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1.
J Am Chem Soc ; 144(30): 13441-13445, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35919985

RESUMO

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our group (J. Am. Chem. Soc. 2022, 144, 1380-1388; DOI: 10.1021/jacs.1c11754) and another (J. Am. Chem. Soc. 2021, 143, 20884-20890; DOI: 10.1021/jacs.1c09455), Huang and Granick refer to the diffusion NMR measurements of molecules during a copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. Here we respond to their comments and maintain that no measurable diffusion enhancement was observed during the reaction. We expand on the physical arguments presented in our original JACS Article regarding the appropriate reference state for the diffusion coefficient and present new data showing that the use of other reference states, as suggested by Huang and Granick, will still support our conclusion that the two reactants and one product of the CuAAC reaction do not exhibit boosted mobility during the reaction.


Assuntos
Azidas , Química Click , Alcinos/química , Azidas/química , Catálise , Cobre/química , Reação de Cicloadição
2.
Nature ; 607(7919): 492-498, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35859200

RESUMO

To impart directionality to the motions of a molecular mechanism, one must overcome the random thermal forces that are ubiquitous on such small scales and in liquid solution at ambient temperature. In equilibrium without energy supply, directional motion cannot be sustained without violating the laws of thermodynamics. Under conditions away from thermodynamic equilibrium, directional motion may be achieved within the framework of Brownian ratchets, which are diffusive mechanisms that have broken inversion symmetry1-5. Ratcheting is thought to underpin the function of many natural biological motors, such as the F1F0-ATPase6-8, and it has been demonstrated experimentally in synthetic microscale systems (for example, to our knowledge, first in ref. 3) and also in artificial molecular motors created by organic chemical synthesis9-12. DNA nanotechnology13 has yielded a variety of nanoscale mechanisms, including pivots, hinges, crank sliders and rotary systems14-17, which can adopt different configurations, for example, triggered by strand-displacement reactions18,19 or by changing environmental parameters such as pH, ionic strength, temperature, external fields and by coupling their motions to those of natural motor proteins20-26. This previous work and considering low-Reynolds-number dynamics and inherent stochasticity27,28 led us to develop a nanoscale rotary motor built from DNA origami that is driven by ratcheting and whose mechanical capabilities approach those of biological motors such as F1F0-ATPase.


Assuntos
DNA , Difusão Facilitada , Proteínas Motores Moleculares , DNA/química , Concentração de Íons de Hidrogênio , Proteínas Motores Moleculares/química , Proteínas Motores Moleculares/metabolismo , Movimento (Física) , Movimento , Concentração Osmolar , ATPases Translocadoras de Prótons/química , ATPases Translocadoras de Prótons/metabolismo , Processos Estocásticos , Temperatura , Termodinâmica
3.
Soft Matter ; 18(28): 5171-5176, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35802129

RESUMO

Gels are soft elastic materials made of a three-dimensional cross-linked polymer network and featuring both elastic and dissipative responses under external mechanical stimuli. Here we investigate how such gels mediate the organization of embedded magnetic microparticles when driven by an external field. By constructing a continuum theory, we demonstrate that the collective dynamics of the embedded particles result from the delicate balance between magnetic dipole-dipole interactions, thermal fluctuations and elasticity of the polymer network, verified by our experiments. The proposed model could be extended to other soft magnetic composites in order to predict how the elastic interactions mediate the aggregation of the embedded elements, fostering technological implications for multifunctional hydrogel materials.

4.
Small ; : e2107854, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35815940

RESUMO

Cilia and flagella are beating rod-like organelles that enable the directional movement of microorganisms in fluids and fluid transport along the surface of biological organisms or inside organs. The molecular motor axonemal dynein drives their beating by interacting with microtubules. Constructing synthetic beating systems with axonemal dynein capable of mimicking ciliary beating still represents a major challenge. Here, the bottom-up engineering of a sustained beating synthoneme consisting of a pair of microtubules connected by a series of periodic arrays of approximately eight axonemal dyneins is reported. A model leads to the understanding of the motion through the cooperative, cyclic association-dissociation of the molecular motor from the microtubules. The synthoneme represents a bottom-up self-organized bio-molecular machine at the nanoscale with cilia-like properties.

5.
Proc Natl Acad Sci U S A ; 119(24): e2122269119, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35679341

RESUMO

A common feature of biological self-organization is how active agents communicate with each other or their environment via chemical signaling. Such communications, mediated by self-generated chemical gradients, have consequences for both individual motility strategies and collective migration patterns. Here, in a purely physicochemical system, we use self-propelling droplets as a model for chemically active particles that modify their environment by leaving chemical footprints, which act as chemorepulsive signals to other droplets. We analyze this communication mechanism quantitatively both on the scale of individual agent-trail collisions as well as on the collective scale where droplets actively remodel their environment while adapting their dynamics to that evolving chemical landscape. We show in experiment and simulation how these interactions cause a transient dynamical arrest in active emulsions where swimmers are caged between each other's trails of secreted chemicals. Our findings provide insight into the collective dynamics of chemically active particles and yield principles for predicting how negative autochemotaxis shapes their navigation strategy.


Assuntos
Quimiotaxia , Simulação por Computador , Emulsões
6.
Nat Commun ; 13(1): 3036, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641506

RESUMO

Fluctuation theorems specify the non-zero probability to observe negative entropy production, contrary to a naive expectation from the second law of thermodynamics. For closed particle trajectories in a fluid, Stokes theorem can be used to give a geometric characterization of the entropy production. Building on this picture, we formulate a topological fluctuation theorem that depends only by the winding number around each vortex core and is insensitive to other aspects of the force. The probability is robust to local deformations of the particle trajectory, reminiscent of topologically protected modes in various classical and quantum systems. We demonstrate that entropy production is quantized in these strongly fluctuating systems, and it is controlled by a topological invariant. We demonstrate that the theorem holds even when the probability distributions are non-Gaussian functions of the generated heat.

7.
Soft Matter ; 18(15): 2928-2935, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35348175

RESUMO

We study the dynamics and conformations of a single active semiflexible polymer whose monomers experience a propulsion force perpendicular to the local tangent, with the end beads being different from the inner beads ("end-tailored"). Using Langevin simulations, we demonstrate that, apart from sideways motion, the relative propulsion strength between the end beads and the polymer backbone significantly changes the conformational properties of the polymers as a function of bending stiffness, end-tailoring and propulsion force. Expectedly, for slower ends the polymer curves away from the moving direction, while faster ends lead to opposite curving, in both cases slightly reducing the center of mass velocity compared to a straight fiber. Interestingly, for faster end beads there is a rich and dynamic morphology diagram: the polymer ends may get folded together to 2D loops or hairpin-like conformations that rotate due to their asymmetry in shape and periodic flapping motion around a rather straight state during full propulsion is also possible. We rationalize the simulations using scaling and kinematic arguments and present the state diagram of the conformations. Sideways propelled fibers comprise a rather unexplored and versatile class of self-propellers, and their study will open novel ways for designing, e.g. motile actuators or mixers in soft robotics.


Assuntos
Fenômenos Mecânicos , Polímeros , Conformação Molecular
8.
Curr Drug Metab ; 23(3): 242-250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35331105

RESUMO

BACKGROUND: Little is known about cytochrome P450 3A4 (CYP3A4) DNA methylation and transcription alterations in gastric cancer. OBJECTIVE: In this paper, we initially aimed to address the effect of diazinon pesticide on DNA methylation and transcription changes of the CYP3A4 gene in a human gastric cell line. In the next step, we studied the methylation differences of CpG sites within the upstream regulatory regions of the CYP3A4 gene among human gastric cancerous and healthy tissues. METHODS: For the in vitro assay, the methylation changes of the C/EBP response element and transcript level of the CYP3A4 gene were studied following treatment of the AGS cell line with various concentrations of diazinon pesticide. In the next phase, the methylation percentages of 24 CpG sites within or around the upstream regulatory elements, including near promoter, C/EBP binding site, XREM, and CLEM4, in 11 specimens of human gastric cancer tissue were compared to their adjacent healthy tissues. RESULTS: Treatment with 10 µM Diazinon significantly increased the CYP3A4 gene transcription by approximately 27-fold, which was correlated with the hypermethylation of 3 CpGs in C/EBP binding sites, including -5998, -5731 and -5725 (p<0.001 for all comparisons). Results of bisulfite sequencing revealed that the CpG sites which are located in -1521 (p=0.003), -1569 (p=0.027), -10813 (p=0.003), -10851 (p=0.001) and -10895 (p=0.0) bp from transcription start site, were significantly hypermethylated in cancerous tissues comparing to their healthy cohort. CONCLUSION: Hypermethylation of CLEM4 and a region near the core promoter may have a significant association with gastric cancer incidence.


Assuntos
Citocromo P-450 CYP3A , Metilação de DNA , Neoplasias Gástricas , Citocromo P-450 CYP3A/genética , Diazinon/farmacologia , Diazinon/uso terapêutico , Humanos , Regiões Promotoras Genéticas , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
10.
J Am Chem Soc ; 144(3): 1380-1388, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35078321

RESUMO

Micrometer-sized objects are widely known to exhibit chemically driven motility in systems away from equilibrium. Experimental observation of reaction-induced motility or enhancement in diffusivity at the much shorter length scale of small molecules is, however, still a matter of debate. Here, we investigate the molecular diffusivity of reactants, catalyst, and product of a model reaction, the copper-catalyzed azide-alkyne cycloaddition click reaction, and develop new NMR diffusion approaches that allow the probing of reaction-induced diffusion enhancement in nanosized molecular systems with higher accuracy than the state of the art. Following two different approaches that enable the accounting of time-dependent concentration changes during NMR experiments, we closely monitored the diffusion coefficient of reaction components during the reaction. The reaction components showed distinct changes in the diffusivity: while the two reactants underwent a time-dependent decrease in their diffusivity, the diffusion coefficient of the product gradually increased and the catalyst showed only slight diffusion enhancement within the range expected for reaction-induced sample heating. The decrease in diffusion coefficient of the alkyne, one of the two reactants of click reaction, was not reproduced during its copper coordination when the second reactant, azide, was absent. Our results do not support the catalysis-induced diffusion enhancement of the components of the click reaction and, instead, point to the role of a relatively large intermediate species within the reaction cycle with diffusivity lower than that of both the reactants and product molecule.

11.
J R Soc Interface ; 19(186): 20210693, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34983201

RESUMO

Biological cilia pump the surrounding fluid by asymmetric beating that is driven by dynein motors between sliding microtubule doublets. The complexity of biological cilia raises the question about minimal systems that can re-create similar patterns of motion. One such system consists of a pair of microtubules that are clamped at the proximal end. They interact through dynein motors that cover one of the filaments and pull against the other one. Here, we study theoretically the static shapes and the active dynamics of such a system. Using the theory of elastica, we analyse the shapes of two filaments of different lengths with clamped ends. Starting from equal lengths, we observe a transition similar to Euler buckling leading to a planar shape. When further increasing the length ratio, the system assumes a non-planar shape with spontaneously broken chiral symmetry after a secondary bifurcation and then transitions to planar again. The predicted curves agree with experimentally observed shapes of microtubule pairs. The dynamical system can have a stable fixed point, with either bent or straight filaments, or limit cycle oscillations. The latter match many properties of ciliary motility, demonstrating that a two-filament system can serve as a minimal actively beating model.


Assuntos
Dineínas , Modelos Biológicos , Cílios/metabolismo , Citoesqueleto/metabolismo , Dineínas/metabolismo , Microtúbulos
12.
Phys Rev Lett ; 127(20): 208103, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34860057

RESUMO

We examine the stochastic dynamics of two enzymes that are mechanically coupled to each other, e.g., through an elastic substrate or a fluid medium. The enzymes undergo conformational changes during their catalytic cycle, which itself is driven by stochastic steps along a biased chemical free energy landscape. We find conditions under which the enzymes can synchronize their catalytic steps, and discover that the coupling can lead to a significant enhancement in their overall catalytic rate. Both effects can be understood as arising from a global bifurcation in the underlying dynamical system at sufficiently strong coupling. Our findings suggest that, despite their molecular scale, enzymes can be cooperative and improve their performance in metabolic clusters.


Assuntos
Biocatálise , Enzimas/química , Enzimas/metabolismo , Processos Estocásticos
13.
Nat Commun ; 12(1): 6293, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725341

RESUMO

Living cells harvest energy from their environments to drive the chemical processes that enable life. We introduce a minimal system that operates at similar protein concentrations, metabolic densities, and length scales as living cells. This approach takes advantage of the tendency of phase-separated protein droplets to strongly partition enzymes, while presenting minimal barriers to transport of small molecules across their interface. By dispersing these microreactors in a reservoir of substrate-loaded buffer, we achieve steady states at metabolic densities that match those of the hungriest microorganisms. We further demonstrate the formation of steady pH gradients, capable of driving microscopic flows. Our approach enables the investigation of the function of diverse enzymes in environments that mimic cytoplasm, and provides a flexible platform for studying the collective behavior of matter driven far from equilibrium.


Assuntos
Células Artificiais/química , Hidroliases/metabolismo , Nanopartículas/química , Urease/metabolismo , Células Artificiais/metabolismo , Catálise , Humanos , Hidroliases/química , Modelos Biológicos , Urease/química
14.
Eur Phys J E Soft Matter ; 44(9): 113, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34478002

RESUMO

Biomolecular condensates in cells are often rich in catalytically active enzymes. This is particularly true in the case of the large enzymatic complexes known as metabolons, which contain different enzymes that participate in the same catalytic pathway. One possible explanation for this self-organization is the combination of the catalytic activity of the enzymes and a chemotactic response to gradients of their substrate, which leads to a substrate-mediated effective interaction between enzymes. These interactions constitute a purely non-equilibrium effect and show exotic features such as non-reciprocity. Here, we analytically study a model describing the phase separation of a mixture of such catalytically active particles. We show that a Michaelis-Menten-like dependence of the particles' activities manifests itself as a screening of the interactions, and that a mixture of two differently sized active species can exhibit phase separation with transient oscillations. We also derive a rich stability phase diagram for a mixture of two species with both concentration-dependent activity and size dispersity. This work highlights the variety of possible phase separation behaviours in mixtures of chemically active particles, which provides an alternative pathway to the passive interactions more commonly associated with phase separation in cells. Our results highlight non-equilibrium organizing principles that can be important for biologically relevant liquid-liquid phase separation.

15.
Elife ; 102021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346311

RESUMO

Cilia are hairlike organelles involved in both sensory functions and motility. We discuss the question of whether the location of chemical receptors on cilia provides an advantage in terms of sensitivity and whether motile sensory cilia have a further advantage. Using a simple advection-diffusion model, we compute the capture rates of diffusive molecules on a cilium. Because of its geometry, a non-motile cilium in a quiescent fluid has a capture rate equivalent to a circular absorbing region with ∼4× its surface area. When the cilium is exposed to an external shear flow, the equivalent surface area increases to ∼6×. Alternatively, if the cilium beats in a non-reciprocal way in an otherwise quiescent fluid, its capture rate increases with the beating frequency to the power of 1/3. Altogether, our results show that the protruding geometry of a cilium could be one of the reasons why so many receptors are located on cilia. They also point to the advantage of combining motility with chemical reception.


Assuntos
Cílios/fisiologia , Compostos Inorgânicos/metabolismo , Compostos Orgânicos/metabolismo , Modelos Teóricos , Organelas/fisiologia
16.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34362846

RESUMO

On surfaces with many motile cilia, beats of the individual cilia coordinate to form metachronal waves. We present a theoretical framework that connects the dynamics of an individual cilium to the collective dynamics of a ciliary carpet via systematic coarse graining. We uncover the criteria that control the selection of frequency and wave vector of stable metachronal waves of the cilia and examine how they depend on the geometric and dynamical characteristics of a single cilium, as well as the geometric properties of the array. We perform agent-based numerical simulations of arrays of cilia with hydrodynamic interactions and find quantitative agreement with the predictions of the analytical framework. Our work sheds light on the question of how the collective properties of beating cilia can be determined using information about the individual units and, as such, exemplifies a bottom-up study of a rich active matter system.


Assuntos
Cílios , Modelos Biológicos , Movimento Celular , Cílios/química , Cílios/fisiologia , Hidrodinâmica
17.
Phys Rev Lett ; 126(15): 158002, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33929248

RESUMO

We study the stochastic dynamics of an electrolyte driven by a uniform external electric field and show that it exhibits generic scale invariance despite the presence of Debye screening. The resulting long-range correlations give rise to a Casimir-like fluctuation-induced force between neutral boundaries that confine the ions; this force is controlled by the external electric field, and it can be both attractive and repulsive with similar boundary conditions, unlike other long-range fluctuation-induced forces. This work highlights the importance of nonequilibrium correlations in electrolytes and shows how they can be used to tune interactions between uncharged biological or synthetic structures at large separations.

18.
Phys Rev Lett ; 126(7): 078001, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33666487

RESUMO

We study an active matter system comprised of magnetic microswimmers confined in a microfluidic channel and show that it exhibits a new type of self-organized behavior. Combining analytical techniques and Brownian dynamics simulations, we demonstrate how the interplay of nonequilibrium activity, external driving, and magnetic interactions leads to the condensation of swimmers at the center of the channel via a nonequilibrium phase transition that is formally akin to Bose-Einstein condensation. We find that the effective dynamics of the microswimmers can be mapped onto a diffusivity-edge problem, and use the mapping to build a generalized thermodynamic framework, which is verified by a parameter-free comparison with our simulations. Our work reveals how driven active matter has the potential to generate exotic classical nonequilibrium phases of matter with traits that are analogous to those observed in quantum systems.

19.
EClinicalMedicine ; 32: 100718, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33521609

RESUMO

BACKGROUND: Many countries worldwide are faced with the choice between the (re)surgence of COVID-19 and endangering the economic and mental well-being of their citizens. While infection numbers are monitored and measures adjusted, a systematic strategy for balancing contact restrictions and socioeconomic life in the absence of a vaccine is currently lacking. METHODS: In a mathematical model, we determine the efficacy of regional containment strategies, where contact restrictions are triggered locally in individual regions upon crossing critical infection number thresholds. Our stochastic meta-population model distinguishes between contacts within a region and cross-regional contacts. We use current data on the spread of COVID-19 in Germany, Italy, England, New York State and Florida, including the effects of their individual national lockdowns, and county population sizes obtained from census data to define individual regions. As a performance measure, we determine the number of days citizens will experience contact restrictions over the next 5 years ('restriction time') and compare it to an equivalent national lockdown strategy. To extract crucial parameters, we vary the proportion of cross-regional contacts (between 0% and 100%), the thresholds for initiating local measures (between 5 and 20 active infections per 100,000 inhabitants) as well as their duration after infection numbers have returned below the threshold (between 7 and 28 days). We compare performance across the five different countries and test how further subdivision of large counties into independently controlled regions of up to 100,000 or 200,000 inhabitants affects the results. FINDINGS: Our numerical simulations show a substantially reduced restriction time for regional containment, if the effective reproduction number of SARS-CoV-2 without restrictions, R 0, is only slightly larger than 1 and the proportion of cross-regional contacts (the so-called leakiness) is low. In Germany, specifically, for R 0=1.14, a leakiness of 1% is sufficiently low to reduce the mean restriction time from 468 days (s.d. 3 days) for the national containment strategy to 43 days (s.d. 3 days across simulations) for the regional strategy, when local measures are initiated at 10 infections per 100,000 inhabitants in the past 7 days. For R 0=1.28, the allowed leakiness for minimal restriction time reduces to approximately 0.3%. The dependence of the restriction time on the leakiness is threshold-like only for regional containment, due to cooperative effects. It rises to levels similar to the national containment strategy for a leakiness > 10% (517 days national vs. 486 days regional for leakiness 32% and R 0=1.14). We find a strong correlation between the population size of each region and the experienced restriction time. For countries with large counties, this can result in only a mild reduction in restriction time for regional containment, which can only be partly compensated by lower thresholds for initiating local measures and increasing their duration. In contrast, further subdividing large counties into smaller units can ensure a strong reduction of the restriction time for the regional strategy. INTERPRETATION: The leakiness, i.e. the proportion of cross-regional contacts, and the regional structure itself were crucial parameters for the performance of the regional strategy. Therefore, regional strategies could offer an adaptive way to contain the epidemic with fewer overall restrictions, if cross-regional infections can be kept below the critical level, which could be achieved without affecting local socioeconomic freedom. Maintaining general hygiene and contact tracing, testing should be intensified to ensure regional measures can be initiated at low infection thresholds, preventing the spread of the disease to other regions before local elimination. While such tight control could lead to more restrictions in the short run, restrictions necessary for long-term containment could be reduced by up to a factor of 10. Our open-source simulation code is freely available and can be readily adapted to other countries. FUNDING: This work was supported by the Max Planck Society.

20.
Phys Rev Lett ; 126(3): 034503, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33543965

RESUMO

We derive a theorem for the lower bound on the energy dissipation rate by a rigid surface-driven active microswimmer of arbitrary shape in a fluid at a low Reynolds number. We show that, for any swimmer, the minimum dissipation at a given velocity can be expressed in terms of the resistance tensors of two passive bodies of the same shape with a no-slip and perfect-slip boundary. To achieve the absolute minimum dissipation, the optimal swimmer needs a surface velocity profile that corresponds to the flow around the perfect-slip body, and a propulsive force density that corresponds to the no-slip body. Using this theorem, we propose an alternative definition of the energetic efficiency of microswimmers that, unlike the commonly used Lighthill efficiency, can never exceed unity. We validate the theory by calculating the efficiency limits of spheroidal swimmers.

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