Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2: Pyridone- and pyrimidinone-derived systems

Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).     

Contamination detection by optical measurements in a real‐life environment: A hospital case study

Organic dirt on touch surfaces can be biological contaminants (microbes) or nutrients for those but is often invisible by the human eye causing challenges for evaluating the need for cleaning. Using hyperspectral scanning algorithm, touch surface cleanliness monitoring by optical imaging was studied in a real‐life hospital environment. As the highlight, a human eye invisible stain from a dirty chair armrest was revealed manually with algorithms including threshold levels for intensity and clustering analysis with two excitation lights (green and red) and one bandpass filter (wavelength λ = 500 nm). The same result was confirmed by automatic k‐means clustering analysis from the entire dirty data of visible light (red, green and blue) and filters 420 to 720 nm with 20 nm increments. Overall, the collected touch surface samples (N = 156) indicated the need for cleaning in some locations by the high culturable bacteria and adenosine triphosphate counts despite the lack of visible dirt. Examples of such locations were toilet door lock knobs and busy registration desk armchairs. Thus, the studied optical imaging system utilizing the safe visible light area shows a promising method for touch surface cleanliness evaluation in real‐life environments.     

Can small‐scale experiments predict ecosystem responses? An example from peatlands

Oligotrophic, Sphagnum -dominated peatlands have been regarded as long-term stable ecosystems that function as carbon sinks. As a result of environmental perturbations, particularly anthropogenic N deposition, this view is now increasingly questioned. We examined whether small-scale field experiments can predict the direction and magnitude of ecosystem responses to increased N supply. We, therefore, compared data from a 10-year field experiment (involving deposition of 2, 15 and 30 kg N ha⁻¹ year⁻¹) with data from a gradient associated with increased N deposition (2, 8 and 12 kg N ha⁻¹ year⁻¹). We chose to compare: (1) the physiological response of Sphagnum balticum , measured in the form of N accumulation as free amino acids (N_AA); and (2) changes in the total Sphagnum cover, the cover of S. balticum , and vascular plant cover. In all cases we found a highly significant correlation between the two data sets. We attribute the high correspondence between the two data sets to the key function of the dominant group of organisms, the Sphagna, that monopolize N availability and control the water balance, creating an environment hostile to vascular plants. Thus the key role of Sphagna as ecosystem engineers seems to supersede the role of other, scale-dependent processes. We also conclude that N_AA is a sensitive indicator that can be used to signal the slow and gradual shift from Sphagnum to vascular plant dominance.     

FinnPRIO: a model for ranking invasive plant pests based on risk

The number of plant pests that may be transported to new areas with international trade is too great for subjecting all of them to a full scale pest risk assessment. There is therefore a need for a quick risk assessment procedure that also ranks the pests according to their risk. The FinnPRIO model can be used to assess the risk of alien plant pests for Finland. It follows the basic structure of a full scale pest risk assessment, i.e. it can be used to separately estimate the probabilities of entry, establishment (including spread), and the likely impacts. The model also includes a section for assessing preventability and controllability of a pest invasion. The model consists of multiple-choice questions with answer options yielding a different number of points. For each question the most likely answer option and the plausible minimum and maximum options are chosen. The total risk score is simulated using a PERT distribution, providing a scale of potential risk for each pest and indicating the level of uncertainty associated with the assessment. The model is accompanied by a guide for the interpretation of the questions and answer options. The model’s functionality has been tested through simulations, and it has been validated by comparing pest rankings produced using the model to those obtained in expert workshops. To date, 95 pests have been assessed with the model. The results indicate that the model is well capable of differentiating pests based on their estimated risk.     

Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells

Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition.     

Some effects of processing on the molecular structure and morphology of thermoplastic starch

Hydroxypropylated and oxidised potato starch (HONPS) was used together with glycerol and water to produce thermoplastic starch. The amount of glycerol was kept constant at 22 parts by weight per 100 parts of dry starch. The thermoplastic starch was converted into films/sheets using three different processing techniques; casting, compression moulding and film blowing. The last two methods represent typical thermoplastic conversion techniques requiring elevated processing temperatures. By means of size-exclusion chromatography, it was found that compression moulding and film blowing led to some degradation of high-molecular weight amylopectin as well as of high-molecular weight amylose-like molecules. The degradation was significantly less pronounced for the cast films. The morphology of the specimens was quite complex and phase separations on different levels were identified. In the cast films and, to a lesser extent, in the compression-moulded specimens, a fine network structure could be distinguished. Such a structure could however not be ascertained in the film-blown material and this is discussed in terms of the thermo-mechanical treatment of the starch materials.