Non-Markovian data-driven modeling of single-cell motility

Trajectories of human breast cancer cells moving on one-dimensional circular tracks are modeled by thenon-Markovian version of the Langevin equation that includes an arbitrary memory function. When averagedover cells, the velocity distribution exhibits spurious non-Gaussian behavior, while single cells are characterizedby Gaussian velocity distributions. Accordingly, the data are described by a linear memory model whichincludes different random walk models that were previously used to account for various aspects of cell motilitysuch as migratory persistence, non-Markovian effects, colored noise, and anomalous diffusion. The memoryfunction is extracted from the trajectory data without restrictions or assumptions, thus making our approachtruly data driven, and is used for unbiased single-cell comparison. The cell memory displays time-delayedsingle-exponential negative friction, which clearly distinguishes cell motion from the simple persistent randomwalk model and suggests a regulatory feedback mechanism that controls cell migration. Based on the extractedmemory function we formulate a generalized exactly solvable cell migration model which indicates thatnegative friction generates cell persistence over long timescales. The nonequilibrium character of cell motionis investigated by mapping the non-Markovian Langevin equation with memory onto a Markovian model thatinvolves a hidden degree of freedom and is equivalent to the underdamped active Ornstein-Uhlenbeck process

Lattice investigation of the tetraquark candidates a0(980) and kappa

It is a long discussed issue whether light scalar mesons have sizeable four-quark components. We present an exploratory study of this question using Nf = 2+1+1 twisted mass lattice QCD. A mixed action approach ignoring disconnected contributions is used to calculate correlatormatrices consisting of mesonic molecule, diquark-antidiquark and two-meson interpolating operators with quantum numbers of the scalar mesons a0(980) (1(0++)) and k (1/2(0+)). The correlation matrices are analyzed by solving the generalized eigenvalue problem. The theoretically expected free two-particle scattering states are identified, while no additional low lying states are observed. We do not observe indications for bound four-quark states in the channels investigated

External Potential Modifies Friction of Molecular Solutes in Water

Stokes’s law for the friction of a sphere in water has been argued to work down to molecular scales, provided the effective hydrodynamic radius includes the hydration layer. In interpretations of experiments and in theoretical models, it is tacitly assumed that the solvent friction experienced by a solute does not depend on whether an external confinement potential acts on the solute. Using a novel method to extract the friction memory function from molecular dynamics simulations, we show that the solvent friction of a strongly harmonically confined methane molecule in water increases by 60% compared to its free-solution value, which is caused by an amplification of the slowest component of the memory function. The friction enhancement occurs for potential strengths typical of physical and chemical bonds and is accompanied by a significant slowing-down of the hydration water dynamics. Thus, the solvent friction acting on molecular solutes is not determined by solvent properties and solute-solvent interactions alone but results from the coupling between solute and solvent dynamics and thereby can be tuned by an external potential acting on the solute. This also explains why simulations of positionally constrained solutes do not reproduce free-solution diffusivities. Dynamic scaling arguments suggest similar effects also for macromolecular solutes provided the solution viscosity is sufficiently enhanced

Scalar mesons and tetraquarks by means of lattice QCD

We study the light scalar mesons a_0(980) and kappa using N_f = 2+1+1 flavor lattice QCD. In order to probe the internal structure of these scalar mesons, and in particular to identify, whether a sizeable tetraquark component is present, we use a large set of operators, including diquark-antidiquark, mesonic molecule and two-meson operators. The inclusion of disconnected diagrams, which are technically rather challenging, but which would allow us to extend our work to e.g. the f_0(980) meson, is introduced and discussed

Lattice investigation of the scalar mesons a_0(980) and \kappa\ using four-quark operators

We carry out an exploratory study of the isospin one a0(980) and the isospin one-half kappa scalar mesons using Nf=2+1+1 Wilson twisted mass fermions at one lattice spacing. The valence strange quark is included as an Osterwalder-Seiler fermion with mass tuned so that the kaon mass matches the corresponding mass in the unitary Nf=2+1+1 theory. We investigate the internal structure of these mesons by using a basis of four-quark interpolating fields. We construct diquark-diquark and molecular-typecinterpolating fields and analyse the resulting correlation matrices keeping only connected contributions. For both channels, the low-lying spectrum is found to be consistent with two-particle scattering states. Therefore, our analysis shows no evidence for an additional state that can be interpreted as either a tetraquark or a tightly-bound molecular state.Comment: 5 figures, 23 page

Butane dihedral angle dynamics in water is dominated by internal friction

The dihedral dynamics of butane in water is known to be rather insensitive to the water viscosity; possible explanations for this involve inertial effects or Kramers’ turnover, the finite memory time of friction, and the presence of so-called internal friction. To disentangle these factors, we introduce a method to directly extract the friction memory function from unconstrained simulations in the presence of an arbitrary free-energy landscape. By analysis of the dihedral friction in butane for varying water viscosity, we demonstrate the existence of an internal friction contribution that does not scale linearly with water viscosity. At normal water viscosity, the internal friction turns out to be eight times larger than the solvent friction and thus completely dominates the effective friction. By comparison with simulations of a constrained butane molecule that has the dihedral as the only degree of freedom, we show that internal friction comes from the six additional degrees of freedom in unconstrained butane that are orthogonal to the dihedral angle reaction coordinate. While the insensitivity of butane’s dihedral dynamics to water viscosity is solely due to the presence of internal friction, inertial effects nevertheless crucially influence the resultant transition rates. In contrast, non-Markovian effects due to the finite memory time are present but do not significantly influence the dihedral barrier-crossing rate of butane. These results not only settle the character of dihedral dynamics in small solvated molecular systems such as butane, they also have important implications for the folding of polymers and proteins

Structure and molecular recognition in riboswitches

Riboswitches are cis-acting gene regulatory RNAs, which function without involvement of proteins. They have been implicated as drug targets and are attractive systems for the study of RNA-ligand binding and RNA folding. The purine riboswitch was used as a model system for RNA-ligand docking. Published binding data was successfully reproduced in silico and compounds predicted to bind the riboswitch in a virtual screening were tested experimentally. Structural data confirming the predicted binding mode for several cases was obtained. The problems encountered were not specific to RNA-ligand docking but known from the far more explored field of protein-ligand docking.The SAM-I riboswitch was also subjected to virtual ligand screening. This receptor is a system of greater complexity than the purine riboswitch and consequently posed a harder challenge to the docking protocol. After initial validation of the docking setup based on previously published data, a set of compounds selected from the in-house database of commercially available compounds was screened. One compound identfied in silico was cofirmed to bind experimentally.The k-turn motif found in the SAM-I riboswitch was investigated with respect to its folding. The k-turn motif was found to be foldable in context of the SAMI riboswitch as well as in isolation as was expected. Furthermore, mutations disrupting key interactions within the k-turn motif were found to be prohibitive of k-turn folding in isolation as well as in context of the riboswitch, leading to a loss of ligand binding. Interestingly, two sequences were identfied which fold in context of the riboswitch but do not fold in isolation. This confirms the contribution of tertiary interactions to k-turn folding. This conclusion was backed up with structural data is a system of greater complexity than the purine riboswitch and consequently posed a harder challenge to the docking protocol. After initial validation of the to its folding. The k-turn motif was found to be foldable in context of the SAMI riboswitch as well as in isolation as was expected. Furthermore, mutations disrupting key interactions within the k-turn motif were found to be prohibitive of k-turn folding in isolation as well as in context of the riboswitch, leading to a loss of ligand binding. Interestingly, two sequences were identi ed which fold in context of the riboswitch but do not fold in isolation. This con rms the contribution of tertiary interactions to k-turn folding. This conclusion was backedEThOS - Electronic Theses Online ServiceWellcome TrustGBUnited Kingdo

An intersectional lens on young leaders:Bias toward young women and young men in leadership positions

Research has recognized age biases against young leaders, yet understanding of how gender, the most frequently studied demographic leader characteristic, influences this bias remains limited. In this study, we examine the gender-specific age bias toward young female and young male leaders through an intersectional lens. By integrating intersectionality theory with insights on status beliefs associated with age and gender, we test whether young female and male leaders face an interactive rather than an additive form of bias. We conducted two preregistered experimental studies ( N1 = 918 and N2 = 985), where participants evaluated leaders based on age, gender, or a combination of both. Our analysis reveals a negative age bias in leader status ascriptions toward young leaders compared to middle-aged and older leaders. This bias persists when gender information is added, as demonstrated in both intersectional categories of young female and young male leaders. This bias pattern does not extend to middle-aged or older female and male leaders, thereby supporting the age bias against young leaders specifically. Interestingly, we also examined whether social dominance orientation strengthens the bias against young (male) leaders, but our results (reported in the SOM) are not as hypothesized. In sum, our results emphasize the importance of young age as a crucial demographic characteristic in leadership perceptions that can even overshadow the role of gender

Molecular Friction and Dynamics in Aqueous Solutions

Dynamic molecular processes in aqueous solutions are essential for biological life, and their fundamental timescale is determined by molecular friction. In this thesis, several basic dynamic phenomena relevant for aqueous biological systems are studied by a combination of molecular dynamics simulations and stochastic models. First, we show by ab initio molecular dynamics simulations that the polarization of continuum bands in infrared spectra of small protonated water clusters allows us to deduce their shape and orientation. The molecular origin of continuum bands of protonated water wires is elucidated. Based on these results and recently recorded, experimental polarization-resolved infrared spectra, we reveal the orientation of a protonated water cluster in the transmembrane protein bacteriorhodopsin. Secondly, the friction of an externally confined, water-solvated methane molecule is extracted from molecular dynamics simulations using a newly developed method to parametrize a generalized Langevin equation. We show that the friction increases by up to 60% with increasing confinement strength, which is accompanied by a slowing down of the translational and rotational water dynamics in the hydration shell. This previously unknown effect is relevant for the interpretation of spectroscopy experiments as well as for trapped particles in viscous solvents. Thirdly, the mass dependence of the methane friction in water is studied by a similar method. We demonstrate that the friction increases with solute mass by up to 70%, which goes along with a slowing down of the hydration shell dynamics by a factor of three. We characterize the scaling behavior of mass-dependent friction and show that the often applied power-law relation holds only for an intermediate regime. Next, we compute the friction memory kernel of the dihedral angle of water-solvated butane by another newly developed method for the parametrization of generalized Langevin equations in the presence of arbitrary, non-linear potentials. This method is applied to a free butane molecule as well as to a constrained butane with the dihedral angle as the only positional degree of freedom, in both cases for different solvent viscosities. The results allow us to answer a long-lasting question by showing that dihedral angle isomerization reactions are dominated by internal friction. Finally, we show that the ensemble properties of so-called transition paths, which connect an initial starting position without return to a target state, deviate significantly from equilibrium. The deviation can be quantified by an effective temperature, which reaches several times the ambient temperature for systems with low friction. All of these results constitute significant advancements to the respective subfields, and together they shed light on the complex and subtle interplay of friction, inertial and non-Markovian effects on the molecular scale.Dynamische molekulare Prozesse in wässrigen Lösungen sind essenziell für jede Form biologischen Lebens, und ihre fundamentale Zeitskala ist durch die molekulare Reibung definiert. In der vorliegenden Arbeit werden grundlegende dynamische Phänomene, die für wässrige biologische Systeme relevant sind, mit einer Kombination aus Molekulardynamik-Simulationen und stochastischen Modellen untersucht. Zuerst zeigen wir mithilfe von Ab-initio-Simulationen, dass die Polarisation von Kontinuumsbanden in Infrarotspektren kleiner protonierter Wassercluster Rückschlüsse auf deren Form und Orientierung zulässt. Außerdem wird die molekulare Ursache von Kontinuumsbanden protonierter Wasserketten aufgedeckt. Als Anwendung wird aus experimentellen, polarisationsaufgelösten Infrarotspektren die Orientierung eines protonierten Wasserclusters im Transmembranprotein Bacteriorhodopsin bestimmt. Im zweiten Teil der Arbeit extrahieren wir die molekulare Reibung eines künstlich festgehaltenen, in Wasser gelösten Methanmoleküls aus Molekulardynamik-Simulationen mittels einer neu entwickelten Methode zur Parametrisierung generalisierter Langevin-Gleichungen. Die Reibung nimmt mit der Stärke des externen Potentials um bis zu 60% zu, was mit einer Verlangsamung der Hydrationsdynamik einhergeht. Dieser bisher unbekannte Effekt ist sowohl für die Interpretation spektroskopischer Experimente relevant als auch für festgehaltene Teilchen in viskosen Lösungsmitteln. Des Weiteren wird die Massenabhängigkeit der Reibung von Methan in Wasser mit ähnlichen Methoden analysiert. Im Vergleich zu leichten Soluten ist die Reibung schwerer Solute um bis zu 70% höher und die Hydrationsdynamik ist verlangsamt. Insbesondere wird das Skalenverhalten der massenabhängigen Reibung vollständig charakterisiert. Im vierten Teil der Arbeit untersuchen wir den Torsionswinkel eines in Wasser gelösten Butanmoleküls mithilfe einer weiteren neu entwickelten Methode zur Parametrisierung generalisierter Langevin-Gleichungen in beliebigen Potentialen. Wir betrachten freies Butan und ein eingeschränktes Butanmolekül mit dem Torsionswinkel als einzigem Freiheitsgrad jeweils bei verschiedenen Viskositäten, um zu zeigen, dass die Isomerisationsreaktion von Torsionswinkeln durch interne Reibung dominiert wird. Zum Schluss zeigen wir, dass die statistischen Eigenschaften sogenannter Übergangspfade, die eine Anfangsposition ohne Wiederkehr mit einer Zielposition verbinden, signifikant vom Gleichgewicht abweichen. Die Abweichung kann durch eine effektive Temperatur beschrieben werden, die für Systeme mit geringer Reibung ein Vielfaches der Umgebungstemperatur erreicht. Diese Ergebnisse sind wesentliche Fortschritte in den jeweiligen Spezialgebieten, und in der Summe tragen sie zum Verständnis des komplexen Zusammenspiels zwischen Reibung, inertialen und nicht-Markovschen Effekten auf der molekularen Skala bei