Synthetic lethality of PARP inhibition in BRCA-network disrupted tumor cells is associated with interferon pathway activation and enhanced by interferon-γ

Tumor suppressor genes BRCA1 and BRCA2 function in a complex gene network that regulates homologous recombination and DNA double-strand break repair. Disruption of the BRCA-network through gene mutation, deletion, or RNAi-mediated silencing can sensitize cells to small molecule inhibitors of poly (ADP-ribose) polymerase (PARPi). Here, we demonstrate that BRCA-network disruption in the presence of PARPi leads to the selective induction and enhancement of interferon pathway and apoptotic gene expression in cultured tumor cells. In addition, we report PARPi cytotoxicity in BRCA1-deficient tumor cells is enhanced >10-fold when combined with interferon-γ. These findings establish a link between synthetic lethality of PARPi in BRCA-network disrupted cells and interferon pathway activation triggered by genetic instability.     

SPATIOTEMPORAL VARIATION IN LINEAR NATURAL SELECTION ON BODY COLOR IN WILD GUPPIES (POECILIA RETICULATA)

We conducted 10 mark–recapture experiments in natural populations of Trinidadian guppies to test hypotheses concerning the role of viability selection in geographic patterns of male color variation. Previous work has reported that male guppies are more colorful in low‐predation sites than in high‐predation sites. This pattern of phenotypic variation has been theorized to reflect differences in the balance between natural (viability) selection that disfavors bright male color (owing to predation) and sexual selection that favors bright color (owing to female choice). Our results support the prediction that male color is disfavored by viability selection in both predation regimes. However, it does not support the prediction that viability selection against male color is weaker in low‐predation experiments. Instead, some of the most intense bouts of selection against color occurred in low‐predation experiments. Our results illustrate considerable spatiotemporal variation in selection among experiments, but such variation was not generally correlated with local patterns of color diversity. More complex selective interactions, possibly including the indirect effects of predators on variation in mating behavior, as well as other environmental factors, might be required to more fully explain patterns of secondary sexual trait variation in this system.     

Exclusion of the HLA locus from a large portion of the long arm of chromosome 6.

HLA antigens were determined in two infants with multiple congenital anomalies and in their healthy parents and one sibling. One infant had a deletion of a major portion of the long arm of chromosome 6. The other child had a translocation of a similar piece of chromosome 6 to the short arm of chromosome 3. The mother and the maternal grandmother showed this translocation in a balanced state. The HLA types of both children and their parents exclude the localization of the major histocompatibility locus from the deleted or translocated portion of the long arm of chromosome 6.     

Thermometry and dosimetry of heat with specific reference to the liquid-crystal optical fiber temperature probe

Summary A temperature sensing probe was designed utilizing the unique optical properties of thermotropic liquid crystals. An electronic and fiberoptic system coupled to the sensor was used to monitor temperature-dependent interactions of light (660 nm) with the liquid crystal mixture. The probe is a nonmetallic, nonperturbing thermal sensor for continuous temperature measurements of biological specimens subjected to electromagnetic fields. The advantages and disadvantages of the Liquid Crystal Optical Fiber (LCOF) temperature probe are discussed along with some typical applications where accurate dosimetry and thermometry are important parameters in experimental studies.     

Quiescent human diploid fibroblasts. Common mechanism for inhibition of DNA replication in density-inhibited and serum-deprived cells

The mechanism for cessation of proliferation in density-inhibited quiescent human diploid fibroblasts (HDF) and serum-deprived quiescent HDF was compared in two ways. Density-inhibited HDF were fused to either replicating HDF or SV40-transformed HDF and DNA synthesis was measured in the resulting heterokaryons. DNA synthesis was inhibited in the replicating HDF nuclei in heterokaryons in a way that suggested that entry into S phase was blocked, but ongoing DNA synthesis was not inhibited. In contrast, DNA synthesis was induced in the quiescent nuclei in heterokaryons formed with SV40-transformed HDF. Previous experiments had shown that serum-deprived HDF also behave in this way in heterokaryons. To test this similarity further, we examined the inhibitory activity of cell membranes prepared from both types of quiescent HDF. We found that both types of quiescent HDF contain DNA synthesis-inhibitory activity that is (1) effective on replicating HDF; (2) ineffective on SV40-transformed HDF; (3) sensitive to heat and trypsin. Thus, these results support the hypothesis that both density-inhibited HDF and serum-deprived HDF share a common mechanism for arrest in G1 phase. They also suggest that a membrane-bound protein plays a role in the inhibition of DNA synthesis in quiescent HDF.     

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: Dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors—Part II

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT_1A/B/D receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.     

Effect of dung burial by the dung beetle Bubas bison on numbers and viability of Cryptosporidium oocysts in cattle dung

Cryptosporidium oocysts were inoculated into fresh dung (∼1.2 × 10⁴ oocysts per gram wet weight) and fed to dung beetles to assess the effect of dung burial by the dung beetle Bubas bison on the distribution of the oocysts in small cores of soil in the laboratory. The experiment consisted of five replicates of each of two treatments; controls (dung but no dung beetles) and the experimental treatment (inoculated dung and seven pairs of dung beetles). After 5 days, when approximately 90% of the dung was buried, the surface and buried dung was recovered and subsampled. The oocysts in the subsamples were recovered and enumerated using qPCR. Oocyst viability was evaluated using an assay based on the exclusion or inclusion of two fluorogenic vital dyes, 4′,6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI). Results revealed that overall 13.7% of oocysts remained on the surface and 86.3% of oocysts were buried. The viability of oocysts in buried dung was only 10% compared to oocysts the surface dung (58%). Therefore, widespread dung burial by B. bison during the winter months could substantially reduce the numbers of Cryptosporidium oocysts available to be washed into waterways following winter rains.