Relaxed risk of predation drives parallel evolution of stickleback behaviour

The occurrence of similar phenotypes in multiple independent populations (viz. parallel evolution) is a testimony of evolution by natural selection. Parallel evolution implies that populations share a common phenotypic response to a common selection pressure associated with habitat similarity. Examples of parallel evolution at the genetic and phenotypic levels are fairly common, but the driving selective agents often remain elusive. Similarly, the role of phenotypic plasticity in facilitating early stages of parallel evolution is unclear. We investigated whether the relaxation of predation pressure associated with the colonization of freshwater ponds by nine-spined sticklebacks (Pungitius pungitius) likely explains the divergence in complex behaviours between marine and pond populations, and whether this divergence is parallel. Using laboratory-raised individuals exposed to different levels of perceived predation risk, we calculated vectors of phenotypic divergence for four behavioural traits between habitats and predation risk treatments. We found a significant correlation between the directions of evolutionary divergence and phenotypic plasticity, suggesting that habitat divergence in behaviour is aligned with the response to relaxation of predation pressure. Finally, we show that this alignment is found across multiple pairs of populations, and that the relaxation of predation pressure has likely driven parallel evolution of behaviour in this species.

Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.

A functional view reveals substantial predictability of pollinator-mediated selection

A predictive understanding of adaptation to changing environments hinges on a mechanistic understanding of the extent and causes of variation in natural selection. Estimating variation in selection is difficult due to the complex relationships between phenotypic traits and fitness, and the uncertainty associated with individual selection estimates. Plant-pollinator interactions provide ideal systems for understanding variation in selection and its predictability, because both the selective agents (pollinators) and the process linking phenotypes to fitness (pollination) are generally known. Through examples from the pollination literature, I discuss how explicit consideration of the functional mechanisms underlying trait-performance relationships can clarify the relationship between traits and fitness, and how variation in the ecological context that generates selection can help disentangle biologically important variation in selection from sampling variation. I then evaluate the predictability of variation in pollinator-mediated selection through a survey, reanalysis, and synthesis of results from the literature. The synthesis demonstrates that pollinator-mediated selection often varies substantially among trait functional groups, as well as in time and space. Covariance between patterns of selection and ecological variables provides additional support for the biological importance of observed selection, but the detection of such covariance depends on careful choice of relevant predictor variables as well as consideration of quantitative measurements and their meaning, an aspect often neglected in selection studies.

Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

Monovalent ions are involved in growth, proliferation, differentiation of cells as well as in their death. This work concerns the ion homeostasis during senescence induction in human mesenchymal endometrium stem cells (hMESC): hMESCs subjected to oxidative stress (pulse H2O2 treatment) enter the premature senescence accompanied by persistent DNA damage, irreversible cell cycle arrest, cell hypertrophy, lipofuscin accumulation, enhanced β-galactosidase activity. Using flame photometry to estimate K+, Na+ content and Rb+ (K+) fluxes we found that during the senescence development in stress-induced hMESCs, Na+/K+pump-mediated K+ fluxes are enhanced due to the increased Na+ content in senescent cells, while ouabain-resistant K+ fluxes remain unchanged. Senescence progression is accompanied by a peculiar decrease in the K+ content in cells from 800-900 µmol/g to 500-600 µmol/g. Since cardiac glycosides are offered as selective agents for eliminating senescent cells, we investigated the effect of ouabain on ion homeostasis and viability of hMESCs and found that in both proliferating and senescent hMESCs, ouabain (1 nM-1 µM, 24-48 h) inhibited pump-mediated K+ transport (ID50 5x10-8 M), decreased cell K+/Na+ ratio to 0,1-0,2, however did not induce apoptosis. Comparison of the effect of ouabain on hMESCs with the literature data on the selective cytotoxic effect of cardiac glycosides on senescent or cancer cells suggests the ion pump blockade and intracellular K+ depletion should be synergized with target apoptotic signal to induce the cell death.

The Advantages and Disadvantages of Prokinetics

Prokinetics are medications that enhance gastrointestinal contractility; they improve the symptoms of patients with delayed gastrointestinal motility. Prokinetics have conventionally been used to stimulate gastrointestinal propulsion and to treat symptoms correlated with motility problems, including gastroparesis and constipation. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists, such as cisapride, very effectively increased human gastrointestinal tract motility. However, cisapride sometimes induced serious tachyarrhythmia; the drug was thus withdrawn from the market. Thereafter, many prokinetics have been developed to treat delayed gastrointestinal motility. However, some exhibit serious side-effects. Recently, a new, highly selective serotonin receptor agonist, prucalopride, has been introduced; there is as yet no evidence of serious cardiac side- effects. The drug has been approved by the Food and Drug Administration to treat chronic constipation. Thus, recently introduced, highly selective agents appear to show promise as treatments for gastrointestinal dysmotility; there seem to be no serious side-effects.

Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs

Invasive fungal infections are a leading cause of death in the immunocompromised patient population. The rise in drug resistance to current antifungals highlights the urgent need to develop more efficacious and highly selective agents.

Assessment of the Use of Gentian Violet and Malachite Green as Selective Agents in the Isolation of Brucella

The aim of the work is to evaluate ability of gentian violet and malachite green to inhibit 2 Brucella test strains and 8 strains of unwanted organisms and the influence of autoclaving on their activity. The study also aims to evaluate variability of inhibition in different batches of colorants and necessity in adjustment of their concentration.Materials and methods. The study included 3 imported lots of gentian violet and malachite green. Inhibitors were put into nutrient medium containing pancreatic hydrolysates of gelatin and fsh meal, yeast extract, sodium chloride, glucose, sodium pyrosulfate, and agar. The same medium without colorants was used as a control medium. Effect of the colorants was studied with the help of test strains of Brucella abortus 19 ВА, B. melitensis Rev I, Enterococcus faecium VKM B-602, Escherichia coli ATCC 25922, Proteus vulgaris HX 19 222, Pseudomonas aeruginosa 22/99, Serracia plymuthica 1, Shigella flexneri 1a 8516, Staphylococcus aureus ATCC 25923, Yersinia enterocolitica C-187.Results and discussion. We have determined biological parameters of nutrient media containing gentian violet (5,0; 2,5 1,25 mg/L) and malachite green (2.0; 1.0; 0.5 mg/L) when cultivating brucella. Gentian violet is able to inhibit Brucella greatly at concentration of 5 mg/L. S. aureus ATCC 25923 did not show any growth on the media containing malachite green or gential violet (5.0 and 2.5 mg/L). Malachite green inhibited the growth of enterococcus more actively than gentian violet. However, it inhibited swarming growth of Proteus less successfully than gentian violet. Other unwanted organisms were not sensitive to such concentrations of colorants at all. We have demonstrated the necessity to combine colorants with other selective agents, as well as advisability to put gentian violet into sterile media, while malachite green – into the media before its autoclaving. Adjustments to the concentration of gentian violet should be made when producing nutrient medium, as variations in inhibiting activity in different batches of this colorant were revealed.

Evolution of Mimicry Rings as a Window into Community Dynamics

Mimicry rings are communities of mimetic organisms that are excellent models for ecological and evolutionary studies because the community composition, the nature of the species interactions, the phenotypes under selection, and the selective agents are well characterized. Here, we review how regional and ecological filtering, density- and frequency-dependent selection, toxicity of prey, and age of mimicry rings shape their assembly. We synthesize findings from theoretical and empirical studies to generate the following hypotheses: ( a) the degree of unpalatability and age of mimicry rings increase mimicry ring size and ( b) the degree of unpalatability, generalization of the aposematic signal, and availability of alternative prey are positively related to the breadth of the protection umbrella for an aposematic signal and negatively related to the degree of mimetic resemblance. We also provide a phylogenetic framework in which key aspects of mimicry ring diversification may be studied. Expected final online publication date for the Annual Review of Ecology, Evolution, and Systematics, Volume 52 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cyclodextrins AS Dominant Chiral Selective Agents in the Capillary Separation Techniques

This review paper shows the dominant role of the cyclodextrins in the chiral separations using capillary columns (GC, SFC, CE). The cyclodextrins (CDs) have extremely broad chiral selectivity spectra because they have several different chiral recognition sites in various arrangements and various interaction modes. Their chiral selectivity features can further improve with their various substitutions. Their selectivities are moderate therefore they need high efficiency separations (capillary columns) for good chiral resolutions. The shape selectivity of cyclodextrins is also shown with non-chiral isomers too. The utility of the cyclodextrins is demonstrated with several examples based on the personal observations of authors and critical review of literature. The theoretical backgrounds of their chiral recognitions (e.g. H-bond interaction, inclusion, induced fit) are discussed in depth. This paper is not application oriented but is dealing with mostly on the physical and chemical background of separations using CDs.

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss

SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might also activate SARM1. Here we show that the nicotinamide analogue 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration and neuronal death. Systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to peripheral nerve induces SARM1-dependent axon degeneration. We also identify a related pyridine derivative, 2-aminopyridine, as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and furthermore, suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.