Many viruses rely on the self-assembly of their capsids to protect and transport their genomic material. For many viral systems, in particular for human viruses like hepatitis B, adeno or human immunodeficiency virus, that lead to persistent infections, capsomeres are continuously produced in the cytoplasm of the host cell while completed capsids exit the cell for a new round of infection. Here we use coarse-grained Brownian dynamics simulations of a generic patchy particle model to elucidate the role of the dynamic supply of capsomeres for the reversible self-assembly of empty T1 icosahedral virus capsids. We find that for high rates of capsomere influx only a narrow range of bond strengths exists for which a steady state of continuous capsid production is possible. For bond strengths smaller and larger than this optimal value, the reaction volume becomes crowded by small and large intermediates, respectively. For lower rates of capsomere influx a broader range of bond strengths exists for which a steady state of continuous capsid production is established, although now the production rate of capsids is smaller. Thus our simulations suggest that the importance of an optimal bond strength for viral capsid assembly typical for in vitro conditions can be reduced by the dynamic influx of capsomeres in a cellular environment.

The cellular age distribution of hierarchically organized tissues can reveal important insights into the dynamics of cell differentiation and self-renewal and associated cancer risks. Here, we examine theoretically the effect of progenitor compartments with varying differentiation and self-renewal capacities on the resulting observable distributions of replicative cellular ages. We find that strongly amplifying progenitor compartments, i.e. compartments with high self-renewal capacities, substantially broaden the age distributions which become skewed towards younger cells with a long tail of few old cells. However, since mutations predominantly accumulate during cell division, a few old cells may considerably increase cancer risk. In contrast, if tissues are organised into many downstream compartments with low self-renewal capacity, the shape of the replicative cell distributions in more differentiated compartments are dominated by stem cell dynamics with little added variation. In the limiting case of a strict binary differentiation tree without self-renewal, the shape of the output distribution becomes indistinguishable from the shape of the input distribution. Our results suggest that a comparison of cellular age distributions between healthy and cancerous tissues may inform about dynamical changes within the hierarchical tissue structure, i.e. an acquired increased self-renewal capacity in certain tumours.

1Models of mRNA translation usually presume that transcripts are linear; upon reaching the 2 end of a transcript each terminating ribosome returns to the cytoplasmic pool before initiating 3 anew on a different transcript. A consequence of linear models is that faster translation of a 4 given mRNA is unlikely to generate more of the encoded protein, particularly at low ribosome 5 availability. Recent evidence indicates that eukaryotic mRNAs are circularized, potentially 6 allowing terminating ribosomes to preferentially reinitiate on the same transcript. Here we 7 model the effect of ribosome reinitiation on translation and show that, at high levels of 8 reinitiation, protein synthesis rates are dominated by the time required to translate a given 9 transcript. Our model provides a simple mechanistic explanation for many previously 10 enigmatic features of eukaryotic translation, including the negative correlation of both 11 ribosome densities and protein abundance on transcript length, the importance of codon 12 usage in determining protein synthesis rates, and the negative correlation between transcript 13 length and both codon adaptation and 5' mRNA folding energies. In contrast to linear models 14 where translation is largely limited by initiation rates, our model reveals that all three stages 15 of translation -initiation, elongation, and termination/reinitiation -determine protein synthesis 16 rates even at low ribosome availability. 17 18 now produced large amounts of data on the translation of eukaryotic mRNA, revealing how 1 transcript features, RNA-binding proteins, and non-coding RNAs influence translation [1,2]. 2 While many of the determinants of translation rates revealed by these empirical studies were 3 predicted by existing models, some remain difficult to explain. Perhaps the most striking 4 correlate of translation rate is the length of the transcript itself. Multiple experimental studies, 5 across a wide range of eukaryotic organisms, have demonstrated a steep negative 6 correlation between the length of a given coding sequence (CDS) and three different 7 measures of translation: translation initiation rates [3][4][5], the density of ribosomes on a 8 transcript [5][6][7][8][9][10][11][12][13][14][15], and the abundance of the encoded protein [16][17][18][19]. 9 Ribosome and polysome profiling experiments have shown a positive relationship between 10 ribosome density and protein abundance, leading to the conclusion that transcripts with 11 higher ribosome densities have higher translation rates [9,11,20]. A positive relationship 12 between ribosome density and translation rate can occur when translation is limited by low 13 initiation rates. In traditional models of translation, initiation can be limiting when other steps 14 in translation, such as elongation, occur quickly enough to prevent collisions between 15 ribosomes [20]. Consistent with this key role of initiation rates in determining translation 16 rates, Arava et al [6] found that the higher densities of ribosomes on sh...

Alzheimer's Disease (AD) is a common neurodegenerative disease and the 6th leading cause of death in the US. One neurological marker of AD is the deposition of extracellular plaques composed of aggregates of the amyloid-b (Ab) protein. Ab aggregation follows a nucleation-dependent pathway, beginning with monomer forming nuclei that grow into soluble aggregates and proceed to form the insoluble fibrils deposited in AD brain. As such, many therapeutic treatments target the inhibition of Ab aggregation. It is hypothesized that compounds containing a phenol structure can interrupt aggregate b-sheet formation by disrupting p-p stacking at phenylalanine residues in the core of the protein. In this study, the phenlyethanoid oleuropein, along with metabolites hydroxytyrosol and tyrosol, were studied for their effect on Ab aggregation. Aggregation of SEC-purified Ab was initiated via agitation in the presence of a 5-fold excess of compound and monitored using thioflavin-T to detect aggregate b-sheet structure. To examine the earliest stages of aggregation, oligomerization was induced by combining DMSO-solubilized Ab with a 10-fold excess of inhibitor and diluting into PBS. Oligomer formation was monitored via SDS-PAGE and Western blotting to quantify oligomer size. Distinct correlations were observed between compound structure and the effect on oligomer size and the formation of larger aggregates. Hydroxytyrosol, a metabolite of oleuropein, exhibited the most effective inhibition among these compounds in aggregation and oligomerization. Thus, effectiveness of phenylthanoid compounds in Ab inhibition is influenced by the substitutions present on the ring. In contrast, the structure with only one hydroxyl group, tyrosol, has little effect. Further study will elucidate the effect that these changes in Ab aggregation have upon Ab neurotoxicity.