Search

We propose a 3D stochastic cellular automaton model, governed by evolutionary game theory, to simulate bone remodeling dynamics. The model includes four voxel states: Formation, Quiescence, Resorption, and Environment. We simulate the Resorption and Formation processes on separate time scales to explore the parameter space and derive a phase diagram that illustrates the sensitivity of these processes to parameter changes. Combining these results, we simulate a full bone remodeling cycle. Furthermore, we show the importance of modeling small neighborhoods for studying local bone microenvironment controls. This model can guide experimental design and, in combination with other models, it could assist to further explore external impacts on bone remodeling. Consequently, this model contributes to an improved understanding of complex dynamics in bone remodeling dynamics and exploring alterations due to disease or drug treatment. [ABSTRACT FROM AUTHOR]

In recent years, the Ribosome profiling technique (Ribo–seq) has emerged as a powerful method for globally monitoring the translation process in vivo at single nucleotide resolution. Based on deep sequencing of mRNA fragments, Ribo–seq allows to obtain profiles that reflect the time spent by ribosomes in translating each part of an open reading frame. Unfortunately, the profiles produced by this method can vary significantly in different experimental setups, being characterized by a poor reproducibility. To address this problem, we have employed a statistical method for the identification of highly reproducible Ribo–seq profiles, which was tested on a set of E. coli genes. State-of-the-art artificial neural network models have been used to validate the quality of the produced sequences. Moreover, new insights into the dynamics of ribosome translation have been provided through a statistical analysis on the obtained sequences. [ABSTRACT FROM AUTHOR]

The egress and fertilization of Plasmodium gametes and development of a motile ookinete are the first crucial steps that mediate the successful transmission of the malaria parasites from humans to the Anopheles vector. However, limited information exists about the cell biology and regulation of this process. Technical impediments in the establishment of in vitro conditions for ookinete maturation in Plasmodium falciparum and other human malaria parasites further constrain a detailed characterization of ookinete maturation. Here, using fluorescence microscopy and immunolabeling, we compared P. falciparum ookinete maturation in Anopheles coluzzii mosquitoes in vivo and in cell culture in vitro. Our results identified two critical steps in ookinete maturation that are regulated by distinct mosquito factors, thereby highlighting the role of the mosquito environment in the transmission efficiency of malaria parasites. Ookinete development within the mosquito blood bolus is a critical step in malaria transmission. Using time-series approaches, we identified two limiting steps of Plasmodium falciparum ookinete development in vitro : (i) inhibition of transition from round forms (stage I) to knobs (stage II), likely caused by an inefficient fertilization, and (ii) arrest of transition between stages III and IV, associated with morphological abnormalities during protuberance elongation and enlargement. The abnormal protuberance at stage IV prevents further nuclear migration from the round body to the appendage. [ABSTRACT FROM AUTHOR]

Pulse-chase experiments are often used to study the degradation of macromolecules such as proteins or mRNA. Considerations for the choice of pulse length include the toxicity of the pulse to the cell and maximization of labeling. In the general case of non-exponential decay, varying the length of the pulse results in decay patterns that look different. Analysis of these patterns without consideration to pulse length would yield incorrect degradation parameters. Here we propose a method that constructively includes pulse length in the analysis of decay patterns and extracts the parameters of the underlying degradation process. We also show how to extract decay parameters reliably from measurements taken during the pulse phase. [ABSTRACT FROM AUTHOR]

Recent experimental results on the effect of miRNA on the decay of its target mRNA have been analyzed against a previously hypothesized single molecule degradation pathway. According to that hypothesis, the silencing complex (miRISC) first interacts with its target mRNA and then recruits the protein complexes associated with NOT1 and PAN3 to trigger deadenylation (and subsequent degradation) of the target mRNA. Our analysis of the experimental decay patterns allowed us to refine the structure of the degradation pathways at the single molecule level. Surprisingly, we found that if the previously hypothesized network was correct, only about 7% of the target mRNA would be regulated by the miRNA mechanism, which is inconsistent with the available knowledge. Based on systematic data analysis, we propose the alternative hypothesis that NOT1 interacts with miRISC before binding to the target mRNA. Moreover, we show that when miRISC binds alone to the target mRNA, the mRNA is degraded more slowly, probably through a deadenylation-independent pathway. The new biochemical pathway proposed here both fits the data and paves the way for new experimental work to identify new interactions. [ABSTRACT FROM AUTHOR]

Experimental studies on mRNA stability have established several, qualitatively distinct decay patterns for the amount of mRNA within the living cell. Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified. The central aim of this paper is to bring together both the experimental evidence about the decay patterns and the biochemical knowledge about the multi-step nature of mRNA degradation in a coherent mathematical theory. We first introduce a mathematical relationship between the mRNA decay pattern and the lifetime distribution of individual mRNA molecules. This relationship reveals that the mRNA decay patterns at steady state expression level must obey a general convexity condition, which applies to any degradation mechanism. Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation. We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs. Thereby, we show how to extract single-molecule properties of an mRNA, such as the age-dependent decay rate and the residual lifetime. Finally, we analyze the decay patterns of the whole translatome of yeast cells and show that yeast mRNAs can be grouped into three broad classes that exhibit three distinct decay patterns. This paper provides both a method to accurately analyze non-exponential mRNA decay patterns and a tool to validate different models of degradation using decay data. [ABSTRACT FROM AUTHOR]

When transcription of a gene is induced by a stimulus, the number of its mRNA molecules changes with time. Here we discuss how this time evolution depends on the shape of the mRNA lifetime distribution. Analysis of the statistical properties of this change reveals transient effects on polysomes, ribosomal profiles, and rate of protein synthesis. Our studies reveal that transient phenomena in gene expression strongly depend on the specific form of the mRNA lifetime distribution. [ABSTRACT FROM AUTHOR]

Abstract: In this study we consider a population subdivided in groups. Each group is connected to two neighboring groups by means of migration channels. The migration channels are used with different probability, according to a gradient that gives a preferential direction of colonization. Within groups we have a fast population dynamics modeled with a Moran process. Between groups we have a process of colonization selection at low migration rate, based on the propagule model. We consider resident and invading individuals, with the invading individuals having a relative fitness r. Groups composed only of invaders will also have a relative group fitness R. We show that, independently of the value of r, a strong gradient reduces the advantage of groups with large fitness and thus works against group selection. [Copyright &y& Elsevier]

Myoviruses, bacteriophages with T4-like architecture, must contract their tails prior to DNA release. However, quantitative kinetic data on myovirus particle opening are lacking, although they are promising tools in bacteriophage-based antimicrobial strategies directed against Gram-negative hosts. For the first time, we show time-resolved DNA ejection from a bacteriophage with a contractile tail, the multi-O-antigen-specific Salmonella myovirus Det7. DNA release from Det7 was triggered by lipopolysaccharide (LPS) O-antigen receptors and notably slower than in noncontractile-tailed siphoviruses. Det7 showed two individual kinetic steps for tail contraction and particle opening. Our in vitro studies showed that highly specialized tailspike proteins (TSPs) are necessary to attach the particle to LPS. A P22-like TSP confers specificity for the Salmonella Typhimurium O-antigen. Moreover, crystal structure analysis at 1.63 Å resolution confirmed that Det7 recognized the Salmonella Anatum O-antigen via an 15-like TSP, DettilonTSP. DNA ejection triggered by LPS from either host showed similar velocities, so particle opening is thus a process independent of O-antigen composition and the recognizing TSP. In Det7, at permissive temperatures TSPs mediate O-antigen cleavage and couple cell surface binding with DNA ejection, but no irreversible adsorption occurred at low temperatures. This finding was in contrast to short-tailed Salmonella podoviruses, illustrating that tailed phages usecommonparticle-opening mechanisms but have specialized into different infection niches. [ABSTRACT FROM AUTHOR]

Summary Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that >10% of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, NED proteins have larger interaction interfaces and assemble earlier than ED subunits. Amplifying genes encoding NED proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance. [ABSTRACT FROM AUTHOR]