A proposal for regularly updated review/survey articles: "Perpetual Reviews"

We advocate the publication of review/survey articles that will be updated regularly, both in traditional journals and novel venues. We call these "perpetual reviews." This idea naturally builds on the dissemination and archival capabilities present in the modern internet, and indeed perpetual reviews exist already in some forms. Perpetual review articles allow authors to maintain over time the relevance of non-research scholarship that requires a significant investment of effort. Further, such reviews published in a purely electronic format without space constraints can also permit more pedagogical scholarship and clearer treatment of technical issues that remain obscure in a brief treatment.Comment: This is a draft white paper and we seek comments from the communit

Alternative communication network designs for an operational Plato 4 CAI system

The cost of alternative communications networks for the dissemination of PLATO IV computer-aided instruction (CAI) was studied. Four communication techniques are compared: leased telephone lines, satellite communication, UHF TV, and low-power microwave radio. For each network design, costs per student contact hour are computed. These costs are derived as functions of student population density, a parameter which can be calculated from census data for one potential market for CAI, the public primary and secondary schools. Calculating costs in this way allows one to determine which of the four communications alternatives can serve this market least expensively for any given area in the U.S. The analysis indicates that radio distribution techniques are cost optimum over a wide range of conditions

Binding of Small-Molecule Ligands to Proteins: “What You See” Is Not Always “What You Get”

We review insights from computational studies of affinities of ligands binding to proteins. The power of structural biology is in translating knowledge of protein structures into insights about their forces, binding, and mechanisms. However, the complementary power of computer modeling is in showing “the rest of the story” (i.e., how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinities). Upon binding to a protein, a ligand can bind in multiple orientations; the protein or ligand can be deformed by the binding event; waters, ions, or cofactors can have unexpected involvement; and conformational or solvation entropies can sometimes play large and otherwise unpredictable roles. Computer modeling is helping to elucidate these factors

Boom and Bust Carbon-Nitrogen Dynamics during Reforestation

Legacies of historical land use strongly shape contemporary ecosystem dynamics. In old-field secondary forests, tree growth embodies a legacy of soil changes affected by previous cultivation. Three patterns of biomass accumulation during reforestation have been hypothesized previously, including monotonic to steady state, non-monotonic with a single peak then decay to steady state, and multiple oscillations around the steady state. In this paper, the conditions leading to the emergence of these patterns is analyzed. Using observations and models, we demonstrate that divergent reforestation patterns can be explained by contrasting time-scales in ecosystem carbon-nitrogen cycles that are influenced by land use legacies. Model analyses characterize non-monotonic plant-soil trajectories as either single peaks or multiple oscillations during an initial transient phase controlled by soil carbon-nitrogen conditions at the time of planting. Oscillations in plant and soil pools appear in modeled systems with rapid tree growth and low initial soil nitrogen, which stimulate nitrogen competition between trees and decomposers and lead the forest into a state of acute nitrogen deficiency. High initial soil nitrogen dampens oscillations, but enhances the magnitude of the tree biomass peak. These model results are supported by data derived from the long-running Calhoun Long-Term Soil-Ecosystem Experiment from 1957 to 2007. Observed carbon and nitrogen pools reveal distinct tree growth and decay phases, coincident with soil nitrogen depletion and partial re-accumulation. Further, contemporary tree biomass loss decreases with the legacy soil C:N ratio. These results support the idea that non-monotonic reforestation trajectories may result from initial transients in the plant-soil system affected by initial conditions derived from soil changes associated with land-use history

Haem acquisition is facilitated by a novel receptor Hma and required by uropathogenic Escherichia coli for kidney infection

Iron acquisition, mediated by specific outer membrane receptors, is critical for colonization of the urinary tract by uropathogenic Escherichia coli (UPEC). The role of specific iron sources in vivo , however, remains largely unknown. In this study, we identified a 79 kDa haem receptor, h ae m a cquisition protein Hma, and established that it functions independently of ChuA to mediate haemin uptake by UPEC strain CFT073. We demonstrated that expression of hma promotes TonB-dependent haemin utilization and the Hma protein binds haemin with high affinity ( K d  = 8 μM). Hma, however, lacks conserved His residues shown to mediate haem uptake by other bacterial receptors. In contrast, we identified Tyr-126 as a residue necessary for Hma-mediated haemin utilization. In a murine co-infection model of UTI, an isogenic hma mutant was out-competed by wild-type CFT073 in the kidneys ( P  < 0.001) and spleens ( P  <  0.0001) of infected mice, indicating its expression provided a competitive advantage in these organs. Furthermore, a hma chuA double mutant, which is unable to utilize haemin, was unable to colonize the kidneys to wild-type levels during independent infection ( P  = 0.02). Thus, we demonstrate that UPEC requires haem for kidney colonization and that uptake of this iron source is mediated, in part, by the novel receptor, Hma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71590/1/j.1365-2958.2008.06509.x.pd

Vaxign: The First Web-Based Vaccine Design Program for Reverse Vaccinology and Applications for Vaccine Development

Vaxign is the first web-based vaccine design system that predicts vaccine targets based on genome sequences using the strategy of reverse vaccinology. Predicted features in the Vaxign pipeline include protein subcellular location, transmembrane helices, adhesin probability, conservation to human and/or mouse proteins, sequence exclusion from genome(s) of nonpathogenic strain(s), and epitope binding to MHC class I and class II. The precomputed Vaxign database contains prediction of vaccine targets for >70 genomes. Vaxign also performs dynamic vaccine target prediction based on input sequences. To demonstrate the utility of this program, the vaccine candidates against uropathogenic Escherichia coli (UPEC) were predicted using Vaxign and compared with various experimental studies. Our results indicate that Vaxign is an accurate and efficient vaccine design program

Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning

We consider the recently developed weighted ensemble milestoning (WEM) scheme [J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulating ligand-receptor dissociation dynamics. We performed WEM simulations on the following host-guest systems: Na$^+$/Cl$^-$ ion pair and 4-hydroxy-2-butanone (BUT) ligand with FK506 binding protein (FKBP). As proof or principle, we show that the WEM formalism reproduces the Na$^+$/Cl$^-$ ion pair dissociation timescale and the free energy profile obtained from long conventional MD simulation. To increase accuracy of WEM calculations applied to kinetics and thermodynamics in protein-ligand binding, we introduced a modified WEM scheme called weighted ensemble milestoning with restraint release (WEM-RR), which can increase the number of starting points per milestone without adding additional computational cost. WEM-RR calculations obtained a ligand residence time and binding free energy in agreement with experimental and previous computational results. Moreover, using the milestoning framework, the binding time and rate constants, dissociation constant and the committor probabilities could also be calculated at a low computational cost. We also present an analytical approach for estimating the association rate constant ($k_{\text{on}}$) when binding is primarily diffusion driven. We show that the WEM method can efficiently calculate multiple experimental observables describing ligand-receptor binding/unbinding and is a promising candidate for computer-aided inhibitor design

Animal Agriculture in South Carolina: A Fact Book

Livestock Production/Industries,