Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme

Induction of Empathy by the Smell of Anxiety

The communication of stress/anxiety between conspecifics through chemosensory signals has been documented in many vertebrates and invertebrates. Here, we investigate how chemosensory anxiety signals conveyed by the sweat of humans (N = 49) awaiting an academic examination are processed by the human brain, as compared to chemosensory control signals obtained from the same sweat donors in a sport condition. The chemosensory stimuli were pooled according to the donation condition and administered to 28 participants (14 males) synchronously to breathing via an olfactometer. The stimuli were perceived with a low intensity and accordingly only about half of the odor presentations were detected by the participants. The fMRI results (event-related design) show that chemosensory anxiety signals activate brain areas involved in the processing of social emotional stimuli (fusiform gyrus), and in the regulation of empathic feelings (insula, precuneus, cingulate cortex). In addition, neuronal activity within attentional (thalamus, dorsomedial prefrontal cortex) and emotional (cerebellum, vermis) control systems were observed. The chemosensory perception of human anxiety seems to automatically recruit empathy-related resources. Even though the participants could not attentively differentiate the chemosensory stimuli, emotional contagion seems to be effectively mediated by the olfactory system

Quantitative thermophoretic study of disease-related protein aggregates

Amyloid fibrils are a hallmark of a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. A detailed understanding of the physico-chemical properties of the different aggregated forms of proteins, and of their interactions with other compounds of diagnostic or therapeutic interest, is crucial for devising effective strategies against such diseases. Protein aggregates are situated at the boundary between soluble and insoluble structures, and are challenging to study because classical biophysical techniques, such as scattering, spectroscopic and calorimetric methods, are not well adapted for their study. Here we present a detailed characterization of the thermophoretic behavior of different forms of the protein a-synuclein, whose aggregation is associated with Parkinson's disease. Thermophoresis is the directed net diffusional flux of molecules and colloidal particles in a temperature gradient. Because of their low volume requirements and rapidity, analytical methods based on this effect have considerable potential for high throughput screening for drug discovery. In this paper we rationalize and describe in quantitative terms the thermophoretic behavior of monomeric, oligomeric and fibrillar forms of a-synuclein. Furthermore, we demonstrate that microscale thermophoresis (MST) is a valuable method for screening for ligands and binding partners of even such highly challenging samples as supramolecular protein aggregates

Fourier Acceleration of Langevin Molecular Dynamics

Fourier acceleration has been successfully applied to the simulation of lattice field theories for more than a decade. In this paper, we extend the method to the dynamics of discrete particles moving in continuum. Although our method is based on a mapping of the particles' dynamics to a regular grid so that discrete Fourier transforms may be taken, it should be emphasized that the introduction of the grid is a purely algorithmic device and that no smoothing, coarse-graining or mean-field approximations are made. The method thus can be applied to the equations of motion of molecular dynamics (MD), or its Langevin or Brownian variants. For example, in Langevin MD simulations our acceleration technique permits a straightforward spectral decomposition of forces so that the long-wavelength modes are integrated with a longer time step, thereby reducing the time required to reach equilibrium or to decorrelate the system in equilibrium. Speedup factors of up to 30 are observed relative to pure (unaccelerated) Langevin MD. As with acceleration of critical lattice models, even further gains relative to the unaccelerated method are expected for larger systems. Preliminary results for Fourier-accelerated molecular dynamics are presented in order to illustrate the basic concepts. Possible extensions of the method and further lines of research are discussed.Comment: 11 pages, two illustrations included using graphic

Search for Nanosecond Optical Pulses from Nearby Solar‐Type Stars

With "Earth 2000" technology we could generate a directed laser pulse that outshines the broadband visible light of the Sun by 4 orders of magnitude. This is a conservative lower bound for the technical capability of a communicating civilization; optical interstellar communication is thus technically plausible. We have built a pair of systems to detect nanosecond pulsed optical signals from a target list that includes some 13,000 Sun-like stars, and we have made some 16,000 observations totaling nearly 2400 hr during five years of operation. A beam splitter-fed pair of hybrid avalanche photodetectors at the 1.5 m Wyeth Telescope at the Harvard/Smithsonian Oak Ridge Observatory (Agassiz Station) triggers on a coincident pulse pair, initiating measurement of pulse width and intensity at subnanosecond resolution. An identical system at the 0.9 m Cassegrain at Princeton's Fitz-Randolph Observatory performs synchronized observations with 0.1 μs event timing, permitting unambiguous identification of even a solitary pulse. Among the 11,600 artifact-free observations at Harvard, the distribution of 274 observed events shows no pattern of repetition, and is consistent with a model with uniform event rate, independent of target. With one possible exception (HIP 107395), no valid event has been seen simultaneously at the two observatories. We describe the search and candidate events and set limits on the prevalence of civilizations transmitting intense optical pulses

Dynamic Critical Behavior of a Swendsen-Wang-Type Algorithm for the Ashkin-Teller Model

We study the dynamic critical behavior of a Swendsen-Wang-type algorithm for the Ashkin--Teller model. We find that the Li--Sokal bound on the autocorrelation time ($\tau_{{\rm int},{\cal E}} \ge {\rm const} \times C_H$) holds along the self-dual curve of the symmetric Ashkin--Teller model, and is almost but not quite sharp. The ratio $\tau_{{\rm int},{\cal E}} / C_H$ appears to tend to infinity either as a logarithm or as a small power ($0.05 \leq p \leq 0.12$). In an appendix we discuss the problem of extracting estimates of the exponential autocorrelation time.Comment: 59 pages including 3 figures, uuencoded g-compressed ps file. Postscript size = 799740 byte

Global equality of resources and the problem of valuation

The principle that every individual on the planet has a claim to an equal share of Earth’s natural resources has an intuitive attraction. Yet the Principle of Natural Resource Equality is not without its problems. This article focuses on the problem of valuation. Unless and until its adherents are able to develop an adequate theoretical mechanism for determining the comparative value of two or more bundles of natural resources the principle lacks applicability and persuasive force. Three adequacy constraints on such a mechanism are presented and then applied to a theorisation of the Principle of Natural Resource Equality that I have already expounded elsewhere: Global Equality of Resources. In each case I try to argue that Global Equality of Resources could satisfy the adequacy constraint, provided that both this theory and the relevant constraint are properly understood

Dynamic Critical Behavior of the Swendsen-Wang Algorithm: The Two-Dimensional 3-State Potts Model Revisited

We have performed a high-precision Monte Carlo study of the dynamic critical behavior of the Swendsen-Wang algorithm for the two-dimensional 3-state Potts model. We find that the Li-Sokal bound ($\tau_{int,E} \geq const \times C_H$) is almost but not quite sharp. The ratio $\tau_{int,E} / C_H$ seems to diverge either as a small power ($\approx 0.08$) or as a logarithm.Comment: 35 pages including 3 figures. Self-unpacking file containing the LaTeX file, the needed macros (epsf.sty, indent.sty, subeqnarray.sty, and eqsection.sty) and the 3 Postscript figures. Revised version fixes a normalization error in \xi (with many thanks to Wolfhard Janke for finding the error!). To be published in J. Stat. Phys. 87, no. 1/2 (April 1997

Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals.

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme

Lorentzian and Euclidean Quantum Gravity - Analytical and Numerical Results

We review some recent attempts to extract information about the nature of quantum gravity, with and without matter, by quantum field theoretical methods. More specifically, we work within a covariant lattice approach where the individual space-time geometries are constructed from fundamental simplicial building blocks, and the path integral over geometries is approximated by summing over a class of piece-wise linear geometries. This method of ``dynamical triangulations'' is very powerful in 2d, where the regularized theory can be solved explicitly, and gives us more insights into the quantum nature of 2d space-time than continuum methods are presently able to provide. It also allows us to establish an explicit relation between the Lorentzian- and Euclidean-signature quantum theories. Analogous regularized gravitational models can be set up in higher dimensions. Some analytic tools exist to study their state sums, but, unlike in 2d, no complete analytic solutions have yet been constructed. However, a great advantage of our approach is the fact that it is well-suited for numerical simulations. In the second part of this review we describe the relevant Monte Carlo techniques, as well as some of the physical results that have been obtained from the simulations of Euclidean gravity. We also explain why the Lorentzian version of dynamical triangulations is a promising candidate for a non-perturbative theory of quantum gravity.Comment: 69 pages, 16 figures, references adde