Publications by authors named "Peter C Doerschuk"

Lipid nanoparticles (LNPs) are a subset of pharmaceutical nanoparticulate formulations designed to encapsulate, stabilize, and deliver nucleic acid cargoes in vivo. Applications for LNPs include new interventions for genetic disorders, novel classes of vaccines, and alternate modes of intracellular delivery for therapeutic proteins. In the pharmaceutical industry, establishing a robust formulation and process to achieve target product performance is a critical component of drug development.

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The macro-scale intrinsic functional network architecture of the human brain has been well characterized. Early studies revealed robust and enduring patterns of static connectivity, while more recent work has begun to explore the temporal dynamics of these large-scale brain networks. Little work to date has investigated directed connectivity within and between these networks, or the temporal patterns of afferent (input) and efferent (output) connections between network nodes.

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Cryo-electron microscopy provides 2D projection images of the 3D electron scattering intensity of many instances of the particle under study (e.g., a virus).

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Nanometre-sized objects with highly symmetrical, cage-like polyhedral shapes, often with icosahedral symmetry, have recently been assembled from DNA, RNA or proteins for applications in biology and medicine. These achievements relied on advances in the development of programmable self-assembling biological materials, and on rapidly developing techniques for generating three-dimensional (3D) reconstructions from cryo-electron microscopy images of single particles, which provide high-resolution structural characterization of biological complexes. Such single-particle 3D reconstruction approaches have not yet been successfully applied to the identification of synthetic inorganic nanomaterials with highly symmetrical cage-like shapes.

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The information content of cryo EM data sets exceeds that of the electron scattering potential (cryo EM) density initially derived for structure determination. Previously we demonstrated the power of data variance analysis for characterizing regions of cryo EM density that displayed functionally important variance anomalies associated with maturation cleavage events in Nudaurelia Omega Capensis Virus and the presence or absence of a maturation protease in bacteriophage HK97 procapsids. Here we extend the analysis in two ways.

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Computations are described which estimate flows in all branches of the cortical surface arteriole network from two-photon excited fluorescence (2PEF) microscopy images which provide the network topology and, in selected branches red blood cell (RBC) speeds and lumen diameters. Validation is done by comparing the flow predicted by the model with experimentally measured flows and by comparing the predicted flow redistribution in the network due to single-vessel strokes with experimental observations. The model predicts that tissue is protected from RBC flow decreases caused by multiple occlusions of surface arterioles but not penetrating arterioles.

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Article Synopsis
  • Resting-state functional MRI (rs-fMRI) is a noninvasive method used to study brain networks by analyzing BOLD signals, but traditional correlation cannot show how information flows between different brain regions.
  • A new method called prediction correlation is introduced, which uses one BOLD signal to predict another, thereby revealing effective connectivity in the brain.
  • Validation of prediction correlation showed it performs well in simulations, avoids false connections in complex scenarios, and successfully captures brain network organization in actual data, allowing for analysis of interregional connectivity in individual subjects.
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Stochastic models of nano-biomachines have been studied by 3-D reconstruction from cryo electron microscopy images in recent years. The image data is the projection of many heterogeneous instances of the object under study (e.g.

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The direct electron detector has revolutionized electron cryo-microscopy (CryoEM). Icosahedral virus structures are routinely produced at 4Å resolution or better and the approach has largely displaced virus crystallography, as it requires less material, less purity and often produces a structure more rapidly. Largely ignored in this new era of CryoEM is the dynamic information in the data sets that was not available in X-ray structures.

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Cryo EM structures of maturation-intermediate Prohead I of bacteriophage HK97 with (PhI(Pro+)) and without (PhI(Pro-)) the viral protease packaged have been reported (Veesler et al., 2014). In spite of PhI(Pro+) containing an additional ∼ 100 × 24 kD of protein, the two structures appeared identical although the two particles have substantially different biochemical properties, e.

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Objective: To describe a toolkit of components for mathematical models of the relationship between cortical neural activity and space-resolved and time-resolved flows and volumes of oxygenated and deoxygenated hemoglobin motivated by optical intrinsic signal imaging (OISI).

Approach: Both blood flow and blood volume and both oxygenated and deoxygenated hemoglobin and their interconversion are accounted for. Flow and volume are described by including analogies to both resistive and capacitive electrical circuit elements.

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Quasi-equivalent viruses that infect animals and bacteria require a maturation process in which particles transition from initially assembled procapsids to infectious virions. Nudaurelia capensis ω virus (NωV) is a T = 4, eukaryotic, single-stranded ribonucleic acid virus that has proved to be an excellent model system for studying the mechanisms of viral maturation. Structures of NωV procapsids (diameter = 480 Å), a maturation intermediate (410 Å), and the mature virion (410 Å) were determined by electron cryo-microscopy and three-dimensional image reconstruction (cryoEM).

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We generalize the concept of allostery from the traditional non-active-site control of enzymes to virus maturation. Virtually, all animal viruses transition from a procapsid noninfectious state to a mature infectious state. The procapsid contains an encoded chemical program that is executed following an environmental cue.

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CryoEM data capture the dynamic character associated with biological macromolecular assemblies by preserving the various conformations of the individual specimens at the moment of flash freezing. Regions of high variation in the data set are apparent in the image reconstruction due to the poor density that results from the lack of superposition of these regions. These observations are qualitative and, to date, only preliminary efforts have been made to quantitate the heterogeneity in the ensemble of particles that are individually imaged.

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An estimation problem for statistical reconstruction of heterogeneous three-dimensional objects from two-dimensional tomographic data (single-particle cryoelectron microscope images) is posed as the problem of estimating class probabilities, means, and covariances for a Gaussian mixture where both the mean and covariance are stochastically structured. Both discrete (i.e.

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Background: The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration (BrAC) acting alone. To test this proposition, a 2-session experiment was designed in which carefully prescribed, constant-slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design.

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Subtle alterations in cerebral blood flow can impact the health and function of brain cells and are linked to cognitive decline and dementia. To understand hemodynamics in the three-dimensional vascular network of the cerebral cortex, we applied two-photon excited fluorescence microscopy to measure the motion of red blood cells (RBCs) in individual microvessels throughout the vascular hierarchy in anesthetized mice. To resolve heartbeat- and respiration-dependent flow dynamics, we simultaneously recorded the electrocardiogram and respiratory waveform.

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The influence of family history and genetics on the risk for the development of abuse or dependence is a major theme in alcoholism research. Recent research have used endophenotypes and behavioral paradigms to help detect further genetic contributions to this disease. Electronic tasks, essentially video games, which provide alcohol as a reward in controlled environments and with specified exposures have been developed to explore some of the behavioral and subjective characteristics of individuals with or at risk for alcohol substance use disorders.

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The cortical microvasculature plays a key role in cortical tissue health by transporting important molecules via blood. Disruptions to blood flow in the microvasculature due to events such as stroke can thus induce damage to the cortex. Recent developments in two-photon microscopy have enabled in vivo imaging of anesthetized rat cortex in three dimensions.

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Sulfolobus Turreted Icosahedral Virus (STIV) experiences an extra-cellular environment of near boiling acid (80°C, pH 3) and particles purified under these conditions were previously analyzed by cryo electron microscopy and image reconstruction. Here we describe cryo-tomograms of Solfolobus cells infected with STIV and the maximum likelihood algorithm employed to compute reconstructions of virions within the cell. Virions in four different tomograms were independently reconstructed with an average of 91 particles per tomogram and their structures compared with each other and with the higher resolution single-particle reconstruction from purified virions.

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Many micro- to nano-scale 3-D biological objects have a helical symmetry. Cryo electron microscopy provides 2-D projection images where, however, the images have low SNR and unknown projection directions. The object is described as a helical array of identical motifs, where both the parameters of the helical symmetry and the motif are unknown.

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We applied whole-cell electron cryotomography to the archaeon Sulfolobus infected by Sulfolobus turreted icosahedral virus (STIV), which belongs to the PRD1-Adeno lineage of dsDNA viruses. STIV infection induced the formation of pyramid-like protrusions with sharply defined facets on the cell surface. They had a thicker cross-section than the cytoplasmic membrane and did not contain an exterior surface protein layer (S-layer).

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The maximum-likelihood method provides a powerful approach to many problems in cryo-electron microscopy (cryo-EM) image processing. This contribution aims to provide an accessible introduction to the underlying theory and reviews existing applications in the field. In addition, current developments to reduce computational costs and to improve the statistical description of cryo-EM images are discussed.

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