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Pairs of endothelial cells on adhesive micropatterns rotate persistently, but pairs of fibroblasts do not; coherent rotation is present in normal mammary acini and kidney cells but absent in cancerous cells. Why? To answer this question, we develop a computational model of pairs of mammalian cells on adhesive micropatterns using a phase field method and study the conditions under which persistent rotational motion (PRM) emerges. Our model couples the shape of the cell, the cell's internal chemical polarity, and interactions between cells such as volume exclusion and adhesion. We show that PRM can emerge from this minimal model and that the cell-cell interface may be influenced by the nucleus. We study the effect of various cell polarity mechanisms on rotational motion, including contact inhibition of locomotion, neighbor alignment, and velocity alignment, where cells align their polarity to their velocity. These polarity mechanisms strongly regulate PRM: Small differences in polarity mechanisms can create significant differences in collective rotation. We argue that the existence or absence of rotation under confinement may lead to insight into the cell's methods for coordinating collective cell motility.

Significance The phenomenon of persistence is important both at a fundamental level in serving as a striking example of adaptive phenotypic variability and from the applied perspective as it contributes to the antibiotic resistance of bacteria in general and biofilms in particular. Our paper presents a unique quantitatively successful model of persistence in Escherichia coli and helps explain many puzzling observations in the literature. It will serve as a guide for further work, both experimental and theoretical. The primary molecular actors in our approach are a toxin–antitoxin pair HipBA, and we use very recent structural data to formulate a comprehensive approach to this problem and to guide further work. Finally, our effort is consistent with recent ideas regarding the fact that many toxin–antitoxin pairs may contribute in a parallel manner to the persister state.

The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.

A sequence analysis-oriented binary search-like algorithm was transformed to a sensitive and accurate analysis tool for processing whole-genome data. The advantage of the algorithm over previous methods is its ability to detect the margins of both short and long genome fragments, enriched by up-regulated signals, at equal accuracy. The score of an enriched genome fragment reflects the difference between the actual concentration of up-regulated signals in the fragment and the chromosome signal baseline. The “divide-and-conquer”-type algorithm detects a series of nonintersecting fragments of various lengths with locally optimal scores. The procedure is applied to detected fragments in a nested manner by recalculating the lower-than-baseline signals in the chromosome. The algorithm was applied to simulated whole-genome data, and its sensitivity/specificity were compared with those of several alternative algorithms. The algorithm was also tested with four biological tiling array datasets comprising Arabidopsis ( i ) expression and ( ii ) histone 3 lysine 27 trimethylation CHIP-on-chip datasets; Saccharomyces cerevisiae ( iii ) spliced intron data and ( iv ) chromatin remodeling factor binding sites. The analyses’ results demonstrate the power of the algorithm in identifying both the short up-regulated fragments (such as exons and transcription factor binding sites) and the long—even moderately up-regulated zones—at their precise genome margins. The algorithm generates an accurate whole-genome landscape that could be used for cross-comparison of signals across the same genome in evolutionary and general genomic studies.

Sibling Paenibacillus dendritiformis bacterial colonies grown on low-nutrient agar medium mutually inhibit growth through secretion of a lethal factor. Analysis of secretions reveals the presence of subtilisin (a protease) and a 12 kDa protein, termed sibling lethal factor (Slf). Purified subtilisin promotes the growth and expansion of P. dendritiformis colonies, whereas Slf is lethal and lyses P. dendritiformis cells in culture. Slf is encoded by a gene belonging to a large family of bacterial genes of unknown function, and the gene is predicted to encode a protein of approximately 20 kDa, termed dendritiformis sibling bacteriocin. The 20 kDa recombinant protein was produced and found to be inactive, but exposure to subtilisin resulted in cleavage to the active, 12 kDa form. The experimental results, combined with mathematical modeling, show that subtilisin serves to regulate growth of the colony. Below a threshold concentration, subtilisin promotes colony growth and expansion. However, once it exceeds a threshold, as occurs at the interface between competing colonies, Slf is then secreted into the medium to rapidly reduce cell density by lysis of the bacterial cells. The presence of genes encoding homologs of dendritiformis sibling bacteriocin in other bacterial species suggests that this mechanism for self-regulation of colony growth might not be limited to P. dendritiformis .

Secretion of extracellular polymeric substances (EPSs) by growing bacteria is an integral part of forming biofilm-like structures. In such dense systems, mechanical interactions among the structural components can be expected to significantly contribute to morphological properties. Here, we use a particle-based modeling approach to study the self-organization of nonmotile rod-shaped bacterial cells growing on a solid substrate in the presence of self-produced EPSs. In our simulation, all of the components interact mechanically via repulsive forces, occurring as the bacterial cells grow and divide (via consuming diffusing nutrient) and produce EPSs. Based on our simulation, we show that mechanical interactions control the collective behavior of the system. In particular, we find that the presence of nonadsorbing EPSs can lead to spontaneous aggregation of bacterial cells by a depletion attraction and thereby generates phase separated patterns in the nonequilibrium growing colony. Both repulsive interactions between cell and EPSs and the overall concentration of EPSs are important factors in the self-organization in a nonequilibrium growing colony. Furthermore, we investigate the interplay of mechanics with the nutrient diffusion and consumption by bacterial cells and observe that suppression of branch formation occurs due to EPSs compared with the case where no EPS is produced.

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically--it represses Delta, but activates Jagged. Although the dynamical role of Notch-Jagged signaling remains elusive, it is widely recognized that Notch-Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt--Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state--a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor-stroma cross-talk, which frequently entails Notch-Jagged communication.

Development of therapy against infections caused by antibiotic-resistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we show that the modified motif per se is resistant to proteolytic degradation and is a candidate antiinfective agent. We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergy with antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D-enantiomer antimicrobial peptidomimetics that target bacterial membranes of certain Gram-negative problem pathogens with promising translational applications.

Most WT bacteria thrive in multicellular communities in the form of biofilms (1). Biofilms have a highly complex 3D architecture that allows the colonization of virtually any nonshedding surface, protection against most environmental stress and a base for future surface colonization by other microorganisms. Biofilms are commonly present in water pipes, oil wells, medical implants, air conditioning, and other systems (2, 3). Much effort has been invested in combating biofilm contamination in industrial settings, agriculture, and health. They are responsible for more than 80% of all microbial infections in humans (4, 5). The remarkable mechanical and chemical properties of biofilms are attributable to a subpopulation of the cells secreting an ECM whose chemical and physical properties are now beginning to be revealed. Novel superresolution imaging approaches, such as laser scanning confocal microscopy, coupled with time-lapse video microscopy and microsensors, revealed the provoking complexity of biofilm formation and 3D architecture (6) (Fig. 1). These descriptive advances have been followed by a number of molecular genetic analyses carried out in biofilms (7, 8). The next challenge is to understand the secrets of biofilm engineering. At the cellular level, the incarceration of cells in a rigid structure requires a complex social synergy among the cells in the colony, particularly to balance and optimize cell growth and the costly production of the ECM. Because there is no individual incentive for a cell living in the biofilm to spend its resources producing ECM components, signaling pathways directing the phenotypic changes are very important. Equally important is the availability of nutrients for the matrix producers. In Bacillus subtilis, for example, lipopeptide surfactin not only induces a phenotypic change into matrix production, but this same subpopulation was found to also become cannibals secreting toxins (to which they are immune) that kill other cells to feed on (9). At the end of the life cycle, the cells engage in the production of resilient spores, which can be carried away and endure the trip to colonize other grounds (10).

Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of interactions (architecture) and susceptibility to stochastic fluctuations (noise). Whether the link between circuit architecture and noise is of biological importance remains, however, poorly understood. To investigate this problem, we performed a computational study of gene expression noise for all possible circuit architectures of feed-forward loop (FFL) motifs. Results revealed that FFL architectures fall into two categories depending on whether their ON (stimulated) or OFF (unstimulated) steady states exhibit noise. To explore the biological importance of this difference in noise behavior, we analyzed 858 documented FFLs in Escherichia coli that were divided into 39 functional categories. The majority of FFLs were found to regulate two subsets of functional categories. Interestingly, these two functional categories associated with FFLs of opposite noise behaviors. This opposite noise preference revealed two noise-based strategies to cope with environmental constraints where cellular responses are either initiated or terminated stochastically to allow probabilistic sampling of alternative states. FFLs may thus be selected for their architecture-dependent noise behavior, revealing a biological role for noise that is encoded in gene circuit architectures.