Drug-induced resistance evolution necessitates less aggressive treatment

Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.     

Food‐web structure and mercury dynamics in a large subarctic lake following multiple species introductions

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Adenovirus-mediated gene transfer of Lp-PLA2 reduces LDL degradation and foam cell formation in vitro

Oxidation of LDL generates biologically active platelet-activating factor (PAF)-like phospholipid derivatives, which have potent proinflammatory activity. These products are inactivated by lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme capable of hydrolyzing PAF-like phospholipids. In this study, we generated an adenovirus (Ad) encoding human Lp-PLA2 and injected 10(8), 10(9), and 10(10) plaque-forming unit doses of Adlp-PLA2 and control AdlacZ intra-arterially into rabbits to achieve overexpression of Lp-PLA2 in liver and in vivo production of Lp-PLA2-enriched LDL. As a result, LDL particles with 3-fold increased Lp-PLA2 activity were produced with the highest virus dose. Increased Lp-PLA2 activity in LDL particles decreased the degradation rate in RAW 264 macrophages after standard in vitro oxidation to 60-80% compared with LDL isolated from LacZ-transduced control rabbits. The decrease was proportional to the virus dose and Lp-PLA2 activity. Lipid accumulation and foam cell formation in RAW 264 macrophages were also decreased when incubated with oxidized LDL containing the highest Lp-PLA2 activity. Inhibition of the Lp-PLA2 activity in the LDL particles led to an increase in lipid accumulation and foam cell formation. It is concluded that increased Lp-PLA2 activity in LDL attenuates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages.     

Length measurement accuracy of adaptive resolution imaging sonar and a predictive model to assess adult Atlantic salmon (Salmo salar) into two size categories with long-range data in a river

Imaging sonars are used around the world for fish population monitoring. The accuracy of the length measurements has been reported in multiple studies for relatively short (<15 m) ranges and high image resolution. However, imaging sonars are often used at longer ranges (i.e., >15 m) where the images produced from sonar returns become less detailed. The accuracy of the length measurements from the Adaptive Resolution Imaging Sonar (ARIS) was tested by releasing n = 69 known-sized adult Atlantic salmon (Salmo salar) directly into the sonar field at ranges between 15 and 29 m, and measuring their echoes manually by four users and semi-automatically using a computer workflow in Echoview software. Overall, the length measurements were very variable: compared to true (fork) lengths, the mean of differences varied between −9.9 cm and 7.8 cm in the human-generated datasets, and between −42.8 cm and −20 cm in the computer-generated dataset. In addition, the length measurements in different datasets were only in poor or moderate agreement with each other (intraclass correlation <0.61). Contrary to our expectations, the distance from the transducer or the subjectively assessed echo quality did not have an effect on the measurement accuracy in most of the datasets and when it did, the effect was not systematic between the datasets. Therefore, a size class and length prediction model was implemented in a Bayesian framework to group salmon into two size categories: One-Sea-Winter (<63 cm) and Multi-Sea-Winter (≥63 cm) groups. The model correctly predicted the size category in 83% of the fish in the computer-generated dataset and ranged from 68% to 74% in the human-generated datasets. We conclude that fish length measurements derived from long-range imaging sonar data should be used with caution, but post-processing can improve the usefulness of the data for specific purposes, such as adult Atlantic salmon population monitoring.     

Increasing frequency of low summer precipitation synchronizes dynamics and compromises metapopulation stability in the Glanville fritillary butterfly

Climate change is known to shift species'' geographical ranges, phenologies and abundances, but less is known about other population dynamic consequences. Here, we analyse spatio-temporal dynamics of the Glanville fritillary butterfly (Melitaea cinxia) in a network of 4000 dry meadows during 21 years. The results demonstrate two strong, related patterns: the amplitude of year-to-year fluctuations in the size of the metapopulation as a whole has increased, though there is no long-term trend in average abundance; and there is a highly significant increase in the level of spatial synchrony in population dynamics. The increased synchrony cannot be explained by increasing within-year spatial correlation in precipitation, the key environmental driver of population change, or in per capita growth rate. On the other hand, the frequency of drought during a critical life-history stage (early larval instars) has increased over the years, which is sufficient to explain the increasing amplitude and the expanding spatial synchrony in metapopulation dynamics. Increased spatial synchrony has the general effect of reducing long-term metapopulation viability even if there is no change in average metapopulation size. This study demonstrates how temporal changes in weather conditions can lead to striking changes in spatio-temporal population dynamics.     

NF1 gene expression in mouse fracture healing and in experimental rat pseudarthrosis.

Neurofibromatosis type 1 (NF1) is an inherited disease with an incidence of about 1:3000 worldwide. Approximately half of all patients with NF1 present osseous manifestations, which can vary from mild to severely debilitating changes such as congenital pseudarthrosis. In the present study, fracture healing of mouse tibia was followed and specimens were collected 5, 9, 14, and 22 days postoperatively. Experimental pseudarthrosis of rat was followed up to 15 weeks postoperatively. In situ hybridization and immunohistochemistry were used to demonstrate expression of NF1 tumor suppressor and phosphorylated p44/42 mitogen-activated protein kinase (MAPK), an indicator of the Ras-MAPK pathway. The results showed that ossified callus was formed in mouse fracture 22 days after the operation. The final outcome of rat pseudarthrosis was detected 9 weeks after the operation, presenting abundant cartilaginous callus at the pseudarthrosis. NF1 gene expression was noted in the maturing and in the hypertrophic cartilages during normal mouse fracture healing, and in rat pseudarthrosis. Phosphorylated p44/42 MAPK was detected in a subpopulation of the hypertrophic chondrocytes in both models. Furthermore, positive labeling for NF1 mRNA and protein was detected in endothelium in both the pseudarthrosis and in the fracture. In conclusion, NF1 gene expression and function are needed for normal fracture healing, possibly restraining excessive Ras-MAPK pathway activation.     

Using the nonlinear control of anaesthesia-induced hypersensitivity of EEG at burst suppression level to test the effects of radiofrequency radiation on brain function

Background  

In this study, investigating the effects of mobile phone radiation on test animals, eleven pigs were anaesthetised to the level where burst-suppression pattern appears in the electroencephalogram (EEG). At this level of anaesthesia both human subjects and animals show high sensitivity to external stimuli which produce EEG bursts during suppression. The burst-suppression phenomenon represents a nonlinear control system, where low-amplitude EEG abruptly switches to very high amplitude bursts. This switching can be triggered by very minor stimuli and the phenomenon has been described as hypersensitivity. To test if also radio frequency (RF) stimulation can trigger this nonlinear control, the animals were exposed to pulse modulated signal of a GSM mobile phone at 890 MHz. In the first phase of the experiment electromagnetic field (EMF) stimulation was randomly switched on and off and the relation between EEG bursts and EMF stimulation onsets and endpoints were studied. In the second phase a continuous RF stimulation at 31 W/kg was applied for 10 minutes. The ECG, the EEG, and the subcutaneous temperature were recorded.     

Storage of environmental samples for guaranteeing nucleic acid yields for molecular microbiological studies

The purpose of this study is to evaluate whether sample preservation can affect the yield of nucleic acid extracts from environmental samples. Storage of microbial samples was studied using three sediment types of varying carbon contents (10–57% carbon of dry weight). Four different storage solutions were tested at three temperatures. Freezing of samples at ?20 °C or ?80 °C, either without preservative or in phenol–chloroform solution, retained nucleic acid quantities very efficiently. Storage of samples in phenol–chloroform solution at +4 °C also gave good yields except for sediment with extremely high-carbon content. Ethanol and RNAlater® preservation decreased nucleic acid yields drastically at all temperatures. To study how sample preservation may affect the result of microbial community analysis, one type of sediment was selected for length heterogeneity-PCR analysis and PCR cloning of the 16S rRNA genes. Ethanol and RNAlater® preservation caused a slight bias towards certain microbial types in the community analyses shown by underrepresentation of Bacteroidetes, Betaproteobacteria and Gammaproteobacteria-affiliated peak sizes and overrepresentation of Actinobacteria, Chloroflexi and Alphaproteobacteria-affiliated peak sizes. Based on the results of this study, preservation in phenol–chloroform solution can be recommended as an alternative storage method when freezing is not possible such as during extended field sampling; however, ethanol and RNAlater® may cause serious problems when used as preservatives for environmental samples containing humic acids.     

Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors

The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.