Targeted inhibition of the oncogenic BCR-ABL1 fusion protein using the ABL1 tyrosine kinase inhibitor imatinib has become standard therapy for chronic myelogenous leukemia (CML), with most patients ...reaching total and durable remission. However, a significant fraction of patients develop resistance, commonly due to mutated ABL1 kinase domains. This motivated development of second-generation drugs with broadened or altered protein kinase selectivity profiles, including dasatinib and nilotinib. Imatinib-resistant patients undergoing treatment with second-line drugs typically develop resistance to them, but dynamic and clonal properties of this response differ. Shared, however, is the observation of clonal competition, reflected in patterns of successive dominance of individual clones. We present three deterministic mathematical models to study the origins of clinically observed dynamics. Each model is a system of coupled first-order differential equations, considering populations of three mutated active stem cell strains and three associated pools of differentiated cells; two models allow for activation of quiescent stem cells. Each approach is distinguished by the way proliferation rates of the primary stem cell reservoir are modulated. Previous studies have concentrated on simulating the response of wild-type leukemic cells to imatinib administration; our focus is on modelling the time dependence of imatinib-resistant clones upon subsequent exposure to dasatinib or nilotinib. Performance of the three computational schemes to reproduce selected CML patient profiles is assessed. While some simple cases can be approximated by a basic design that does not invoke quiescence, others are more complex and require involvement of non-cycling stem cells for reproduction. We implement a new feedback mechanism for regulation of coupling between cycling and non-cycling stem cell reservoirs that depends on total cell populations. A bifurcation landscape analysis is also performed for solutions to the basic ansatz. Computational models reproducing patient data illustrate potential dynamic mechanisms that may guide optimization of therapy of drug resistant CML.
Critical thinking is considered one of the most important results of university education. However, approaches to its development are controversial: there is very conflicting empirical data on the ...effectiveness of different approaches to the development of critical thinking.
Comparing approaches is difficult because different studies differ in the sets of critical thinking skills diagnosed, the learning conditions and the disciplines in which these approaches are implemented. Therefore, to carry out a comparative study of the effectiveness of infusion, immersion and mixed approaches to the development of critical thinking, a single discipline was chosen - “Concepts of modern natural science”, the differences between the approaches were formulated, which determined the general and different conditions for their implementation, a local definition of critical thinking for natural science was created, based on which identified a single set of diagnosable skills and developed a tool for their assessment. The study, covering 2019-2022, involved 619 students of the Faculty of Philology of RUDN University.
The mixed approach turned out to be optimal; it statistically significantly improved all groups of critical thinking skills. The infusion approach is less effective in developing decision-making skills and formulating inferences, but in other respects is not inferior to the mixed approach. The immersion approach is the least effective and primarily affects the group of information comprehension skills. The duration of the formation of critical thinking skills has a significant impact on the results: an impact spread over two semesters is more effective than one compressed into one semester. The difference in results between first and second year students may be explained by the cumulative nature of cognitive growth: learning has a delayed effect and there are epistemological crises in the perception of knowledge.
It is a widely accepted fact that the computational capability of recurrent neural networks (RNNs) is maximized on the so-called "edge of criticality." Once the network operates in this ...configuration, it performs efficiently on a specific application both in terms of: 1) low prediction error and 2) high short-term memory capacity. Since the behavior of recurrent networks is strongly influenced by the particular input signal driving the dynamics, a universal, application-independent method for determining the edge of criticality is still missing. In this paper, we aim at addressing this issue by proposing a theoretically motivated, unsupervised method based on Fisher information for determining the edge of criticality in RNNs. It is proved that Fisher information is maximized for (finite-size) systems operating in such critical regions. However, Fisher information is notoriously difficult to compute and requires the analytic form of the probability density function ruling the system behavior. This paper takes advantage of a recently developed nonparametric estimator of the Fisher information matrix and provides a method to determine the critical region of echo state networks (ESNs), a particular class of recurrent networks. The considered control parameters, which indirectly affect the ESN performance, are explored to identify those configurations lying on the edge of criticality and, as such, maximizing Fisher information and computational performance. Experimental results on benchmarks and real-world data demonstrate the effectiveness of the proposed method.
The pool of fungal secondary metabolites can be extended by activating silent gene clusters of cultured strains or by using sensitive biological assays that detect metabolites missed by analytical ...methods. Alternatively, or in parallel with the first approach, one can increase the diversity of existing culture collections to improve the access to new natural products. This review focuses on the latter approach of screening previously uncultured fungi for chemodiversity. Both strategies have been practiced since the early days of fungal biodiscovery, yet relatively little has been done to overcome the challenge of cultivability of as-yet-uncultivated fungi. Whereas earlier cultivability studies using media formulations and biological assays to scrutinize fungal growth and associated factors were actively conducted, the application of modern omics methods remains limited to test how to culture the fungal dark matter and recalcitrant groups of described fungi. This review discusses the development of techniques to increase the cultivability of filamentous fungi that include culture media formulations and the utilization of known chemical growth factors,
in situ
culturing and current synthetic biology approaches that build upon knowledge from sequenced genomes. We list more than 100 growth factors, i.e., molecules, biological or physical factors that have been demonstrated to induce spore germination as well as tens of inducers of mycelial growth. We review culturing conditions that can be successfully manipulated for growth of fungi and visit recent information from omics methods to discuss the metabolic basis of cultivability. Earlier work has demonstrated the power of co-culturing fungi with their host, other microorganisms or their exudates to increase their cultivability. Co-culturing of two or more organisms is also a strategy used today for increasing cultivability. However, fungi possess an increased risk for cross-contaminations between isolates in existing
in situ
or microfluidics culturing devices. Technological improvements for culturing fungi are discussed in the review. We emphasize that improving the cultivability of fungi remains a relevant strategy in drug discovery and underline the importance of ecological and taxonomic knowledge in culture-dependent drug discovery. Combining traditional and omics techniques such as single cell or metagenome sequencing opens up a new era in the study of growth factors of hundreds of thousands of fungal species with high drug discovery potential.
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•Cuticular wax morphology in glossy (GT) bilberry differs from wildtype (WT) bilberry.•Proportion of triterpenoids is higher but fatty acids and ketones lower in GT fruit.•Composition ...of cuticular wax changes during development similarly in WT and GT fruit.•Wax chemical composition affects epicuticular wax morphology in bilberry.•Peel-specific expression reveals genes in bilberry cuticular wax biosynthesis.
In this study, cuticular wax load, its chemical composition, and biosynthesis, was studied during development of wild type (WT) bilberry fruit and its natural glossy type (GT) mutant. GT fruit cuticular wax load was comparable with WT fruits. In both, the proportion of triterpenoids decreased during fruit development concomitant with increasing proportions of total aliphatic compounds. In GT fruit, a higher proportion of triterpenoids in cuticular wax was accompanied by a lower proportion of fatty acids and ketones compared to WT fruit as well as lower density of crystalloid structures on berry surfaces. Our results suggest that the glossy phenotype could be caused by the absence of rod-like structures in GT fruit associated with reduction in proportions of ketones and fatty acids in the cuticular wax. Especially CER26-like, FAR2, CER3-like, LTP, MIXTA, and BAS genes showed fruit skin preferential expression patterns indicating their role in cuticular wax biosynthesis and secretion.
Virtual reality (VR) systems (Neumann et al., 2017), which are currently receiving considerable attention from athletes, create a two- or three-dimensional environment in the form of emulated ...pictures and/or video-recordings where in addition to being mentally present, the athlete even often feels like he/she is there physically as well. As she/he interacts with and/or reacts to this environment, movement is captured by sensors, allowing the system to provide feedback.
As with every newly evolving technology related to human movement and behavior, it is important to be aware of the strengths, weaknesses, opportunities and threats (SWOT) associated with the use of this particular type of technology. SWOT analyses are widely utilized for strategic planning of developmental processes (Pickton and Wright, 1998; Tao and Shi, 2016) and it is of great interest to consider whether VR systems should be adopted by athletes or not. Aspects more inherent to the employed technologies of VR systems, and aspects more related to the application of VR systems with athletes are considered as strength/weaknesses and opportunities/threats, respectively. Analogously, SWOT analysis concerning another emerging technology involving sensors of individual parameters (i.e., “implantables”) has been performed (Sperlich et al., 2017).
We present a study of decameter scale ionospheric irregularities using in‐situ electron density data from the NorSat‐1 satellite. During the current period of low solar activity, NorSat‐1 frequently ...observes significant plasma irregularities from several 10 s km down to several decameter. These are often observed near the dayside cusp and dawnside auroral zone. The decameter‐scale irregularities are positively correlated with intermediate‐scale (10 km) density gradients, for both negative and positive gradients encountered by the satellite. The statistical distribution of electron density over two winter months in the northern hemisphere along NorSat‐1 orbits, shows significant density increases in the cusp ionosphere (75°–80° Magnetic LATitude) and in regions near the dawnside auroral oval. Intermediate scale density gradients and small‐scale irregularities are clearly associated with these density enhancements. We postulate that these density enhancements and irregularities are due to auroral particle precipitation/plasma dynamics.
Plain Language Summary
The polar ionosphere is often irregular and turbulent with significant plasma structures. As a result, the satellite‐based navigation and communication systems that rely on trans‐ionospheric radio signals can be severely affected. In the present study, we take advantage of the high‐resolution electron density observations of a polar orbiting satellite to address plasma structures at several 10 s of meters that are responsible for scattering of High Frequency radar signals. The statistical results indicate that enhanced decameter scale structures are often located within the auroral region during the period of low solar activity. This finding highlights the auroral dynamics in creating plasma turbulence at high latitudes.
Key Points
Decameter scale irregularities are positively correlated with intermediate scale density gradients irrespective of directions
Decameter scale ionospheric irregularities are enhanced at the dayside cusp and dawnside auroral region
These irregularities are likely caused by auroral particle precipitation/plasma dynamics
The high Arctic archipelago of Svalbard (74°–81° north) experiences extended periods of uninterrupted daylight in summer and uninterrupted night in winter, apparently relaxing the major driver for ...the evolution of circadian rhythmicity. Svalbard ptarmigan (Lagopus muta hyperborea) is the only year-round resident terrestrial bird species endemic to the high Arctic and is remarkably adapted to the extreme annual variation in environmental conditions.1 Here, we demonstrate that, although circadian control of behavior disappears rapidly upon transfer to constant light conditions, consistent with the loss of daily activity patterns observed during the polar summer and polar night, Svalbard ptarmigans nonetheless employ a circadian-based mechanism for photoperiodic timekeeping. First, we show the persistence of rhythmic clock gene expression under constant light within the mediobasal hypothalamus and pars tuberalis, the key tissues in the seasonal neuroendocrine cascade. We then employ a “sliding skeleton photoperiod” protocol, revealing that the driving force behind seasonal biology of the Svalbard ptarmigan is rhythmic sensitivity to light, a feature that depends on a functioning circadian rhythm. Hence, the unusual selective pressures of life in the high Arctic have favored decoupling of the circadian clock from organization of daily activity patterns, while preserving its importance for seasonal synchronization.
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•Ptarmigan circadian activity patterns rapidly dampen under controlled constant light•Clock gene expression is rhythmic in the seasonal neuroendocrine cascade circuit•Skeleton photoperiods stimulate summer-associated phenotype and genetic markers•Svalbard ptarmigan likely time their seasonal biology using a circadian mechanism
During the Arctic summer, Svalbard ptarmigan have weak/absent circadian activity patterns. Appenroth et al. show that despite this unusual phenotype, the circadian clock persists in constant conditions and forms the basis for photoperiodic sensitivity. Their findings emphasize the importance of the circadian clock for seasonal timekeeping.
Nickel norcorrole provides an unusual example of a molecule that is strongly antiaromatic according to the magnetic criterion, but which exhibits, according to high-quality DFT calculations, a ...symmetric, delocalized structure with no difference in bond length between adjacent C
-C
bonds. A fragment molecular orbital analysis suggests that these discordant observations are a manifestation of the high stability of the dipyrrin fragments, which retain their electronic and structural integrity even as part of the norcorrole ring system.
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