cell aggregation does not require long-range signaling in the population.

Finally, we consider a case of long-range guiding between cells and show that circular aggregates are able to form without cells increasing speed.

These findings present a possibility to discriminate between short-range and long-range guiding mechanisms in myxobacteria by experimentally measuring distribution of cell speeds in circular aggregates.

Cells have been observed to travel long distances in streams and enter distant aggregates rather that the ones nearby, suggesting that aggregation is not caused by a long-range diffusible signal emitted from aggregation centers [18].

cell aggregation does not require long-range signaling in the population.

Recent studies on aggregate merging and dispersal dynamics further argues against the presence of long-range diffusible molecules to signal the aggregation process [6].

In addition, we also consider a case of long-range guiding that is analogous to slime trail following by myxobacteria cells.

For long-range guiding simulations, FEW was also set to 200 pN and Ax = 0.25 pm (half of bacterium width W).

On the tertiary level, the simulated ensembles are overly compact, even though they appear to recapitulate the overall features of transient long-range contacts qualitatively.

A key finding is that, while p53-TAD and its cancer mutants sample a similar set of conformational states, cancer mutants could introduce both local and long-range structural modulations to potentially perturb the balance of p53 binding to various regulatory proteins and further alter how this balance is regulated by multisite phosphorylation of p53-TAD.

The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP conformations, and at the same time reveals important limitations in the current implicit solvent protein force field that must be sufficiently addressed for reliable description of long-range structural features of the disordered ensembles.

The results suggest that, While all sequences sample a similar set of conformational substates, cancer mutants could introduce both local and long-range structural modulations and in turn perturb the balance of p53 binding to various regulatory proteins and further alter how this balance is regulated by multisite phosphorylation of p53-TAD.

Comparison with NMR: Local structural propensities and long-range ordering

Long-range tertiary structural properties of the simulated ensembles have been examined based on their ability to reproduce the experimental PRE effects [42].

PRE coupled with site-di-rected spin-labeling techniques is one of the most powerful techniques for characterizing transient long-range contacts of disordered proteins [51—53].

Furthermore, as shown in Fig 3, the structural ensembles derived from the control and folding simulations of the wild-type protein contain essentially identical sets of long-range contacts and with largely similar probabilities.

The level of convergence observed here for local and long-range structural properties of a 61-residue IDP is noteworthy.

Further analysis of all resulting atomistic ensembles Will then be performed to obtain a preliminary understanding of how cancer-associated mutations may introduce both local and long-range structural changes in unbound p53-TAD, Which could have functional consequences on how p53-TAD may differentially interact With key regulatory pathways and on how these differential interactions may be regulated through multi-site phosphorylations.

Probabilities of long-range contacts calculated from the last 80-ns segments of the folding (upper half) and control (lower half) RE-GA simulations.

By contrast, long-range cytokine signaling requires a high density of cytokine producers or weak consumption (9.9., by sparsely distributed target cells).

Long-range signals will only occur with multiple secreting cells or/ and slow consumption by sparse target cells.

Long-range communication requires coherent secretion by tens to hundreds of producers or/ and sparse uptake.

The spatial range of cytokine signaling can be tuned from purely autocrine via intrasynaptic and short-range paracrine to long-range paracrine.

Therefore, IL-2 from an individual producer will act locally whereas only large clusters of activated cells could cause long-range signals.

Taken together, our simulations of long-range cytokine diffusion and uptake show that long-range paracrine signals are possible in principle, but require exceptional circumstances (extremely high rates of cytokine production or large clusters of cytokine producing cells) that might not readily occur in vivo.

Although we focus on the output of L5 pyramidal neurons, other neurons in the cortical column such as L2/ 3 pyramidal neurons also support Ca2+ dendritic electrogene-sis and NMDA spiking [27] , extend tuft dendrites into the upper layers, and, importantly, have long-range axons which project to other cortical areas.

These cells uniquely possess dendrites spanning all cortical layers and receive both long-range excitatory and local excitatory and inhibitory inputs [1].

Alongside these long-range axons, reciprocal excitatory connections also exist [1].