Publications

Statistical analysis of microbial genomic data within epidemiological cohort studies holds the promise to assess the influence of environmental exposures on both the host and the host-associated microbiome. The observational character of prospective cohort data and the intricate characteristics of microbiome data make it, however, challenging to discover causal associations between environment and microbiome. Here, we introduce a causal inference framework based on the Rubin Causal Model that can help scientists to investigate such environment-host microbiome relationships, to capitalize on existing, possibly powerful, test statistics, and test plausible sharp null hypotheses. Using data from the German KORA cohort study, we illustrate our framework by designing two hypothetical randomized experiments with interventions of (i) air pollution reduction and (ii) smoking prevention. We study the effects of these interventions on the human gut microbiome by testing shifts in microbial diversity, changes in individual microbial abundances, and microbial network wiring between groups of matched subjects via randomization-based inference. In the smoking prevention scenario, we identify a small interconnected group of taxa worth further scrutiny, including Christensenellaceae and Ruminococcaceae genera, that have been previously associated with blood metabolite changes. These findings demonstrate that our framework may uncover potentially causal links between environmental exposure and the gut microbiome from observational data. We anticipate the present statistical framework to be a good starting point for further discoveries on the role of the gut microbiome in environmental health.

The radio emission anomaly coincident with the 2016 glitch of the Vela pulsar may be caused by a star quake that launches Alfvén waves into the magnetosphere, disturbing the original radio emitting region. To quantify the lifetime of the Alfvén waves, we investigate a possible energy loss mechanism, the conversion of Alfvénwaves into fast magnetosonic waves. Using axisymmetric force-free simulations, we follow the propagation of Alfvén waves launched from the stellar surface with small amplitude into the closed zone of a force-free dipolar pulsar magnetosphere. We observe mode conversion happening in the ideal force-free regime. The conversion efficiency during the first passage of the Alfvén wave through the equator can be large, for waves that reach large amplitudes as they travel away from the star, or propagate on the field lines passing close to the Y-point. However, the conversion efficiency is reduced due to dephasing on subsequent passages and considerable Alfvén power on the closed field lines remains. Thus while some leakage into the fast mode happens, we need detailed understanding of the original quenching in order to say whether mode conversion alone can lead to reactivation of the pulsar on a short timescale.

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future.

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future

To exploit the power of next-generation large-scale structure surveys, ensembles of numerical simulations are necessary to give accurate theoretical predictions of the statistics of observables. High-fidelity simulations come at a towering computational cost. Therefore, approximate but fast simulations, surrogates, are widely used to gain speed at the price of introducing model error. We propose a general method that exploits the correlation between simulations and surrogates to compute fast, reduced-variance statistics of large-scale structure observables without model error at the cost of only a few simulations. We call this approach Convergence Acceleration by Regression and Pooling (CARPool). In numerical experiments with intentionally minimal tuning, we apply CARPool to a handful of GADGET-III N-body simulations paired with surrogates computed using COmoving Lagrangian Acceleration (COLA). We find ∼100-fold variance reduction even in the non-linear regime, up to kmax≈1.2 hMpc−1 for the matter power spectrum. CARPool realises similar improvements for the matter bispectrum. In the nearly linear regime CARPool attains far larger sample variance reductions. By comparing to the 15,000 simulations from the Quijote suite, we verify that the CARPool estimates are unbiased, as guaranteed by construction, even though the surrogate misses the simulation truth by up to 60% at high k. Furthermore, even with a fully configuration-space statistic like the non-linear matter density probability density function, CARPool achieves unbiased variance reduction factors of up to ∼10, without any further tuning. Conversely, CARPool can be used to remove model error from ensembles of fast surrogates by combining them with a few high-accuracy simulations.

Evaluating microbial community composition through next-generation sequencing has become increasingly accessible. However, metagenomic sequencing data sets provide researchers with only a snapshot of a dynamic ecosystem and do not provide information about the total microbial number, or load, of a sample. Additionally, DNA can be detected long after a microorganism is dead, making it unsafe to assume that all microbial sequences detected in a community came from living organisms. By combining relic DNA removal by propidium monoazide (PMA) with microbial quantification with flow cytometry, we present a novel workflow to quantify live microbial load in parallel with metagenomic sequencing. We applied this method to unstimulated saliva samples, which can easily be collected longitudinally and standardized by passive collection time. We found that the number of live microorganisms detected in saliva was inversely correlated with salivary flow rate and fluctuated by an order of magnitude throughout the day in healthy individuals. In an acute perturbation experiment, alcohol-free mouthwash resulted in a massive decrease in live bacteria, which would have been missed if we did not consider dead cell signal. While removing relic DNA from saliva samples did not greatly impact the microbial composition, it did increase our resolution among samples collected over time. These results provide novel insight into the dynamic nature of host-associated microbiomes and underline the importance of applying scale-invariant tools in the analysis of next-generation sequencing data sets.

Gravitational waves can provide an accurate measurement of the luminosity distance to the source, but cannot provide the source redshift unless the degeneracy between mass and redshift can be broken. This makes it essential to infer the redshift of the source independently to measure the expansion history of the Universe. We show that by exploiting the clustering scale of the gravitational wave sources with galaxies of known redshift, we can infer the expansion history from redshift unknown gravitational wave sources. By using gravitational wave sources of unknown redshift that are detectable from the network of gravitational wave detectors with Advanced LIGO design sensitivity, we will be able to obtain accurate and precise measurements of the local Hubble constant, the expansion history of the universe, and the gravitational wave bias parameter, which captures the distribution of gravitational wave sources with respect to the redshift tracer distribution. While we showcase its application to low redshift gravitational waves, this technique will be applicable also to the high redshift gravitational wave sources detectable from Laser Interferometer Space Antenna (LISA), Cosmic Explorer (CE), and Einstein Telescope (ET). Moreover, this method will also be applicable to samples of supernovae and fast radio bursts with unknown or photometric redshifts.

Turbulence is a predominant process for energizing electrons and ions in collisionless astrophysical plasmas, and thus is responsible for shaping their radiative signatures (luminosity, spectra, and variability). To better understand the kinetic properties of a collisionless radiative plasma subject to externally driven turbulence, we investigate particle-in-cell simulations of relativistic plasma turbulence with external inverse Compton cooling acting on the electrons. We find that ions continuously heat up while electrons gradually cool down (due to the net effect of radiation), and hence the ion-to-electron temperature ratio Ti/Te grows in time. We show that Ti/Te is limited only by the size and duration of the simulations (reaching ${T}_{i}/{T}_{e}\sim {10}^{3}$), indicating that there are no efficient collisionless mechanisms of electron–ion thermal coupling. This result has implications for models of radiatively inefficient accretion flows, such as observed in the Galactic center and in M87, for which so-called two-temperature plasmas with ${T}_{i}/{T}_{e}\gg 1$ have been invoked to explain their low luminosity. Additionally, we find that electrons acquire a quasi-thermal distribution (dictated by the competition of turbulent particle energization and radiative cooling), while ions undergo efficient nonthermal acceleration (acquiring a harder distribution than in equivalent nonradiative simulations). There is a modest nonthermal population of high-energy electrons that are beamed intermittently in space, time, and direction; these beamed electrons may explain rapid flares in certain high-energy astrophysical systems (e.g., in the Galactic center). These numerical results demonstrate that extreme two-temperature plasmas can be produced and maintained by relativistic radiative turbulence.

The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. We present structure-guided computational methods for designing peptide macrocycles built from mixtures of L- and D-amino acids that are able to bind to and inhibit targets of therapeutic interest. Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC50 values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, bindingcompetent macrocycles should have broad applicability to a wide range of therapeutic targets.

Since the seminal 1961 paper of Monod and Jacob, mathematical models of biomolecular circuits have guided our understanding of cell regulation. Model-based exploration of the functional capabilities of any given circuit requires systematic mapping of multidimensional spaces of model parameters. Despite significant advances in computational dynamical systems approaches, this analysis remains a nontrivial task. Here, we use a nonlinear system of ordinary differential equations to model oocyte selection in Drosophila, a robust symmetry-breaking event that relies on autoregulatory localization of oocyte-specification factors. By applying an algorithmic approach that implements symbolic computation and topological methods, we enumerate all phase portraits of stable steady states in the limit when nonlinear regulatory interactions become discrete switches. Leveraging this initial exact partitioning and further using numerical exploration, we locate parameter regions that are dense in purely asymmetric steady states when the nonlinearities are not infinitely sharp, enabling systematic identification of parameter regions that correspond to robust oocyte selection. This framework can be generalized to map the full parameter spaces in a broad class of models involving biological switches.