Synthesis and Characterization of Novel Quinazoline Type Inhibitors for Mutant and Wild-Type EGFR and RICK Kinases

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97. A total of 52 quinazoline derivatives were synthesized and tested on the basis of these leads to specifically target the hydrophobic pocket of the ATP-binding site. Selected compounds were tested on wild-type and mutant forms of EGFR, RICK, and pUL97 kinases; their logP and logS values for assessing suitability as drugs were calculated and hit or lead compounds identified.     

Transcriptomic response to differentiation induction

Background  

Microarrays used for gene expression studies yield large amounts of data. The processing of such data typically leads to lists of differentially-regulated genes. A common terminal data analysis step is to map pathways of potentially interrelated genes.     

Dynamic localisation of Ran GTPase during the cell cycle

Background  

Ran GTPase has multiple functions during the cell division cycle, including nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. The activity of Ran is determined by both its guanine nucleotide-bound state and its subcellular localization.     

Effect of carbonate chemistry alteration on the early embryonic development of the Pacific oyster (Crassostrea gigas)

Ocean acidification, due to anthropogenic CO₂ absorption by the ocean, may have profound impacts on marine biota. Calcareous organisms are expected to be particularly sensitive due to the decreasing availability of carbonate ions driven by decreasing pH levels. Recently, some studies focused on the early life stages of mollusks that are supposedly more sensitive to environmental disturbances than adult stages. Although these studies have shown decreased growth rates and increased proportions of abnormal development under low pH conditions, they did not allow attribution to pH induced changes in physiology or changes due to a decrease in aragonite saturation state. This study aims to assess the impact of several carbonate-system perturbations on the growth of Pacific oyster (Crassostrea gigas) larvae during the first 3 days of development (until shelled D-veliger larvae). Seawater with five different chemistries was obtained by separately manipulating pH, total alkalinity and aragonite saturation state (calcium addition). Results showed that the developmental success and growth rates were not directly affected by changes in pH or aragonite saturation state but were highly correlated with the availability of carbonate ions. In contrast to previous studies, both developmental success into viable D-shaped larvae and growth rates were not significantly altered as long as carbonate ion concentrations were above aragonite saturation levels, but they strongly decreased below saturation levels. These results suggest that the mechanisms used by these organisms to regulate calcification rates are not efficient enough to compensate for the low availability of carbonate ions under corrosive conditions.     

Reproductive behaviour and vibratory communication of the neotropical predatory stink bug Podisus nigrispinus

Vibratory communication during reproductive behaviour is less well described in predatory (Asopinae) than in phytophagous (Pentatominae) stink bugs. Different steps in the mating behaviour of the predatory stink bug Podisus nigrispinus (Dallas) (Hemiptera: Pentatomidae; Asopinae) are described in the present study, together with vibratory signals emitted on artificial and natural substrate during courtship and copulation. Vibratory signals in Podisus nigrispinus have a decisive role in copulation success and are produced in both sexes by abdominal vibration and tremulation. In P. nigrispinus, one species‐specific female and two male songs, which do not show the calling function typically found in phytophagous stink bugs, are produced by abdominal vibration and are emitted during reproductive behaviour. Additionally, P. nigrispinus produces tremulatory signals that have no species or sex specificity. Tremulatory signals emitted spontaneously on a plant as a sequence of readily repeated pulses are similar to the calling songs of the Pentatominae stink bug. These signals may carry information on the presence of a mate; however, in other behavioural contexts, they may have a different function, such as advertisement or even alarm signals. Plants transmit vibratory signals produced by both mechanisms as a low‐pass filter, increasing the amount of low‐frequency components. The results of the present study raise important questions about the interaction between chemical and vibratory signals in the mating behaviour of predatory stink bugs.