Parallel In Vivo and In Vitro Melanoma RNAi Dropout Screens Reveal Synthetic Lethality between Hypoxia and DNA Damage Response Inhibition

SummaryTo identify factors preferentially necessary for driving tumor expansion, we performed parallel in vitro and in vivo negative-selection short hairpin RNA (shRNA) screens. Melanoma cells harboring shRNAs targeting several DNA damage response (DDR) kinases had a greater selective disadvantage in vivo than in vitro, indicating an essential contribution of these factors during tumor expansion. In growing tumors, DDR kinases were activated following hypoxia. Correspondingly, depletion or pharmacologic inhibition of DDR kinases was toxic to melanoma cells, including those that were resistant to BRAF inhibitor, and this could be enhanced by angiogenesis blockade. These results reveal that hypoxia sensitizes melanomas to targeted inhibition of the DDR and illustrate the utility of in vivo shRNA dropout screens for the identification of pharmacologically tractable targets

Robust Graph-Based Semisupervised Learning for Noisy Labeled Data via Maximum Correntropy Criterion.

Semisupervised learning (SSL) methods have been proved to be effective at solving the labeled samples shortage problem by using a large number of unlabeled samples together with a small number of labeled samples. However, many traditional SSL methods may not be robust with too much labeling noisy data. To address this issue, in this paper, we propose a robust graph-based SSL method based on maximum correntropy criterion to learn a robust and strong generalization model. In detail, the graph-based SSL framework is improved by imposing supervised information on the regularizer, which can strengthen the constraint on labels, thus ensuring that the predicted labels of each cluster are close to the true labels. Furthermore, the maximum correntropy criterion is introduced into the graph-based SSL framework to suppress labeling noise. Extensive image classification experiments prove the generalization and robustness of the proposed SSL method

An Analysis of Conductor Surface Roughness Effects on Signal Propagation for Stripline Interconnects

Conductors with a roughened surface have significant effects on high-speed signal propagation on backplane traces designed for a 10+ Gb/s network. An accurate approach to evaluate these effects, including the signal attenuation and the phase delay, is proposed in this paper. A differential extrapolation roughness measurement technique is first used to extract the dielectric properties of the substrate used for lamination, and then a periodic model is used to calculate an equivalent roughened conductor surface impedance, which is then used to modify the transmission line per-unit-length parameters R and L. The results indicate that the conductor surface roughness increases the conductor loss significantly as well as noticeably increasing the effective dielectric constant. This approach is validated using both a full-wave simulation tool and measurements, and is shown to be able to provide robust results for the attenuation constant within ±0.2 Np/m up to 20 GHz

Multiple group I introns in the small-subunit rDNA of Botryosphaeria dothidea: implication for intraspecific genetic diversity.

Botryosphaeria dothidea is a widespread and economically important pathogen on various fruit trees, and it often causes die-back and canker on limbs and fruit rot. In characterizing intraspecies genetic variation within this fungus, group I introns, rich in rDNA of fungi, may provide a productive region for exploration. In this research, we analysed complete small subunit (SSU) ribosomal DNA (rDNA) sequences of 37 B. dothidea strains, and found four insertions, designated Bdo.S943, Bdo.S1199-A, Bdo.S1199-B and Bdo.S1506, at three positions. Sequence analysis and structure prediction revealed that both Bdo.S943 and Bdo.S1506 belonged to subgroup IC1 of group I introns, whereas Bdo.S1199-A and Bdo.S1199-B corresponded to group IE introns. Moreover, Bdo.S1199-A was found to host an open reading frame (ORF) for encoding the homing endonuclease (HE), whereas Bdo.S1199-B, an evolutionary descendant of Bdo.S1199-A, included a degenerate HE. The above four introns were novel, and were the first group I introns observed and characterized in this species. Differential distribution of these introns revealed that all strains could be separated into four genotypes. Genotype III (no intron) and genotype IV (Bdo.S1199-B) were each found in only one strain, whereas genotype I (Bdo.S1199-A) and genotype II (Bdo.S943 and Bdo.S1506) occurred in 95% of the strains. There is a correlation between B. dothidea genotypes and hosts or geographic locations. Thus, these newly discovered group I introns can help to advance understanding of genetic differentiation within B. dothidea

Design Methodology for Behavioral Surface Roughness Model

The surface roughness of copper foils has a considerable impact on the signal integrity performance of transmission lines at high data rates and long propagation distances. Existing surface roughness models for low-loss transmission lines are inadequate for accurate characterization. A new behavioral model for analyzing the surface roughness effects has been developed. The model is applied in the design process by adding a dispersive term to the bulk dielectric to represent the loss due to the foil surface roughness. By adding a broadband dielectric model into the original transmission model, time- and frequency-domain performance improvements are achieved

Neuromagnetic abnormality of motor cortical activation and phases of headache attacks in childhood migraine.

The cerebral cortex serves a primary role in the pathogenesis of migraine. This aberrant brain activation in migraine can be noninvasively detected with magnetoencephalography (MEG). The objective of this study was to investigate the differences in motor cortical activation between attacks (ictal) and pain free intervals (interictal) in children and adolescents with migraine using both low- and high-frequency neuromagnetic signals. Thirty subjects with an acute migraine and 30 subjects with a history of migraine, while pain free, were compared to age- and gender-matched controls using MEG. Motor cortical activation was elicited by a standardized, validated finger-tapping task. Low-frequency brain activation (1~50 Hz) was analyzed with waveform measurements and high-frequency oscillations (65-150 Hz) were analyzed with wavelet-based beamforming. MEG waveforms showed that the ictal latency of low-frequency brain activation was significantly delayed as compared with controls, while the interictal latency of brain activation was similar to that of controls. The ictal amplitude of low-frequency brain activation was significantly increased as compared with controls, while the interictal amplitude of brain activation was similar to that of controls. The ictal source power of high-frequency oscillations was significantly stronger than that of the controls, while the interictal source power of high-frequency oscillations was significantly weaker than that of controls. The results suggest that aberrant low-frequency brain activation in migraine during a headache attack returned to normal interictally. However, high-frequency oscillations changed from ictal hyper-activation to interictal hypo-activation. Noninvasive assessment of cortical abnormality in migraine with MEG opens a new window for developing novel therapeutic strategies for childhood migraine by maintaining a balanced cortical excitability

Distribution of the different introns across hosts and populations.

<p>Four different colours represent four populations divided by presence or absence and types of introns. Hosts for each population are listed in the corresponding colours. Ratios of the four populations are marked at the relevant position of the pie chart.</p

His-Cys box homing endonucleases used for alignment.

<p>Note: ACT: Enzyme with demonstrated activity; FL: predicted full-length ORF.</p

Pairwise alignment between Bdo.S1199-A and Bdo.S1199-B.

<p>The two bars refer to the RNA sequences of Bdo.S1199-A (left) and Bdo.S1199-B (right), respectively. The pink bars correspond to the identical regions of two sequences. The purple stripes on the bars point to SNPs or insertion position whereas the white areas represent deletions.</p