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The low efficiency of somatic cell nuclear transfer (SCNT) greatly limits its application. Compared with the fertilized embryo, cloned embryos display abnormal epigenetic modification and other inferior developmental properties. In this study, small RNAs were isolated, and miR-34c and miR-125b were quantified by real-time PCR; results showed that these micro-RNAs were highly expressed in sperm. The test sample was divided into three groups: one was the fertilized group, one was the SCNT control group (NT-C group), and the third group consisted of SCNT embryos injected with sperm-borne small RNA (NT-T group). The level of tri-methylation of lysine 9 on histone H3 (H3K9me3) at the 8-cell stage was determined by immunofluorescence staining, and the cleavage ratio, blastocyst ratio, apoptotic cell index of the blastocyst and total cell number of blastocysts in each group were analyzed. Results showed that the H3K9me3 level was significantly higher in the NT-C group than in the fertilized group and the NT-T group. The apoptosis index of blastocysts in the NT-C group was significantly higher than that in the fertilized group and the NT-T group. The total cell number of SCNT embryos was significantly lower than that of fertilized embryos, and injecting sperm-borne small RNAs could significantly increase the total cell number of SCNT blastocysts. Our study not only demonstrates that sperm-borne small RNAs have an important role in embryo development, but also provides a new strategy for improving the efficiency of SCNT in rabbit.
ABSTRACT IMPACT: Screening the effect of thousands of non-coding genetic variants will help identify variants important in the etiology of diseases OBJECTIVES/GOALS: Massively parallel reporter assays (MPRAs) can experimentally evaluate the impact of genetic variants on gene expression. In this study, our objective was to systematically evaluate the functional activity of 3’-UTR SNPs associated with neurological disorders and use those results to help understand their contributions to disease etiology. METHODS/STUDY POPULATION: To choose variants to evaluate with the MPRA, we first gathered SNPs from the GWAS Catalog that were associated with any neurological disorder trait with p-value < 10-5. For each SNP, we identified the region that was in linkage disequilibrium (r2 > 0.8) and retrieved all the common 3’-UTR SNPs (allele-frequency > 0.05) within that region. We used an MPRA to measure the impact of these 3’-UTR variants in SH-SY5Y neuroblastoma cells and a microglial cell line. These results were then used to train a deep-learning model to predict the impact of variants and identify features that contribute to the predictions. RESULTS/ANTICIPATED RESULTS: Of the 13,515 3’-UTR SNPs tested, 400 and 657 significantly impacted gene expression in SH-SY5Y and microglia, respectively. Of the 84 SNPs significantly impacted in both cells, the direction of impact was the same in 81. The direction of eQTL in GTEx tissues agreed with the assay SNP effect in SH-SY5Y cells but not microglial cells. The deep-learning model predicted sequence activity level correlated with the experimental activity level (Spearman’s corr = 0.45). The deep-learning model identified several predictive motifs similar to motifs of RNA-binding proteins. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study demonstrates that MPRAs can be used to evaluate the effect of non-coding variants, and the results can be used to train a machine learning model and interpret its predictions. Together, these can help identify causal variants and further understand the etiology of diseases.
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.
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.
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.
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.
An 8-week feeding experiment was conducted to investigate the effects of dl-methionine (Met) supplementation in a low-fishmeal diet on growth, key gene expressions of amino acid transporters and target of rapamycin (TOR) pathway in juvenile cobia, Rachycentron canadum. Seven isonitrogenous and isolipidic diets were formulated, containing 0·72, 0·90, 1·00, 1·24, 1·41, 1·63 and 1·86 % Met. Weight gain and specific growth rates increased gradually with Met levels of up to 1·24 % and then decreased gradually. In dorsal muscle, mRNA levels of ASCT2 in the 1·00 % Met group were significantly up-regulated compared with 0·72, 1·63, and 1·86 %. The insulin-like growth factor-I (IGF-I) mRNA levels in the dorsal muscle of fish fed 1·00 and 1·24 % Met were higher than those in fish fed other Met levels. In addition, fish fed 1·24 % Met showed the highest mRNA levels of TOR and phosphorylation of TOR on Ser2448. The phosphorylation of ribosomal p70-S6 kinase (S6K) on Ser371 in the dorsal muscle of fish fed 1·86 % Met was higher than those in the 0·72 % group. In conclusion, straight broken-line analysis of weight gain rate against dietary Met level indicates that the optimal Met requirement for juvenile cobia is 1·24 % (of DM, or 2·71 % dietary protein). Met supplementation in a low-fishmeal diet increased cobia growth via a mechanism that can partly be attributed to Met’s ability to affect the TOR/S6K signalling pathway by enhancing ASCT2 and IGF-I transcription in cobia dorsal muscle.
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.
This paper is concerned with the invisibility cloaking in acoustic wave scattering from a new perspective. We are especially interested in achieving the invisibility cloaking by completely regular and isotropic mediums. It is shown that an interior transmission eigenvalue problem arises in our study, which is the one considered theoretically in Cakoni et al. (Transmission eigenvalues for inhomogeneous media containing obstacles, Inverse Problems and Imaging, 6 (2012), 373–398). Based on such an observation, we propose a cloaking scheme that takes a three-layer structure including a cloaked region, a lossy layer and a cloaking shell. The target medium in the cloaked region can be arbitrary but regular, whereas the mediums in the lossy layer and the cloaking shell are both regular and isotropic. We establish that if a certain non-transparency condition is satisfied, then there exists an infinite set of incident waves such that the cloaking device is nearly invisible under the corresponding wave interrogation. The set of waves is generated from the Herglotz approximation of the associated interior transmission eigenfunctions. We provide both theoretical and numerical justifications.
The purpose of this paper is to numerically realize the inverse scattering scheme proposed in  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 . Moreover, we develop a two-stage technique, which can significantly speed up the reconstruction to yield a fast imaging scheme.
Usually, the high-power microwave (HPM) devices suffer from impedance collapse and cathode material degradation or even failure. When the intense electron beam bombards the anode (or named as collector in HPM device), an anode plasma could appear under certain conditions. In this case, the impedance collapse is caused by the expansions of the cathode and anode plasmas and diode current overshot caused by the bipolar flow. In this paper, characterization of a short-pulse high-power diode operated with anode effects with a dielectric fiber (velvet) cathode is discussed. The bipolar flow (or anode plasma) is indeed evident at beam power densities ~11 MW/cm2 and the pulse durations of ~50 ns. The analysis results of the deposit dose and thermal regime of the anode show that the electron stimulated desorption played an important role in the generation of anode plasma in this case. With the effect of anode plasma, the appearance of local cathode plasma flares (or nonuniform electron emission) is particularly detrimental for the diode closure. Micro-structure and elemental surface compositions of cathode are changed by the anode splashing, which is very harmful to the performance of cathode.
Vertical Integrative Analysis (Methods Specialized to Particular Data Types)
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.
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 , which is usually referred to as the “one drug – one target” approach. This paradigm has indeed enjoyed some successes . 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 . Specifically, this philosophy ignores the fact that disease occurrence is usually the result of an extremely complex combination of molecular events  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 . Due to these limitations of the “one drug – one target” approach, a new concept of drug discovery – polypharmacology  – 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.
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
Hydrogenated amorphous silicon (a-Si:H) TCO/n+/i/Ni Schottky barrier solar cells were degraded with illuminations of white and red light through both sides of the structure. Because the forward dark I-V's are sensitive to the distribution and any spatial variation of defects in the i-layer, these measurements were used to characterize the degraded cell structures. These characteristics were analyzed using a charged defect distribution of gap states consisting of D+, D°, and D states derived from corresponding film analysis. It was found that the non-uniformities of light induced defects created in the i-layer can be represented by two regions of different defect densities. The relative densities depend on the direction of illumination and their ratio even with white light is about a factor of four. This non-uniformity is expected to be less for p-i-n cells which have higher built-in potential and hence electric fields.
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