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 effect of a mutation on the organism often depends on what other mutations are already present in its genome. Geneticists refer to such mutational interactions as epistasis. Pairwise epistatic ...effects have been recognized for over a century, and their evolutionary implications have received theoretical attention for nearly as long. However, pairwise epistatic interactions themselves can vary with genomic background. This is called higher-order epistasis, and its consequences for evolution are much less well understood. Here, we assess the influence that higher-order epistasis has on the topography of 16 published, biological fitness landscapes. We find that on average, their effects on fitness landscape declines with order, and suggest that notable exceptions to this trend may deserve experimental scrutiny. We conclude by highlighting opportunities for further theoretical and experimental work dissecting the influence that epistasis of all orders has on fitness landscape topography and on the efficiency of evolution by natural selection.
Abstract
Background
It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the ...macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process.
Methods
A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process.
Results
Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage.
Conclusion
Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.
The fundamental interaction between the immune and skeletal systems, termed as osteoimmunology, has been demonstrated to play indispensable roles in the maintenance of balance between bone resorption ...and formation. The pleiotropic sphingolipid metabolite, sphingosine 1-phosphate (S1P), together with its cognate receptor, sphingosine-1-phosphate receptor-1 (S1PR1), are known as key players in osteoimmunology due to the regulation on both immune system and bone remodeling. The role of S1P-S1PR1 signaling in bone remodeling can be directly targeting both osteoclastogenesis and osteogenesis. Meanwhile, inflammatory cell function and polarization in both adaptive immune (T cell subsets) and innate immune cells (macrophages) are also regulated by this signaling axis, suggesting that S1P-S1PR1 signaling could aslo indirectly regulate bone remodeling
modulating the immune system. Therefore, it could be likely that S1P-S1PR1 signaling might take part in the maintenance of continuous bone turnover under physiological conditions, while lead to the pathogenesis of bone deformities during inflammation. In this review, we summarized the immunological regulation of S1P-S1PR1 signal axis during bone remodeling with an emphasis on how osteo-immune regulators are affected by inflammation, an issue with relevance to chronical bone disorders such as rheumatoid arthritis, spondyloarthritis and periodontitis.
Pantograph arcing is a key electromagnetic disturbance source to affect train control system in high-speed railway. Since the characteristics of pantograph arcing are related to train speed, it is ...necessary to investigate effective numerical modeling and measurement method. However, due to the uncontrollable train speed during onsite measurement, it is difficult to study the radiated disturbance from arcing in the corresponding speed and repeat the same measurement. Therefore, a method that combines numerical modeling and reverberation chamber measurements for calculating the radiated disturbance from pantograph arcing in a high-speed railway is proposed. Numerical models of train and sensitive equipment are built to calculate the coupling coefficient in CONCEPT II. And a new measurement procedure in reverberation chamber using pulse signal as the reference source is proposed based on a speed-controllable laboratory replica to measure the total radiated power of pantograph arcing. Then, the radiated disturbance from pantograph arcing to the sensitive equipment is achieved with the coupling coefficient and the total radiated power of arcing. The method is verified by laboratory experiments. This method can solve the uncontrollable train speed problem during on-site measurement and improve the repeatability of measurement.
BackgroundSingle-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (SRT) have led to groundbreaking advancements in life sciences. To develop bioinformatics tools for scRNA-seq ...and SRT data and perform unbiased benchmarks, data simulation has been widely adopted by providing explicit ground truth and generating customized datasets. However, the performance of simulation methods under multiple scenarios has not been comprehensively assessed, making it challenging to choose suitable methods without practical guidelines.ResultsWe systematically evaluated 49 simulation methods developed for scRNA-seq and/or SRT data in terms of accuracy, functionality, scalability, and usability using 152 reference datasets derived from 24 platforms. SRTsim, scDesign3, ZINB-WaVE, and scDesign2 have the best accuracy performance across various platforms. Unexpectedly, some methods tailored to scRNA-seq data have potential compatibility for simulating SRT data. Lun, SPARSim, and scDesign3-tree outperform other methods under corresponding simulation scenarios. Phenopath, Lun, Simple, and MFA yield high scalability scores but they cannot generate realistic simulated data. Users should consider the trade-offs between method accuracy and scalability (or functionality) when making decisions. Additionally, execution errors are mainly caused by failed parameter estimations and appearance of missing or infinite values in calculations. We provide practical guidelines for method selection, a standard pipeline Simpipe (https://github.com/duohongrui/simpipe; https://doi.org/10.5281/zenodo.11178409), and an online tool Simsite (https://www.ciblab.net/software/simshiny/) for data simulation.ConclusionsNo method performs best on all criteria, thus a good-yet-not-the-best method is recommended if it solves problems effectively and reasonably. Our comprehensive work provides crucial insights for developers on modeling gene expression data and fosters the simulation process for users.
•RCA embedment results in a minor decrease of post-fire compressive strength.•Exposed to high temperature, RAC performs better bond than those of NCA.•The descending branch of bond-slip curve becomes ...flatter at higher temperature.•Bond-slip relation between RAC and rebar after high temperature is suggested.
In this paper, 84 pull-out specimens and 60 cubic specimens with different levels of recycled coarse aggregate (i.e. 0%, 30%, 50%, 70% and 100%) were fabricated to evaluate the post-fire bond at the interface between recycled aggregate concrete (RAC) and deformed rebar. Those specimens designed for thermal temperature were first heated to high temperatures of 300, 400, and 500°C for 6h, and then were submitted to the test. The testing results were compared with the results obtained from the testing for the specimens at ambient temperature (about 20°C). A semi-empirical formula was finally suggested to model the bond-slip relation between the heated RAC and the deformed rebar. The results demonstrate that an increment of the heating temperature decreases both the bond strength and the compressive strength continuously but increase the peak slip. Before and after high temperature, increasing the RAC replacement percentage gradually increases the relative bond strength. The ascending branches of bond-slip curves are uniform for all the tests. However, as an increment of the temperature and of the lateral confinement provided by stirrups, the descending branch curve of RAC becomes flatter.
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