Incorporating Betweenness Centrality in Compressive Sensing for Congestion Detection

This paper presents a new Compressive Sensing (CS) scheme for detecting network congested links. We focus on decreasing the required number of measurements to detect all congested links in the context of network tomography. We have expanded the LASSO objective function by adding a new term corresponding to the prior knowledge based on the relationship between the congested links and the corresponding link Betweenness Centrality (BC). The accuracy of the proposed model is verified by simulations on two real datasets. The results demonstrate that our model outperformed the state-of-the-art CS based method with significant improvements in terms of F-Score

GENETIC DISSECTION OF THE MYC-INDUCED DNA DAMAGE RESPONSE

In pre-cancerous lesions the overexpression of oncogenes such as Myc not only drives aberrant cellular proliferation, but also triggers a strong DNA damage response (DDR) that is in part due to DNA damage accumulating at the level of stalled replication forks. This oncogene-induced DDR is an effective barrier to cancer development and represents a relevant tumor suppressive mechanism. Conversely, at later stages of malignancy DDR signaling may function in favor of cancer progression. Such tumor promoting role of DDR may be needed for cancer cells to avoid accumulation of cytotoxic DNA damage under high level of oncogene-induced replication stress. Recently it has been shown that targeting regulators of replication checkpoint such as ATR or Chk1 in Myc-overexpressing cells caused apoptosis and prevented tumor formation, suggesting a crucial role for this pathway in ensuring cancer cell viability and offering the chance of developing new targeted therapies against cancer cells. In an effort to identify the modulators of Myc-induced replicative stress, we carried out a high-throughput RNAi screen based on immunofluorescence detection of \u3d2H2AX, a DNA damage marker. Quantification of the number of cells and the percentage of \u3d2H2AX-positive cells, identified hits that exhibited differential cell viability (synthetic lethal hits) and/or enhanced \u3d2H2AX signal (DDR-up hits) in Myc-overexpressing cells compared to normal cells. Validated hits encompass a variety of pathways and biological processes and have different molecular functions. As a proof of principal, we selected SRSF3 and Cdk12 and confirmed the synergistic effect of Myc overexpression and depletion of SRSF3 or Cdk12 on accumulation of cytotoxic DNA damage response as marked by H2AX phosphorylation. For further mechanistic investigations, we selected Rad21, a component of the cohesin complex, which was also reported as a Myc-synthetic lethal candidate previously. Using small inhibitory RNAs against Rad21, we confirmed that depletion of Rad21, increased \u3d2H2AX level and subsequently led to cell death, selectively in Myc-overexpressing cells. We provide evidence that while Rad21 is necessary for proper and efficient DNA synthesis, replication reinforcement imposed by Myc overexpression in Rad21-depleted cells results in replicative stress. In addition, we observed that Myc, as a transcription factor, could partially rescue transcriptional alterations due to Rad21 depletion. The conflicts between DNA replication and transcription in Rad21-depleted cells upon Myc activation may be the source of increased R-loops detected in these cells. In summary, by means of a genetic loss of function screen we identified several candidates that may be involved in protecting Myc-overexpressing cells against ample replicative stress, thus revealing targets for potential therapeutic intervention in Myc-driven cancers

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Data-analysis strategies for image-based cell profiling

Image-based cell profiling is a high-throughput strategy for the quantification of phenotypic differences among a variety of cell populations. It paves the way to studying biological systems on a large scale by using chemical and genetic perturbations. The general workflow for this technology involves image acquisition with high-throughput microscopy systems and subsequent image processing and analysis. Here, we introduce the steps required to create high-quality image-based (i.e., morphological) profiles from a collection of microscopy images. We recommend techniques that have proven useful in each stage of the data analysis process, on the basis of the experience of 20 laboratories worldwide that are refining their image-based cell-profiling methodologies in pursuit of biological discovery. The recommended techniques cover alternatives that may suit various biological goals, experimental designs, and laboratories' preferences.Peer reviewe

Association between cancer risk and polycyclic aromatic hydrocarbons� exposure in the ambient air of Ahvaz, southwest of Iran

Nowadays, a large number of health endpoints such as disease rates, treatment costs, and death, by air pollutants, have been a serious health problem for humans. One of the most hazardous air pollutants, which is highly dangerous for human health, is polycyclic aromatic hydrocarbons (PAHs). The existence of the emission of industries� pollutants and seasonal variations are the primary agents affecting PAHs� concentration. The purposes of this study were to calculate the cancer risk and measure PAHs� exposure in the ambient air of Ahvaz, southwest of Iran, during 2017. Three distinct areas ((S1) industrial, (S2) high traffic, and (S3) residential) of Ahvaz metropolitan were selected. Omni sampler equipped with polytetrafluoroethylene (PTFE) filters were used for active sampling of PAHs. To detect the level of PAHs, gas chromatography with mass spectrometry (GC/MS) was used. Incremental lifetime cancer risk (ILCR) and lifetime average daily dose (LADD) were used to estimate the health risk caused by PAHs. The results showed that the residential and industrial areas had the lowest and highest level of PAHs. Moreover, the average levels of PAHs in industrial, high traffic, and residential areas were 8.44 ± 3.37, 7.11 ± 2.64, and 5.52 ± 1.63 ng m�3, respectively. Furthermore, ILCR in autumn and winter was higher than EPA standard, 0.06307 and 0.04718, respectively. In addition, ILCR in different areas was significantly higher than standard. Research findings imply that the levels of exposure to PAHs can increase ILCR and risk of health endpoint. The cancer risk attributed to PAHs should be further investigated from the perspective of the public health in metropolitans. © 2018, ISB