Adaptation in tunably rugged fitness landscapes: The Rough Mount Fuji Model

Much of the current theory of adaptation is based on Gillespie's mutational landscape model (MLM), which assumes that the fitness values of genotypes linked by single mutational steps are independent random variables. On the other hand, a growing body of empirical evidence shows that real fitness landscapes, while possessing a considerable amount of ruggedness, are smoother than predicted by the MLM. In the present article we propose and analyse a simple fitness landscape model with tunable ruggedness based on the Rough Mount Fuji (RMF) model originally introduced by Aita et al. [Biopolymers 54:64-79 (2000)] in the context of protein evolution. We provide a comprehensive collection of results pertaining to the topographical structure of RMF landscapes, including explicit formulae for the expected number of local fitness maxima, the location of the global peak, and the fitness correlation function. The statistics of single and multiple adaptive steps on the RMF landscape are explored mainly through simulations, and the results are compared to the known behavior in the MLM model. Finally, we show that the RMF model can explain the large number of second-step mutations observed on a highly-fit first step backgound in a recent evolution experiment with a microvirid bacteriophage [Miller et al., Genetics 187:185-202 (2011)].Comment: 43 pages, 12 figures; revised version with new results on the number of fitness maxim

Exact Results for Amplitude Spectra of Fitness Landscapes

Starting from fitness correlation functions, we calculate exact expressions for the amplitude spectra of fitness landscapes as defined by P.F. Stadler [J. Math. Chem. 20, 1 (1996)] for common landscape models, including Kauffman's NK-model, rough Mount Fuji landscapes and general linear superpositions of such landscapes. We further show that correlations decaying exponentially with the Hamming distance yield exponentially decaying spectra similar to those reported recently for a model of molecular signal transduction. Finally, we compare our results for the model systems to the spectra of various experimentally measured fitness landscapes. We claim that our analytical results should be helpful when trying to interpret empirical data and guide the search for improved fitness landscape models.Comment: 13 pages, 5 figures; revised and final versio

Multidimensional epistasis and the transitory advantage of sex

Identifying and quantifying the benefits of sex and recombination is a long standing problem in evolutionary theory. In particular, contradictory claims have been made about the existence of a benefit of recombination on high dimensional fitness landscapes in the presence of sign epistasis. Here we present a comparative numerical study of sexual and asexual evolutionary dynamics of haploids on tunably rugged model landscapes under strong selection, paying special attention to the temporal development of the evolutionary advantage of recombination and the link between population diversity and the rate of adaptation. We show that the adaptive advantage of recombination on static rugged landscapes is strictly transitory. At early times, an advantage of recombination arises through the possibility to combine individually occurring beneficial mutations, but this effect is reversed at longer times by the much more efficient trapping of recombining populations at local fitness peaks. These findings are explained by means of well established results for a setup with only two loci. In accordance with the Red Queen hypothesis the transitory advantage can be prolonged indefinitely in fluctuating environments, and it is maximal when the environment fluctuates on the same time scale on which trapping at local optima typically occurs.Comment: 34 pages, 9 figures and 8 supplementary figures; revised and final versio

Diversity of new Martian crater clusters informs meteoroid atmospheric interactions

We investigated 634 crater clusters on Mars detected between 2007 and 2021, which represent more than half of all impacts discovered in this period. Crater clusters form when meteoroids in the 10 kg to 10 ton mass range break-up in Mars' atmosphere to produce a few to a few hundred fragments that hit the ground. The properties of the clusters can inform our understanding of meteoroid properties and the processes that govern their fragmentation. We mapped individual craters $>$1 m within each cluster and defined a range of cluster properties based on the spatial and size distributions of the craters. The large data set, with over eight times more cluster observations than previous work, provides a more robust statistical investigation of crater cluster parameters and their correlations. Trends in size, dispersion and large crater fraction with elevation support weak atmospheric filtering of material. The diversity in the number of individual craters within a cluster, and their size-frequency distributions, may reflect either a diversity in fragmentation style, fragility or internal particle sizes.Comment: 12 pages, 12 figures at the en

Homeostasis of metabolites in Escherichia coli on transition from anaerobic to aerobic conditions and the transient secretion of pyruvate

We have developed a method for rapid quenching of samples taken from chemostat cultures of Escherichia coli that gives reproducible and reliable measurements of extracellular and intracellular metabolites by 1H NMR and have applied it to study the major central metabolites during the transition from anaerobic to aerobic growth. Almost all metabolites showed a gradual change after perturbation with air, consistent with immediate inhibition of pyruvate formate-lyase, dilution of overflow metabolites and induction of aerobic enzymes. Surprisingly, although pyruvate showed almost no change in intracellular concentration, the extracellular concentration transiently increased. The absence of intracellular accumulation of pyruvate suggested that one or more glycolytic enzymes might relocate to the cell membrane. To test this hypothesis, chromosomal pyruvate kinase (pykF) was modified to express either PykF-green fluorescent protein or PykF-FLAG fusion proteins. Measurements showed that PykF-FLAG relocates to the cell membrane within 5 min of aeration and then slowly returns to the cytoplasm, suggesting that on aeration, PykF associates with the membrane to facilitate secretion of pyruvate to maintain constant intracellular levels

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Enhanced cartilage regeneration in MIA/CD-RAP deficient mice

Melanoma inhibitory activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from chondrocytes. It was identified as the prototype of a family of extracellular proteins adopting an SH3 domain-like fold. In order to study the consequences of MIA/CD-RAP deficiency in detail we used mice with a targeted gene disruption of MIA/CD-RAP (MIA−/−) and analyzed cartilage organisation and differentiation in in vivo and in vitro models. Cartilage formation and regeneration was determined in models for osteoarthritis and fracture healing in vivo, in addition to in vitro studies using mesenchymal stem cells of MIA−/− mice. Interestingly, our data suggest enhanced chondrocytic regeneration in the MIA−/− mice, modulated by enhanced proliferation and delayed differentiation. Expression analysis of cartilage tissue derived from MIA−/− mice revealed strong downregulation of nuclear RNA-binding protein 54-kDa (p54nrb), a recently described modulator of Sox9 activity. In this study, we present p54nrb as a mediator of MIA/CD-RAP to promote chondrogenesis. Taken together, our data indicate that MIA/CD-RAP is required for differentiation in cartilage potentially by regulating signaling processes during differentiation

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m−2 day−1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m−2 day−1. Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m−2 day−1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m−2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m−2 day−1. The mean half-life of ssHHT was 11.01±3.4 h, the volume of distribution at steady state was 2±1.4 l kg−1 and the plasma clearance was 11.6±10.4 l h−1. Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m−2 day−1

Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides

Objectives: Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA).Methods: A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested.Results: β-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. β-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to β-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1β, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. RNASEq upon β-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance.Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels