant Chinese stripe rust races at both the seedling and adult plant stage. These novel amphiploids provide new germplasm for the potential improvement of bread wheat quality and stripe rust resistance.
The purpose of this paper is to numerically realize the inverse scattering scheme proposed in [19] of reconstructing complex elastic objects by a single far-field measurement. The unknown elastic scatterers might consist of both rigid bodies and traction-free cavities with components of multiscale sizes presented simultaneously. We conduct extensive numerical experiments to show the effectiveness and efficiency of the imaging scheme proposed in [19]. Moreover, we develop a two-stage technique, which can significantly speed up the reconstruction to yield a fast imaging scheme.
After the completion of the Human Genome Project (Lander et al., 2001; Venter et al., 2001) and initiation of the International HapMap Project (Sachidanandam et al., 2001), genome-wide association studies (GWAS) were designed to survey the role of common genetic variations in complex human diseases. It was expected that GWAS would have the advantage of not relying on prior knowledge of biological pathways compared with “candidate gene” studies (Tabor et al., 2002; Wang et al., 2005), because it assays a dense set of single-nucleotide polymorphisms (SNPs) across the whole genome. This advantage allows GWAS to overcome the bias of “candidate gene” studies due to incomplete prior knowledge. It was also expected that GWAS would have higher power and finer resolution to identify genetic variants of modest effects compared to family-based linkage studies (Risch & Merikangas, 1996).
The success of identifying genes for age-related macular degeneration (AMD) under the GWAS paradigm (Klein et al., 2005) convinced the genetics community on the efficiency and feasibility of the GWAS approach to identify unknown disease-associated variants. This study used a commercial genotyping array and assayed about 100,000 SNPs throughout the human genome. It identified the association of complement factor H (CFH) with AMD. The success of finding a common risk allele with an odds ratio (OR) of 4.6 in a small sample set of 96 cases and 50 controls has generated considerable excitement in the genetics community. The p-value of the strongest SNP association surpassed the genome-wide significance threshold after the Bonferroni correction. More importantly, this finding was replicated in the following-up studies (Donoso et al., 2010). Undoubtedly, this encouraging finding raised the confidence among researchers to detect genetic variants that underlie various complex diseases through GWAS. In 2007, the Wellcome Trust Case Control Consortium (WTCCC) published the results of seven GWAS, including Bipolar Disorder, Coronary Artery Disease, Crohn's Disease, Hypertension, Rheumatoid Arthritis, Type 1 Diabetes, and Type 2 Diabetes (The Wellcome Trust Case Control Consortium, 2007). The WTCCC study is considered the starting point of large-scale GWAS (Visscher et al., 2012). Since then, an increasing number of GWAS have been conducted and over 10,000 loci have been reported to be significantly associated with at least one complex trait (see the web resource of GWAS catalog (Hindorff et al., 2009), http://www.genome.gov/gwastudies/).
With an influx of successful genome-wide association studies to identify genetic variations associated with complex diseases, an unprecedented wealth of knowledge has been accumulated for SNP–phenotype associations (McCarthy et al., 2008; Witte 2010; Manolio 2013). However, many SNP–disease associations do not lend themselves to molecular interpretations, because many of the identified loci are located outside of the coding regions. Even when a gene can be inferred to be causal, there is often a significant gap towards the understanding of the underlying molecular mechanisms (Schadt et al., 2005; McCarthy et al., 2008). Genome-wide eQTL mapping has been one effective approach to bridge this gap (Mackay et al., 2009). In eQTL studies, gene expression levels measured by high-throughput technologies, such as microarrays and RNA-Seq, are treated as quantitative traits. Marker genotypes are also collected from the same set of individuals, and statistical analyses are performed to detect associations between markers and expression traits. By simultaneously capturing many regulatory interactions, eQTLs offer valuable insights on the genetic architecture of expression regulation (Rockman and Kruglyak 2006). The ultimate goal of eQTL studies is to elucidate how genetic variations affect phenotypes by using gene expression levels as intermediate molecular phenotypes (Nica and Dermitzakis 2008). In this chapter, we provide an overview of the eQTL analysis workflow (Figure 14.1), introduce publicly available tools for analysis, and further discuss challenges and issues.
Data pre-processing
Genome-wide eQTL mapping considers high-density SNP genotype data and gene expression data from the same individuals in a segregating population. Both require appropriate pre-processing as described below for subsequent analysis.
Genotype data
Three quality control (QC) criteria are often used in the pre-processing of the genotype data. (1) Missing rate: individuals with a large proportion of missing SNP genotypes (e.g., 10%) should be excluded because the DNA samples of those individuals may be of poor quality. SNPs with a large missing rate (e.g., 5%) should also be filtered out. (2) Hardy–Weinberg Equilibrium (HWE): statistically significant deviations from HWE often result from genotyping errors. Therefore, SNPs that fail an exact HWE test (e.g., a P-value less than 0.001) should be filtered out. The criterion does not apply to haploid organisms, such as yeast. (3) Minor allele frequency (MAF): SNPs with low MAF (e.g., 0.05) are sometimes filtered out because of the insufficient statistical power for studies with a relatively small sample size and potentially higher genotype calling error.
from
Part C
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Vertical Integrative Analysis (Methods Specialized to Particular Data Types)
By
Cong Li, Yale University, New Haven, CT,
Can Yang, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China,
Greg Hather, Takeda Pharmaceuticals International Co., Cambridge, MA,
Ray Liu, Takeda Pharmaceuticals International Co., Cambridge, MA,
Hongyu Zhao, Yale University, New Haven, CT
Traditional drug discovery practices usually adopt the “one drug – one target” approach, which ignore the fact the disease occurrence is usually the result of an extremely complex combination of molecular events. Pathway-based approaches address this limitation by considering biological pathways as potential drug targets. A first step of pathwaybased drug discovery is to identify associations between drug candidates and biological pathways. This has been made possible by the availability of high-dimensional transcriptional and drug sensitivity profile data. In this chapter, we describe two statistical methods, “iFad” and “iPad”, which perform drug-pathway association analysis by integrating these two types high-dimensional data. We also demonstrate their utilities by applying them to the NCI-60 data set.
Introduction
Drug discovery is the process of identifying new candidate medications for diseases of interest. The common practice adopted by the pharmaceutical industry is to design maximally selective drug molecules to act on individual drug targets [11], which is usually referred to as the “one drug – one target” approach. This paradigm has indeed enjoyed some successes [27]. Yet, the last 15 years have witnessed a significant increase in the attrition rate of new candidate drugs due to their low efficacy and serious side effects [17, 29]. One fundamental reason for the decline in the productivity of the pharmaceutical industry may lie in the core philosophy of the “one drug – one target” approach [11]. Specifically, this philosophy ignores the fact that disease occurrence is usually the result of an extremely complex combination of molecular events [20] among certain sets of functionally related genes, usually referred to as “pathways”. Targeting an individual drug target may not provide sufficient interference to the whole disease-related pathway and therefore usually results in unsatisfactory efficacy. Moreover, it fails to consider the mechanism of a candidate drug at a systems level, making it extremely difficult to evaluate drug safety and toxicity in the early developmental stages [14]. Due to these limitations of the “one drug – one target” approach, a new concept of drug discovery – polypharmacology [6] – is emerging as a promising alternative for drug developments. Instead of targeting individual drug targets, polypharmacology seeks to design or find candidate drugs that interfere multiple molecular targets. For example, pathway-based drug discovery, which pursues candidate drugs that interfere the activity of a whole biological pathway, has become increasingly appealing.
Laser surface melting is one of the most important processes in laser material processing. Selective vaporization of alloying elements in laser melting offers fundamental understanding of laser processing on metallic alloys. This work provides linkage between laser melting and material properties using secondary ion mass spectrometry (SIMS) for tiny vaporized species in laser-generated plume and energy dispersive spectroscopy (EDS) for solid solution range in molten pool, both qualitatively and quantitatively (up to hundreds of micron). Silicon wafer was used to collect the generated plume. Chemical analysis was carried out on top surface and sub-surface of the deposited plume. Transport behavior as well as distribution of the vaporized species inside the plume was further proposed.
Background: Although accumulating research demonstrates the association between attentional bias and social anxiety, the bias for positive stimuli has so far not been adequately studied. Aims: The aim is to investigate the time-course of attentional bias for positive social words in participants with high and low social anxiety. Method: In a modified dot-probe task, word-pairs of neutral and positive social words were randomly presented for 100, 500, and 1250 milliseconds in a nonclinical sample of students to test their attentional bias. Results: Non-significant interaction of Group × Exposure Duration was found. However, there was a significant main effect of group, with significantly different response latencies between the high social anxiety (HSA) and low social anxiety (LSA) groups in the 100 ms condition, without for 500 or 1250 ms. With respect to attentional bias, the LSA group showed enhanced preferential attention for positive social words to which the HSA group showed avoidance in the 100 ms condition. In the 500 ms condition, preferential attention to positive social words was at trend in the LSA group, relative to the HSA group. Neither group showed attentional bias in the 1250 ms condition. Conclusions: These findings extend recent research about the attention training program and add to the empirical literature suggesting that the initial avoidance of positive stimuli may contribute to maintaining social anxiety.
The effects of total surface roughness of Cu bond layers and applied load during bonding on the bond strength and the contact resistance of the bonded interface were studied for three-dimensional (3D) devices. The 3D structures were fabricated by thermocompression bonding of two wafers, each fabricated with a Cu damascene process. The average bond strength of the samples was found to increase with increasing load, and with decreasing roughness. On the other hand, the average contact resistance increased as the total surface roughness of the bonded interface increased, as well as when the applied load decreased. The increase in bond strength (and also the dicing yield) is related to a smaller true contact area, which can be estimated using a model based on contact mechanics theory. The theory takes into account the roughness of the bonded surface, the applied load during bonding and the nominal bond area. A contact resistance model can also be used to estimate the contact resistance of bonded interfaces based on their true contact area. However, within each set of measurements, a significant spread about the average value of bond strength and contact resistance was observed, suggesting issues of contact and bonding non-uniformity of the wafers. Nonetheless, the contact resistance values given by the model were in good agreement with the minimum values observed in experiments, which may represent the ideal cases of bonding of rough surfaces. Our results show that the impact of surface roughness and applied load on the contact resistance of Cu-Cu thermocompression bonds can be quantified experimentally, and understood in the context of established theory for contact mechanics.
Electromigration (EM) in copper dual-damascene interconnects with extensions(also described as overhang regions or reservoirs) in the upper metal (M2) were investigated. It was found that as the extension length increases from 0 to 60 nm, the median-time-to-failure increased from 50 to 140 h, representing a ∼200% improvement in lifetimes. However, further increment of the extension length from 60 to 120 nm did not result in any significant improvement in EM lifetimes. Based on calculations of current densities in the reservoir regions and recently reported nucleation, void movement, and agglomeration-based EM phenomena, it is proposed that there is a critical extension length beyond which increasing extension lengths will not lead to longer EM lifetimes.
We have applied real time spectroellipsometry (RTSE) to study hydrogenated amorphous silicon (a-Si:H) solar cells fabricated in the Cr/n-i-p configuration using plasma-enhanced chemical vapor deposition (PECVD) in a single-chamber system. The microstructural evolution of the n-, i-, and p-layers of the devices has been determined, including the thicknesses of the bulk, interface, and surface roughness layers versus time. The optical properties of the individual layers, including the dielectric functions and optical gaps, have also been obtained in the same analysis. In this study, we have focused on i/p interface formation and, in particular, on the nucleation process for differently-prepared a-Si:C:H and mixed-phase μc-Si:H/a-Si1-xCx:H p-layers on the a-Si:H i-layer. From the thickness dependence of the p-layer void volume fraction, we can obtain an estimate of the thickness at which nuclei make contact to form a continuous film. For the mixed-phase p-layers, the nuclei contact thickness can be reduced by exposing the i-layer to a H2-plasma prior to p-layer deposition. We have found that for similarly-prepared p-layers this reduction in contact thickness leads to an increase in open-circuit voltage of the solar cell
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