117 research outputs found
Get on the Cart! Wesleyan Discipleship in an Age of Endemic (Chapter 15 of Thinking Theologically About Mass Incarceration)
Excerpt: Fyodor Dostoyevsky once said that the so,ul of society can be measured by its prisons. 1 If that is true, then the soul of society in the United States is sick. The statistics on mass incarceration provided elsewhere in this volume illustrate the endemic nature of the problem much like epidemiological data shows the occurrence of a disease, but the stories from prisoners and their families-which the three of us have heard and told-show even more poignantly the depth of the wounds caused by the tragedy of incarceration that defies Christian virtues in this country. We pray this chapter will be one of many applications of healing b\u3c~Jlm to address this societal disease
Electrostatic Contributions to Protein Stability and Folding Energy
The ability to predict the thermal stability of proteins based on their corresponding sequence is a problem of great fundamental and practical importance. Here we report an approach for calculating the electrostatic contribution to protein stability based on the use of the semimacroscopic protein dipole Langevin dipole (PDLD/S) in its linear response approximation version for self-energy with a dielectric constant, (εpεp) and an effective dielectric for charge–charge interactions (εeffεeff). The method is applied to the test cases of ubiquitin, lipase, dihydrofolate reductase and cold shock proteins with series of εpεp and εeffεeff. It is found that the optimal values of these dielectric constants lead to very promising results, both for the relative stability and the absolute folding energy. Consideration of the specific values of the optimal dielectric constants leads to an exciting conceptual description of the reorganization effect during the folding process. Although this description should be examined by further microscopic studies, the practical use of the current approach seems to offer a powerful tool for protein design and for studies of the energetics of protein folding.This work was supported by NIH Grant GM2449
On the relationship between thermal stability and catalytic power of enzymes
The possible relationship between the thermal stability and the catalytic power of enzymes is of great current interest. In particular, it has been suggested that thermophilic or hyperthermophilic (Tm) enzymes have lower catalytic power at a given temperature than the corresponding mesophilic (Ms) enzymes, because the thermophilic enzymes are less flexible (assuming that flexibility and catalysis are directly correlated). These suggestions presume that the reduced dynamics of the thermophilic enzymes is the reason for their reduced catalytic power. The present paper takes the specific case of dihydrofolate reductase (DHFR) and explores the validity of the above argument by simulation approaches. It is found that the Tm enzymes have restricted motions in the direction of the folding coordinate, but this is not relevant to the chemical process, since the motions along the reaction coordinate are perpendicular to the folding motions. Moreover, it is shown that the rate of the chemical reaction is determined by the activation barrier and the corresponding reorganization energy, rather than by dynamics or flexibility in the ground state. In fact, as far as flexibility is concerned, we conclude that the displacement along the reaction coordinate is larger in the Tm enzyme than in the Ms enzyme and that the general trend in enzyme catalysis is that the best catalyst involves less motion during the reaction than the less optimal catalyst. The relationship between thermal stability and catalysis appears to reflect the fact that in order to obtain small electrostatic reorganization energy it is necessary to invest some folding energy in the overall preorganization process. Thus, the optimized catalysts are less stable. This trend is clearly observed in the DHFR case
Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1
ABSTRACT The four dengue virus (DENV) serotypes, DENV1 through 4, are endemic throughout tropical and subtropical regions of the world. While first infection confers long-term protective immunity against viruses of the infecting serotype, a second infection with virus of a different serotype carries a greater risk of severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. Recent studies demonstrate that humans exposed to DENV infections develop neutralizing antibodies that bind to quaternary epitopes formed by the viral envelope (E) protein dimers or higher-order assemblies required for the formation of the icosahedral viral envelope. Here we show that the quaternary epitope target of the human DENV3-specific neutralizing monoclonal antibody (MAb) 5J7 can be partially transplanted into a DENV1 strain by changing the core residues of the epitope contained within a single monomeric E molecule. MAb 5J7 neutralized the recombinant DENV1/3 strain in cell culture and was protective in a mouse model of infection with the DENV1/3 strain. However, the 5J7 epitope was only partially recreated by transplantation of the core residues because MAb 5J7 bound and neutralized wild-type (WT) DENV3 better than the DENV1/3 recombinant. Our studies demonstrate that it is possible to transplant a large number of discontinuous residues between DENV serotypes and partially recreate a complex antibody epitope, while retaining virus viability. Further refinement of this approach may lead to new tools for measuring epitope-specific antibody responses and new vaccine platforms. IMPORTANCE Dengue virus is the most important mosquito-borne pathogen of humans worldwide, with approximately one-half the world's population living in regions where dengue is endemic. Dengue immunity following infection is robust and thought to be conferred by antibodies raised against the infecting virus. However, the specific viral components that these antibodies recognize and how they neutralize the virus have been incompletely described. Here we map a region on dengue virus serotype 3 recognized by the human neutralizing antibody 5J7 and then test the functional significance of this region by transplanting it into a serotype 1 virus. Our studies demonstrate a region on dengue virus necessary for 5J7 binding and neutralization. Our work also demonstrates the technical feasibility of engineering dengue viruses to display targets of protective antibodies. This technology can be used to develop new dengue vaccines and diagnostic assays
Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity
Dengue virus is the most important arthropod-borne viral disease of humans worldwide, with an estimated 390 million acute infections annually. The best means to control this global health threat is a vaccine, but dengue vaccine development has progressed slowly, partly because the antigenic targets required to stimulate long-term immunity are not well-defined. Here, we show a specific region on the viral surface (the envelope domain I/II hinge) that is the target of protective antibodies after primary human infections. These results are critically important for dengue vaccine design, because we hypothesize that a successful dengue vaccine will stimulate antibodies that target this region. More broadly, this study establishes a template for similar approaches for improving vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens
The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance
The James Webb Space Telescope (JWST) is a large, infrared space telescope
that has recently started its science program which will enable breakthroughs
in astrophysics and planetary science. Notably, JWST will provide the very
first observations of the earliest luminous objects in the Universe and start a
new era of exoplanet atmospheric characterization. This transformative science
is enabled by a 6.6 m telescope that is passively cooled with a 5-layer
sunshield. The primary mirror is comprised of 18 controllable, low areal
density hexagonal segments, that were aligned and phased relative to each other
in orbit using innovative image-based wavefront sensing and control algorithms.
This revolutionary telescope took more than two decades to develop with a
widely distributed team across engineering disciplines. We present an overview
of the telescope requirements, architecture, development, superb on-orbit
performance, and lessons learned. JWST successfully demonstrates a segmented
aperture space telescope and establishes a path to building even larger space
telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25
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iEEG-BIDS, extending the Brain Imaging Data Structure specification to human intracranial electrophysiology
The Brain Imaging Data Structure (BIDS) is a community-driven specification for organizing neuroscience data and metadata with the aim to make datasets more transparent, reusable, and reproducible. Intracranial electroencephalography (iEEG) data offer a unique combination of high spatial and temporal resolution measurements of the living human brain. To improve internal (re)use and external sharing of these unique data, we present a specification for storing and sharing iEEG data: iEEG-BIDS
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