The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. ...A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hydrogen sulfide (H2S) has been identified as an important cell‐signaling mediator and has a number of biological functions, such as vascular smooth muscle relaxation, neurotransmission, and ...regulation of inflammation. A facile and versatile approach for H2S production initiated by light irradiation and controlled by reaction with an amine or an amino acid was developed. The donor was synthesized in a one‐pot reaction, and simple crystallization led to a yield of approximately 90 %. The synthetic strategy is scalable and versatile, and the H2S donors can be expressed ina number of different molecular and macromolecular forms, including crystalline small‐molecule compounds, water‐soluble polymers, polystyrene films, and hydrogels. The H2S donors based on polystyrene film and hydrogel were used as cell‐culture scaffolds. The H2S donor based on water‐soluble polymer was applied in photocontrolled inhibition of P‐selectin expression on human platelets and subsequent regulation of platelet aggregation. This study provides the simplest controllable H2S source to study its biological functions. The developed materials are also new therapeutic platforms to deliver H2S, as there is no accumulation of toxic byproducts, and the donor materials from polystyrene films and hydrogels can be readily removed after releasing H2S.
Dual‐trigger H2S donors: A facile and versatile approach to H2S release has been developed by trapping photogenerated thiobenzaldehydes with amines. The H2S release process can be controlled with light and an amine. In addition to a crystalline small‐molecule H2S donor, water‐soluble polymer, polystyrene film, and hydrogel H2S donors were easily obtained. The new materials showed excellent biocompatibility and were used for controlled delivery of H2S to cells and antiplatelet applications (see scheme).
Using light and serial electron microscopy, we show profound refinements in motor axonal branching and synaptic connectivity before and after birth. Embryonic axons become maximally connected just ...before birth when they innervate ∼10-fold more muscle fibers than in maturity. In some developing muscles, axons innervate almost every muscle fiber. At birth, each neuromuscular junction is coinnervated by approximately ten highly intermingled axons (versus one in adults). Extensive die off of terminal branches occurs during the first several postnatal days, leading to much sparser arbors that still span the same territory. Despite the extensive pruning, total axoplasm per neuron increases as axons elongate, thicken, and add more synaptic release sites on their remaining targets. Motor axons therefore initially establish weak connections with nearly all available postsynaptic targets but, beginning at birth, massively redistribute synaptic resources, concentrating many more synaptic sites on many fewer muscle fibers. Analogous changes in connectivity may occur in the CNS.
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► Pervasive axonal pruning in the mouse neuromuscular system during early development ► Pruning occurs by removal of terminal as opposed to proximal branches ► At the peak, target cells are innervated by up to ∼10 axons with none dominant ► At peak, there is nearly all-to-all pre- to postsynaptic connectivity
Synaptic connectivity between neurons and muscle fibers changes dramatically during development. Here, Tapia et al. show that nerve-muscle connections peak just before birth with a nearly all-to-all connectional pattern that is trimmed 10-fold after birth when axons focus more synaptic sites on far fewer targets.
•Household air pollution exposure during pregnancy affects birth outcomes in Ghana.•Effects are strongest in pregnancies unaffected by placental malaria.•Carbon monoxide during pregnancy is ...associated with reduced fetal growth.•Carbon monoxide during pregnancy is also associated with shorter gestational age.•Malaria during pregnancy may obscure the effects of air pollution on fetal growth.
Low birth weight and prematurity are important risk factors for death and disability, and may be affected by prenatal exposure to household air pollution (HAP).
We investigate associations between maternal exposure to carbon monoxide (CO) during pregnancy and birth outcomes (birth weight, birth length, head circumference, gestational age, low birth weight, small for gestational age, and preterm birth) among 1288 live-born infants in the Ghana Randomized Air Pollution and Health Study (GRAPHS). We evaluate whether evidence of malaria during pregnancy, as determined by placental histopathology, modifies these associations.
We observed effects of CO on birth weight, birth length, and gestational age that were modified by placental malarial status. Among infants from pregnancies without evidence of placental malaria, each 1 ppm increase in CO was associated with reduced birth weight (−53.4 g 95% CI: −84.8, −21.9 g), birth length (−0.3 cm −0.6, −0.1 cm), gestational age (−1.0 days −1.8, −0.2 days), and weight-for-age Z score (−0.08 standard deviations −0.16, −0.01 standard deviations). These associations were not observed in pregnancies with evidence of placental malaria. Each 1 ppm increase in maternal exposure to CO was associated with elevated odds of low birth weight (LBW, OR 1.14 0.97, 1.33) and small for gestational age (SGA, OR 1.14 0.98, 1.32) among all infants.
Even modest reductions in exposure to HAP among pregnant women could yield substantial public health benefits, underscoring a need for interventions to effectively reduce exposure. Adverse associations with HAP were discernible only among those without evidence of placental malaria, a key driver of impaired fetal growth in this malaria-endemic area.
Natural selection drives evolving populations up the fitness landscape, the projection from nucleotide sequence space to organismal reproductive success. While it has long been appreciated that ...topographic complexities on fitness landscapes can arise only as a consequence of epistatic interactions between mutations, evolutionary genetics has mainly focused on epistasis between pairs of mutations. Here we propose a generalization to the classical population genetic treatment of pairwise epistasis that yields expressions for epistasis among arbitrary subsets of mutations of all orders (pairwise, three-way, etc.). Our approach reveals substantial higher-order epistasis in almost every published fitness landscape. Furthermore we demonstrate that higher-order epistasis is critically important in two systems we know best. We conclude that higher-order epistasis deserves empirical and theoretical attention from evolutionary geneticists.
The Scalasca performance toolset architecture Geimer, Markus; Wolf, Felix; Wylie, Brian J. N. ...
Concurrency and computation,
25 April 2010, Letnik:
22, Številka:
6
Journal Article
Soft nanoparticles with precisely controlled shape and morphologies hold great potential for the preparation of novel materials with tailored chemical and biophysical properties. In this review, we ...highlight the synthetic approaches and hierarchical strategies to manipulate the shape and morphology of nanostructures assembled from four major building units, namely block copolymers, peptide amphiphiles, proteins and nucleic acid building blocks. Special attention is given to anisotropic, stimuli-responsive nanoparticles that are tuned by assembly conditions. Their tunable nature is of particular significance as it allows the design of smart and dynamic materials. The immediate and potential applications of these shape controlled nanostructures are also summarized together with their limitations.
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