@article {163323, title = {Bottleneck size drives the evolution of cooperative traits in an aggregative multicellular myxobacterium.}, journal = {PLoS Biol}, volume = {24}, year = {2026}, month = {2026 Jan}, pages = {e3003499}, abstract = {

Repeated population bottlenecks influence the evolution and maintenance of cooperation. However, it remains unclear whether bottlenecks select all cooperative traits expressed by an organism or only a subset of them. Myxococcus xanthus, a social bacterium, displays multiple cooperative traits, including growth, predation, sporulation in multicellular fruiting bodies, and germination. Using laboratory evolution experiments, we investigated the effect of repeated stringent versus relaxed population bottlenecks on the evolution of these four cooperative traits when they were all under selection. We found that only fruiting body formation and growth were positively selected under the stringent regimen, while the other two traits were selected against. The pattern was reversed in the relaxed regimen. Populations propagated under the relaxed regimen also exhibited greater fitness across the entire\ life cycle\ and maintained higher trait variations, including coexistence of cooperative and exploitative strategies. Genomic analyses identified mutations in σ54 interacting protein and DNA binding response regulator protein associated with adaptations in stringent and relaxed regimens, respectively. Furthermore, similar trade-offs, for example, between sporulation and germination, are also seen among natural populations of M. xanthus. Overall, we demonstrate that different bottleneck sizes drive the evolution of cooperative life history traits in distinct ways, often via trade-offs that constrain their joint optimization.

}, keywords = {Bacterial Proteins, Biological Evolution, Mutation, Myxococcus xanthus, Selection, Genetic, Spores, Bacterial}, issn = {1545-7885}, doi = {10.1371/journal.pbio.3003499}, url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003499}, author = {Kalathera, Jyotsna and Jaiswal, Prakhar and Mandal, Neha and Patel, Vishwa and Guttal, Vishwesha and Krishna, Sandeep and Pande, Samay} } @article {149385, title = {Roles of network topology in the relaxation dynamics of simple chemical reaction network models.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Sep 27}, pages = {22187}, abstract = {

Understanding the relationship between the structure of chemical reaction networks and their reaction dynamics is essential for unveiling the design principles of living organisms. However, while some network-structural features are known to relate to the steady-state characteristics of chemical reaction networks, mathematical frameworks describing the links between out-of-steady-state dynamics and network structure are still underdeveloped. Here, we characterize the out-of-steady-state behavior of a class of artificial chemical reaction networks consisting of the ligation and splitting reactions of polymers. Within this class, we examine minimal networks that can convert a given set of sources (e.g., nutrients) to a specified set of targets (e.g., biomass precursors). By exploring the dynamics of the models with a simple setup, we find three distinct types of relaxation dynamics after perturbation from a steady-state: exponential-, power-law-, and plateau-dominated. We computationally show that we can predict this out-of-steady-state dynamical behavior from just three features computed from the network{\textquoteright}s stoichiometric matrix, namely, (1) the rank gap, determining the existence of a steady-state; (2) the left null-space, being related to conserved quantities in the dynamics; and (3) the stoichiometric cone, dictating the range of achievable chemical concentrations. We further demonstrate that these three quantities relates to the type of relaxation dynamics of combinations of our minimal networks, larger networks with many redundant pathways, and a real example of a metabolic network. The relationship between the topological features of reaction networks and the relaxation dynamics presented here are useful clues for understanding the design of metabolic reaction networks as well as industrially useful chemical production pathways.

}, issn = {2045-2322}, doi = {10.1038/s41598-024-73104-5}, author = {Himeoka, Yusuke and Kirkegaard, Julius B and Mitarai, Namiko and Krishna, Sandeep} } @article {118724, title = {Effect of hybrid immunity, school reopening, and the Omicron variant on trajectory of COVID-19 epidemic in India: A modelling study.}, journal = {Lancet Reg Health Southeast Asia}, year = {2023}, month = {2022 Oct 13}, pages = {100095}, abstract = {

Background: The course of the COVID-19 pandemic has been driven by several dynamic behavioral, immunological, and viral factors. We used mathematical modeling to explore how the concurrent reopening of schools, increasing levels of hybrid immunity, and the emergence of the Omicron variant affected the trajectory of the pandemic in India, using Andhra Pradesh (pop: 53 million) as an exemplar Indian state.

Methods: We constructed an age- and contact-structured compartmental model that allows for individuals to proceed through various states depending on whether they have received zero, one, or two doses of the COVID-19 vaccine. We calibrated our model using results from another model (ie, INDSCI-SIM) as well as available context-specific serosurvey data. The introduction of the Omicron variant is modelled alongside protection gained from hybrid immunity. We predict disease dynamics in the background of hybrid immunity coming from infections and an ongoing vaccination program, given prior levels of seropositivity from earlier waves of infection. We describe the consequences of school reopening on cases across different age-bands, as well as the impact of the Omicron (BA.2) variant.

Findings: We show the existence of an epidemic peak in India that is strongly related to the value of background seroprevalence. As expected, because children were not vaccinated in India, re-opening schools increases the number of cases in children more than in adults, although in all scenarios, the peak number of active hospitalizations was never greater than 0.45 times the corresponding peak in the Delta wave before schools were reopened. We varied the level of infection induced seropositivity in our model and found the height of the peak associated with schools reopening reduced as background infection-induced seropositivity increased from 20\% to 40\%. At reported values of seropositivity of 64\% from representative surveys done in India, no discernable peak was observed. We also explored counterfactual scenarios regarding the effect of vaccination on hybrid immunity. We found that in the absence of vaccination, even at high levels of seroprevalence (\>60\%), the emergence of the Omicron variant would have resulted in a large rise in cases across all age bands by as much as 1.8 times. We conclude that the presence of high levels of hybrid immunity resulted in fewer cases in the Omicron wave than in the Delta wave.

Interpretation: In India, decreasing prevalence of immunologically na{\"\i}ve individuals of all ages was associated with fewer cases reported once schools were reopened. In addition, hybrid immunity, together with the lower intrinsic severity of disease associated with the Omicron variant, contributed to low reported COVID-19 hospitalizations and deaths.

Funding: World Health Organization, Mphasis.

}, issn = {2772-3682}, doi = {10.1016/j.lansea.2022.100095}, author = {Mozaffer, Farhina and Cherian, Philip and Krishna, Sandeep and Wahl, Brian and Menon, Gautam I} } @article {101897, title = {Analysis of Infection Time Courses Shows CII Levels Determine the Frequency of Lysogeny in Phage 186.}, journal = {Pharmaceuticals (Basel)}, volume = {14}, year = {2021}, month = {2021 Sep 29}, abstract = {

Engineered phage with properties optimised for the treatment of bacterial infections hold great promise, but require careful characterisation by a number of approaches. Phage-bacteria infection time courses, where populations of bacteriophage and bacteria are mixed and followed over many infection cycles, can be used to deduce properties of phage infection at the individual cell level. Here, we apply this approach to analysis of infection of by the temperate bacteriophage 186 and explore which properties of the infection process can be reliably inferred. By applying established modelling methods to such data, we extract the frequency at which phage 186 chooses the lysogenic pathway after infection, and show that lysogenisation increases in a graded manner with increased expression of the lysogenic establishment factor CII. The data also suggest that, like phage λ, the rate of lysogeny of phage 186 increases with multiple infections.

}, issn = {1424-8247}, doi = {10.3390/ph14100998}, author = {Hao, Nan and Agnew, Dylan and Krishna, Sandeep and Dodd, Ian B and Shearwin, Keith E} } @article {96414, title = {Optimizing testing for COVID-19 in India.}, journal = {PLoS Comput Biol}, volume = {17}, year = {2021}, month = {2021 Jul}, pages = {e1009126}, abstract = {

COVID-19 testing across India uses a mix of two types of tests. Rapid Antigen Tests (RATs) are relatively inexpensive point-of-care lateral-flow-assay tests, but they are also less sensitive. The reverse-transcriptase polymerase-chain-reaction (RT-PCR) test has close to 100\% sensitivity and specificity in a laboratory setting, but delays in returning results, as well as increased costs relative to RATs, may vitiate this advantage. India-wide, about 49\% of COVID-19 tests are RATs, but some Indian states, including the large states of Uttar Pradesh (pop. 227.9 million) and Bihar (pop. 121.3 million) use a much higher proportion of such tests. Here we show, using simulations based on epidemiological network models, that the judicious use of RATs can yield epidemiological outcomes comparable to those obtained through RT-PCR-based testing and isolation of positives, provided a few conditions are met. These are (a) that RAT test sensitivity is not too low, (b) that a reasonably large fraction of the population, of order 0.5\% per day, can be tested, (c) that those testing positive are isolated for a sufficient duration, and that (d) testing is accompanied by other non-pharmaceutical interventions for increased effectiveness. We assess optimal testing regimes, taking into account test sensitivity and specificity, background seroprevalence and current test pricing. We find, surprisingly, that even 100\% RAT test regimes should be acceptable, from both an epidemiological as well as a economic standpoint, provided the conditions outlined above are met.

}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1009126}, author = {Cherian, Philip and Krishna, Sandeep and Menon, Gautam I} } @article {95781, title = {RNA diversification by a self-reproducing ribozyme revealed by deep sequencing and kinetic modelling.}, journal = {Chem Commun (Camb)}, year = {2021}, month = {2021 Jul 08}, abstract = {

We demonstrate that a recombinase ribozyme achieves multiple functions in the same reaction network: self-reproduction, iterative elongation and circularization of other RNAs, leading to synthesis of diverse products predicted by a kinetic model. This shows that key mechanisms can be integrated and controlled toward Darwinian evolution in RNA reaction networks.

}, issn = {1364-548X}, doi = {10.1039/d1cc02290c}, author = {Jeancolas, Cyrille and Matsubara, Yoshiya J and Vybornyi, Mykhailo and Lambert, Camille N and Blokhuis, Alex and Alline, Thomas and Griffiths, Andrew D and Ameta, Sandeep and Krishna, Sandeep and Nghe, Philippe} } @article {92883, title = {Self-Reproduction and Darwinian Evolution in Autocatalytic Chemical Reaction Systems.}, journal = {Life (Basel)}, volume = {11}, year = {2021}, month = {2021 Apr 01}, abstract = {

Understanding the emergence of life from (primitive) abiotic components has arguably been one of the deepest and yet one of the most elusive scientific questions. Notwithstanding the lack of a clear definition for a living system, it is widely argued that heredity (involving self-reproduction) along with compartmentalization and metabolism are key features that contrast living systems from their non-living counterparts. A minimal living system may be viewed as "a self-sustaining chemical system capable of Darwinian evolution". It has been proposed that autocatalytic sets of chemical reactions (ACSs) could serve as a mechanism to establish chemical compositional identity, heritable self-reproduction, and evolution in a minimal chemical system. Following years of theoretical work, autocatalytic chemical systems have been constructed experimentally using a wide variety of substrates, and most studies, thus far, have focused on the demonstration of chemical self-reproduction under specific conditions. While several recent experimental studies have raised the possibility of carrying out some aspects of experimental evolution using autocatalytic reaction networks, there remain many open challenges. In this review, we start by evaluating theoretical studies of ACSs specifically with a view to establish the conditions required for such chemical systems to exhibit self-reproduction and Darwinian evolution. Then, we follow with an extensive overview of experimental ACS systems and use the theoretically established conditions to critically evaluate these empirical systems for their potential to exhibit Darwinian evolution. We identify various technical and conceptual challenges limiting experimental progress and, finally, conclude with some remarks about open questions.

}, issn = {2075-1729}, doi = {10.3390/life11040308}, author = {Ameta, Sandeep and Matsubara, Yoshiya J and Chakraborty, Nayan and Krishna, Sandeep and Thutupalli, Shashi} } @article {92877, title = {A tale of two rhythms: Locked clocks and chaos in biology.}, journal = {Cell Syst}, volume = {12}, year = {2021}, month = {2021 Apr 21}, pages = {291-303}, abstract = {

The fundamental mechanisms that control and regulate biological organisms exhibit a surprising level of complexity. Oscillators are perhaps the simplest motifs that produce time-varying dynamics and are ubiquitous in biological systems. It is also known that such biological oscillators interact with each other-for instance, circadian oscillators affect the cell cycle, and somitogenesis clock proteins in adjacent cells affect each other in developing embryos. Therefore, it is vital to understand the effects that can emerge from non-linear interaction between oscillations. Here, we show how oscillations typically arise in biology and take the reader on a tour through the great variety in dynamics that can emerge even from a single pair of coupled oscillators. We explain how chaotic dynamics can emerge and outline the methods of detecting this in experimental time traces. Finally, we discuss the potential role of such complex dynamical features in biological systems.

}, issn = {2405-4720}, doi = {10.1016/j.cels.2021.03.003}, author = {Heltberg, Mathias L and Krishna, Sandeep and Kadanoff, Leo P and Jensen, Mogens H} } @article {84575, title = {Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments.}, journal = {Mol Biol Cell}, volume = {31}, year = {2020}, month = {12/2020}, pages = {2920-2931}, abstract = {

Faithful propagation of life requires coordination of DNA replication and segregation with cell growth and division. In bacteria, this results in cell size homeostasis and periodicity in replication and division. The situation is perturbed under stress such as DNA damage, which induces filamentation as cell cycle progression is blocked to allow for repair. Mechanisms that release this morphological state for re-entry into wild type growth are unclear. Here we show that damage-induced filaments divide asymmetrically, producing short daughter cells that tend to be devoid of damage and have wild type size and growth dynamics. The Min system primarily determines division site location in the filament, with additional regulation of division completion by chromosome segregation. Collectively, we propose that coordination between chromosome (and specifically segregation and cell division may result in asymmetric division in damage-induced filaments and facilitate recovery from a stressed state.

}, issn = {1939-4586}, doi = {10.1091/mbc.E20-08-0547}, author = {Raghunathan, Suchitha and Chimthanawala, Afroze and Krishna, Sandeep and Vecchiarelli, Anthony G and Badrinarayanan, Anjana} } @article {83749, title = {Defence versus growth in a hostile world: lessons from phage and bacteria.}, journal = {R Soc Open Sci}, volume = {7}, year = {2020}, month = {2020 Sep}, pages = {201118}, abstract = {

Bacterial communities are often highly diverse with several closely related species (or strains) coexisting together. These bacteria compete for resources and the competitive exclusion principle predicts that all but the fastest-growing bacteria will go extinct. When exposed to phage, it is predicted that bacterial strains with restriction-modification (RM) systems can circumvent the competitive exclusion principle and reach diversity of the order of the phage burst size. We show that with a trade-off between bacterial growth rates and the strength of their RM systems, the diversity of such an ecosystem can further increase several fold beyond the burst size limit. Moreover, we find that the ratio of the growth rate of a bacterial strain to the imperfection of its RM system is an excellent predictor of (i) whether the strain will go extinct or not, and (ii) the biomass of the strain if it survives. In contrast, the growth rate alone is not a determinant of either of these properties. Our work provides a quantitative example of a model ecosystem where the fitness of a species is determined not by growth rate, but by a trade-off between growth and defence against predators.

}, issn = {2054-5703}, doi = {10.1098/rsos.201118}, author = {Eriksen, Rasmus Skytte and Krishna, Sandeep} } @article {84572, title = {Pooling Samples to Increase SARS-CoV-2 Testing.}, journal = {J Indian Inst Sci}, year = {2020}, month = {2020 Oct 18}, pages = {1-6}, abstract = {

As SARS-CoV-2 continues to propagate around the world, it is becoming increasingly important to scale up testing. This is necessary both at the individual level, to inform diagnosis, treatment and contract tracing, as well as at the population level to inform policies to control spread of the infection. The gold-standard RT-qPCR test for the virus is relatively expensive and takes time, so combining multiple samples into "pools" that are tested together has emerged as a useful way to test many individuals with less than one test per person. Here, we describe the basic idea behind pooling of samples and different methods for reconstructing the result for each individual from the test of pooled samples. The methods range from simple pooling, where each pool is disjoint from the other, to more complex combinatorial pooling where each sample is split into multiple pools and each pool has a specified combination of samples. We describe efforts to validate these testing methods clinically and the potential advantages of the combinatorial pooling method named Tapestry Pooling that relies on compressed sensing techniques.

}, issn = {0970-4140}, doi = {10.1007/s41745-020-00204-2}, author = {Gopalkrishnan, Manoj and Krishna, Sandeep} } @article {82602, title = {Resource plasticity-driven carbon-nitrogen budgeting enables specialization and division of labor in a clonal community }, journal = {Elife}, volume = {9}, year = {2020}, month = {09/2020}, abstract = {

Previously, we found that in glucose-limited Saccharomyces cerevisiae colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic or glycolytic states. In that study, threshold amounts of trehalose - a limiting, produced carbon-resource, controls the emergence and self-organization of cells exhibiting the glycolytic state, serving as a carbon source that fuels glycolysis (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential metabolic budgeting. In gluconeogenic cells, aspartate is a carbon source for trehalose production, while in glycolytic cells using trehalose for carbon, aspartate is predominantly a nitrogen source for nucleotide synthesis. This metabolic plasticity of aspartate enables carbon-nitrogen budgeting, thereby driving the biochemical self-organization of distinct cell states. Through this organization, cells in each state exhibit true division of labor, providing growth/survival advantages for the whole community.

}, doi = {10.7554/eLife.57609 }, author = {Varahan, Sriram and Sinha, Vaibhhav and Walvekar, Adhish and Krishna, Sandeep and Laxman, Sunil} } @article {50999, title = {On chaotic dynamics in transcription factors and the associated effects in differential gene regulation.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 08}, pages = {71}, abstract = {

The control of proteins by a transcription factor with periodically varying concentration exhibits intriguing dynamical behaviour. Even though it is accepted that transcription factors vary their dynamics in response to different situations, insight into how this affects downstream genes is lacking. Here, we investigate how oscillations and chaotic dynamics in the transcription factor NF-κB can affect downstream protein production. We describe how it is possible to control the effective dynamics of the transcription factor by stimulating it with an oscillating ligand. We find that chaotic dynamics modulates gene expression and up-regulates certain families of low-affinity genes, even in the presence of extrinsic and intrinsic noise. Furthermore, this leads to an increase in the production of protein complexes and the efficiency of their assembly. Finally, we show how chaotic dynamics creates a heterogeneous population of cell states, and describe how this can be beneficial in multi-toxic environments.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-07932-1}, author = {Heltberg, Mathias L and Krishna, Sandeep and Jensen, Mogens H} } @article {65308, title = {Constraints on somite formation in developing embryos.}, journal = {J R Soc Interface}, volume = {16}, year = {2019}, month = {2019 Sep 27}, pages = {20190451}, abstract = {

Segment formation in vertebrate embryos is a stunning example of biological self-organization. Here, we present an idealized framework, in which we treat the presomitic mesoderm (PSM) as a one-dimensional line of oscillators. We use the framework to derive constraints that connect the size of somites, and the timing of their formation, to the growth of the PSM and the gradient of the somitogenesis clock period across the PSM. Our analysis recapitulates the observations made recently in cultures of mouse PSM cells, and makes predictions for how perturbations, such as increased Wnt levels, would alter somite widths. Finally, our analysis makes testable predictions for the shape of the phase profile and somite widths at different stages of PSM growth. In particular, we show that the phase profile is robustly concave when the PSM length is steady and slightly convex in an important special case when it is decreasing exponentially. In both cases, the phase profile scales with the PSM length; in the latter case, it scales dynamically. This has important consequences for the velocity of the waves that traverse the PSM and trigger somite formation, as well as the effect of errors in phase measurement on somite widths.

}, issn = {1742-5662}, doi = {10.1098/rsif.2019.0451}, author = {Juul, Jonas S and Jensen, Mogens H and Krishna, Sandeep} } @article {60325, title = {Metabolic constraints drive self-organization of specialized cell groups.}, journal = {Elife}, volume = {8}, year = {2019}, month = {2019 Jun 26}, abstract = {

How phenotypically distinct states in isogenic cell populations appear and stably co-exist remains unresolved. We find that within a mature, clonal yeast colony developing in low glucose, cells arrange into metabolically disparate cell groups. Using this system, we model and experimentally identify metabolic constraints sufficient to drive such self-assembly. Beginning in a uniformly gluconeogenic state, cells exhibiting a contrary, high pentose phosphate pathway activity state, spontaneously appear and proliferate, in a spatially constrained manner. Gluconeogenic cells in the colony produce and provide a resource, which we identify as trehalose. Above threshold concentrations of external trehalose, cells switch to the new metabolic state and proliferate. A self-organized system establishes, where cells in this new state are sustained by trehalose consumption, which thereby restrains other cells in the trehalose producing, gluconeogenic state. Our work suggests simple physico-chemical principles that determine how isogenic cells spontaneously self-organize into structured assemblies in complimentary, specialized states.

}, issn = {2050-084X}, doi = {10.7554/eLife.46735}, author = {Varahan, Sriram and Walvekar, Adhish and Sinha, Vaibhhav and Krishna, Sandeep and Laxman, Sunil} } @article {39424, title = {Detection of cooperatively bound transcription factor pairs using ChIP-seq peak intensities and expectation maximization.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0199771}, abstract = {

Transcription factors (TFs) often work cooperatively, where the binding of one TF to DNA enhances the binding affinity of a second TF to a nearby location. Such cooperative binding is important for activating gene expression from promoters and enhancers in both prokaryotic and eukaryotic cells. Existing methods to detect cooperative binding of a TF pair rely on analyzing the sequence that is bound. We propose a method that uses, instead, only ChIP-seq peak intensities and an expectation maximization (CPI-EM) algorithm. We validate our method using ChIP-seq data from cells where one of a pair of TFs under consideration has been genetically knocked out. Our algorithm relies on our observation that cooperative TF-TF binding is correlated with weak binding of one of the TFs, which we demonstrate in a variety of cell types, including E. coli, S. cerevisiae and M. musculus cells. We show that this method performs significantly better than a predictor based only on the ChIP-seq peak distance of the TFs under consideration. This suggests that peak intensities contain information that can help detect the cooperative binding of a TF pair. CPI-EM also outperforms an existing sequence-based algorithm in detecting cooperative binding. The CPI-EM algorithm is available at https://github.com/vishakad/cpi-em.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0199771}, author = {Datta, Vishaka and Siddharthan, Rahul and Krishna, Sandeep} } @article {30018, title = {Evidence of sinks and sources in the phospholipase C activated PIP2 cycle.}, journal = {FEBS Lett}, year = {2018}, month = {2018 Feb 10}, abstract = {

In many eukaryotic signalling cascades, receptor mediated phospholipase C (PLC) activity triggers phosphatidylinositol-4,5-bisphosphate (PIP2 ) hydrolysis leading to information transfer. Coupled with PLC activation is a sequence of reactions spread across multiple compartments which resynthesize PIP2 , a process essential for supporting sustained PLC signalling. The biochemical strategies coordinating these reactions and, in particular, whether this is a closed cycle with no net addition or loss of metabolites, are poorly understood. Using mathematical models, we find that most closed PIP2 cycles cannot explain experimentally observed changes in key metabolic intermediates in particular mutants. Thus, we propose that the PIP2 cycle likely includes at least one metabolic source and one sink whose net activity results in the experimentally observed regulation of this key signalling pathway. This article is protected by copyright. All rights reserved.

}, issn = {1873-3468}, doi = {10.1002/1873-3468.12998}, author = {Suratekar, Rohit and Panda, Aniruddha and Padinjat, Raghu and Krishna, Sandeep} } @article {39420, title = {A minimal "push-pull" bistability model explains oscillations between quiescent and proliferative cell states.}, journal = {Mol Biol Cell}, year = {2018}, month = {2018 Jul 25}, pages = {mbcE18010017}, abstract = {

A minimal model for oscillating between quiescent and growth/proliferation states, dependent on the availability of a central metabolic resource, is presented. From the yeast metabolic cycles (YMCs), metabolic oscillations in oxygen consumption are represented as transitions between quiescent and growth states. We consider metabolic resource availability, growth rates, and switching rates (between states) to model a relaxation oscillator explaining transitions between these states. This frustrated bistability model reveals a required communication between the metabolic resource that determines oscillations, and the quiescent and growth state cells. Cells in each state reflect memory, or hysteresis of their current state, and "push-pull" cells from the other state. Finally, a parsimonious argument is made for a specific central metabolite as the controller of switching between quiescence and growth states. We discuss how an oscillator built around the availability of such a metabolic resource is sufficient to generally regulate oscillations between growth and quiescence, through committed transitions.

}, issn = {1939-4586}, doi = {10.1091/mbc.E18-01-0017}, author = {Krishna, Sandeep and Laxman, Sunil} } @article {33715, title = {Regulation of Global Transcription in by Rsd and 6S RNA.}, journal = {G3 (Bethesda)}, year = {2018}, month = {2018 Apr 23}, abstract = {

In , the sigma factor σ directs RNA polymerase to transcribe growth-related genes, while σ directs transcription of stress response genes during stationary phase. Two molecules hypothesized to regulate RNA polymerase are the protein Rsd, which binds to σ, and the non-coding 6S RNA which binds to the RNA polymerase-σ holoenzyme. Despite multiple studies, the functions of Rsd and 6S RNA remain controversial. Here we use RNA-Seq in five phases of growth to elucidate their function on a genome-wide scale. We show for the first time that Rsd and 6S RNA facilitate σ activity throughout bacterial growth, while 6S RNA also regulates widely different genes depending upon growth phase. We discover novel interactions between 6S RNA and Rsd and show widespread expression changes in a strain lacking both regulators. Finally, we present a mathematical model of transcription which highlights the crosstalk between Rsd and 6S RNA as a crucial factor in controlling sigma factor competition and global gene expression.

}, issn = {2160-1836}, doi = {10.1534/g3.118.200265}, author = {Lal, Avantika and Krishna, Sandeep and Seshasayee, Aswin Sai Narain} } @article {22088, title = {In silico Evolution of Lysis-Lysogeny Strategies Reproduces Observed Lysogeny Propensities in Temperate Bacteriophages.}, journal = {Front Microbiol}, volume = {8}, year = {2017}, month = {2017}, pages = {1386}, abstract = {

Bacteriophages are the most abundant organisms on the planet and both lytic and temperate phages play key roles as shapers of ecosystems and drivers of bacterial evolution. Temperate phages can choose between (i) lysis: exploiting their bacterial hosts by producing multiple phage particles and releasing them by lysing the host cell, and (ii) lysogeny: establishing a potentially mutually beneficial relationship with the host by integrating their chromosome into the host cell{\textquoteright}s genome. Temperate phages exhibit lysogeny propensities in the curiously narrow range of 5-15\%. For some temperate phages, the propensity is further regulated by the multiplicity of infection, such that single infections go predominantly lytic while multiple infections go predominantly lysogenic. We ask whether these observations can be explained by selection pressures in environments where multiple phage variants compete for the same host. Our models of pairwise competition, between phage variants that differ only in their propensity to lysogenize, predict the optimal lysogeny propensity to fall within the experimentally observed range. This prediction is robust to large variation in parameters such as the phage infection rate, burst size, decision rate, as well as bacterial growth rate, and initial phage to bacteria ratio. When we compete phage variants whose lysogeny strategies are allowed to depend upon multiplicity of infection, we find that the optimal strategy is one which switches from full lysis for single infections to full lysogeny for multiple infections. Previous attempts to explain lysogeny propensity have argued for bet-hedging that optimizes the response to fluctuating environmental conditions. Our results suggest that there is an additional selection pressure for lysogeny propensity within phage populations infecting a bacterial host, independent of environmental conditions.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2017.01386}, author = {Sinha, Vaibhhav and Goyal, Akshit and Svenningsen, Sine L and Semsey, Szabolcs and Krishna, Sandeep} } @article {26658, title = {Time Correlations in Mode Hopping of Coupled Oscillators}, journal = {Journal of Statistical Physics}, volume = {167}, year = {2017}, month = {05/2017}, pages = {792{\textendash}805}, abstract = {

We study the dynamics in a system of coupled oscillators when Arnold Tongues overlap. By varying the initial conditions, the deterministic system can be attracted to different limit cycles. Adding noise, the mode hopping between different states become a dominating part of the dynamics. We simplify the system through a Poincare section, and derive a 1D model to describe the dynamics. We explain that for some parameter values of the external oscillator, the time distribution of occupancy in a state is exponential and thus memoryless. In the general case, on the other hand, it is a sum of exponential distributions characteristic of a system with time correlations.

}, author = {Heltberg, ML and Krishna, Sandeep and Jensen, Mogens H} } @article {997, title = {Effects of Four Different Regulatory Mechanisms on the Dynamics of Gene Regulatory Cascades.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {12186}, abstract = {

Gene regulatory cascades (GRCs) are common motifs in cellular molecular networks. A given logical function in these cascades, such as the repression of the activity of a transcription factor, can be implemented by a number of different regulatory mechanisms. The potential consequences for the dynamic performance of the GRC of choosing one mechanism over another have not been analysed systematically. Here, we report the construction of a synthetic GRC in Escherichia coli, which allows us for the first time to directly compare and contrast the dynamics of four different regulatory mechanisms, affecting the transcription, translation, stability, or activity of a transcriptional repressor. We developed a biologically motivated mathematical model which is sufficient to reproduce the response dynamics determined by experimental measurements. Using the model, we explored the potential response dynamics that the constructed GRC can perform. We conclude that dynamic differences between regulatory mechanisms at an individual step in a GRC are often concealed in the overall performance of the GRC, and suggest that the presence of a given regulatory mechanism in a certain network environment does not necessarily mean that it represents a single optimal evolutionary solution.

}, issn = {2045-2322}, doi = {10.1038/srep12186}, author = {Hansen, Sabine and Krishna, Sandeep and Semsey, Szabolcs and Svenningsen, Sine Lo} } @article {1006, title = {Restriction modification systems as engines of diversity.}, journal = {Front Microbiol}, volume = {6}, year = {2015}, month = {2015}, pages = {528}, abstract = {

Restriction modification (RM) systems provide protection against a broad spectrum of phages. However, the likelihood of a phage permanently bypassing this can be as high as 0.1 per infection (Korona et al., 1993) which makes for a relatively weak defense. Here we argue that, apart from providing such transient defenses, RM systems can facilitate long-term coexistence of many bacterial strains. We show that this diversity can be as large as the burst size of the phage but no larger-a curious correspondence between a number at the level of species and another number at the level of individuals. Such a highly diverse and stably coexisting ecosystem is robust to substantial variation in both bacterial growth rates and strength of their RM systems, which might be one reason why quite weak RM systems exist in the wild.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2015.00528}, author = {Sneppen, Kim and Semsey, Szabolcs and Seshasayee, Aswin S N and Krishna, Sandeep} } @article {1034, title = {The role of mRNA and protein stability in the function of coupled positive and negative feedback systems in eukaryotic cells.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {13910}, abstract = {

Oscillators and switches are important elements of regulation in biological systems. These are composed of coupling negative feedback loops, which cause oscillations when delayed, and positive feedback loops, which lead to memory formation. Here, we examine the behavior of a coupled feedback system, the Negative Autoregulated Frustrated bistability motif (NAF). This motif is a combination of two previously explored motifs, the frustrated bistability motif (FBM) and the negative auto regulation motif (NAR), which both can produce oscillations. The NAF motif was previously suggested to govern long term memory formation in animals, and was used as a synthetic oscillator in bacteria. We build a mathematical model to analyze the dynamics of the NAF motif. We show analytically that the NAF motif requires an asymmetry in the strengths of activation and repression links in order to produce oscillations. We show that the effect of time delays in eukaryotic cells, originating from mRNA export and protein import, are negligible in this system. Based on the reported protein and mRNA half-lives in eukaryotic cells, we find that even though the NAF motif possesses the ability for oscillations, it mostly promotes constant protein expression at the biologically relevant parameter regimes.

}, issn = {2045-2322}, doi = {10.1038/srep13910}, author = {Moss Bendtsen, Kristian and Jensen, Mogens H and Krishna, Sandeep and Semsey, Szabolcs} } @article {1025, title = {Why do bacteria regulate public goods by quorum sensing?-How the shapes of cost and benefit functions determine the form of optimal regulation.}, journal = {Front Microbiol}, volume = {6}, year = {2015}, month = {2015}, pages = {767}, abstract = {

Many bacteria secrete compounds which act as public goods. Such compounds are often under quorum sensing (QS) regulation, yet it is not understood exactly when bacteria may gain from having a public good under QS regulation. Here, we show that the optimal public good production rate per cell as a function of population size (the optimal production curve, OPC) depends crucially on the cost and benefit functions of the public good and that the OPC will fall into one of two categories: Either it is continuous or it jumps from zero discontinuously at a critical population size. If, e.g., the public good has accelerating returns and linear cost, then the OPC is discontinuous and the best strategy thus to ramp up production sharply at a precise population size. By using the example of public goods with accelerating and diminishing returns (and linear cost) we are able to determine how the two different categories of OPSs can best be matched by production regulated through a QS signal feeding back on its own production. We find that the optimal QS parameters are different for the two categories and specifically that public goods which provide accelerating returns, call for stronger positive signal feedback.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2015.00767}, author = {Heilmann, Silja and Krishna, Sandeep and Kerr, Benjamin} }