Entropy based distance cutoff for protein internal contact networks

Protein structure networks (PSNs) have long been used to provide a coarse yet meaningful representation of protein structure, dynamics, and internal communication pathways. An important question is what criteria should be applied to construct the network so that to include relevant interresidue contacts while avoiding unnecessary connections. To address this issue we systematically considered varying residue distance cutoff length and the probability threshold for contact formation to construct PSNs based on atomistic molecular dynamics in order to assess the amount of mutual information within the resulting representations. We found that the minimum in mutual information is universally achieved at the cutoff length of 5 Å, irrespective of the applied contact formation probability threshold in all considered, distinct proteins. Assuming that the optimal PSNs should be characterised by the least amount of redundancy, which corresponds to the minimum in mutual information, this finding suggests an objective criterion for cutoff distance and supports the existing preference towards its customary selection around 5 Å length, typically based to date on heuristic criteria.

Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides

Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to mRNA and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization-driven, while differential expression events are more common and driven by other mechanisms. We further evaluated the performance of in silico screens for off-target events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR. Despite these large improvements in performance, the approach does not detect the majority of events at a false discovery rate below 99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs.

Molecular Epidemiology of Azole-Resistant Aspergillus fumigatus in Sawmills of Eastern France by Microsatellite Genotyping

Background: Wood chipping has been described as a potential hotspot for the selection of azole-resistant Aspergillus fumigatus (ARAf). We previously reported ARAf isolates in sawmills (Eastern France), most of which contained the TR34/L98H mutation. Methods: To study genotypic relatedness, microsatellite genotyping (short tandem repeat for A. fumigatus (STRAf)) was performed on 41 azole-susceptible A. fumigatus (ASAf) and 23 ARAf isolated from 18 sawmills and two clinical A. fumigatus (sensitive and resistant) isolated from a sinus sample of a woodworker. Results: Fifty-four unique multilocus genotypes (MLGs) were described among the 66 isolates: 13/24 ARAf and 41/42 ASAf. Allelic diversity was higher for ASAf than for ARAf. Among the 24 ARAf, five isolates had their own MLGs. Thirteen ARAf (54%) belonged to the same group, composed of four close MLGs, defined using Bruvo’s distance. Thirty-two of the 42 ASAf (76%) had their own MLGs and could not be grouped with the Bruvo’s distance cutoff used (0.2). Conclusion: Thus, at a regional scale and in the particular environment of the wood industry, common but also different distinct genotypes, even in the same sawmill, were identified. This suggests that the hypothesis of ARAf clonal expansion from a common strain is probably insufficient to explain genotype emergence and distribution.

Genomic Nucleotide-Based Distance Analysis for Delimiting Old World Monkey Derived Herpes Simplex Virus Species.

Herpes simplex viruses form a genus within the alphaherpesvirus subfamily, with three identified viral species isolated from Old World monkeys (OWM); Macacine alphaherpesvirus 1 (herpes B), Cercopithecine alphaherpesvirus 2 (SA8), and Papiine alphaherpesvirus 2 (PaHV-2; herpes papio). Herpes B is endemic to macaques, while PaHV-2 and SA8 appear endemic to baboons. All three viruses are genetically and antigenically similar, with SA8 and PaHV-2 thought to be avirulent in humans, while herpes B is a biosafety level 4 pathogen. Recently, next-generation sequencing (NGS) has resulted in an increased number of published OWM herpes simplex genomes, allowing an encompassing phylogenetic analysis. In this study, phylogenetic networks, in conjunction with a genome-based genetic distance cutoff method were used to examine 27 OWM monkey herpes simplex isolates. Genome-based genetic distances were calculated, resulting in distances between Lion and Pig-tailed simplex viruses themselves, and versus herpes B core strains that were higher than those between PaHV-2 and SA8 (approximately 14% and 10% respectively). The species distance cutoff was determined to be 8.94%, with the method recovering separate species status for PaHV-2 and SA8 and showed that Lion and Pig-tailed simplex viruses (vs core herpes B strains) were well over the distance species cutoff. In conclusion, we propose designating Lion and Pig-tailed simplex viruses as separate, individual viral species, and that this may be the first identification of viral cryptic species.

Genomic Nucleotide-Based Distance Analysis for Delimiting Old World Monkey Derived Herpes Simplex Viruses Species.

Herpes simplex viruses form a genus within the alphaherpesvirus subfamily, with three identified viral species isolated from Old World monkeys (OWM); Macacine alphaherpesvirus 1 (herpes B), Cercopithecine alphaherpesvirus 2 (SA8), and Papiine alphaherpesvirus 2 (PaHV-2; herpes papio). Herpes B is endemic to macaques, while PaHV-2 and SA8 appear endemic to baboons. All three viruses are genetically and antigenically similar, with SA8 and PaHV-2 thought to be avirulent in humans, while herpes B is a biosafety level 4 pathogen. Recently, next-generation sequencing (NGS) has resulted in an increased number of published OWM herpes simplex genomes, allowing an encompassing phylogenetic analysis. In this study, phylogenetic networks, in conjunction with a genome-based genetic distance cutoff method were used to examine 27 OWM monkey herpes simplex isolates. Genome-based genetic distances were calculated, resulting in distances between Lion and Pig-tailed simplex viruses themselves, and versus herpes B core strains that were higher than those between PaHV-2 and SA8 (approximately 14% and 10% respectively). The species distance cutoff was determined to be 8.94%, with the method recovering separate species status for PaHV-2 and SA8 and showed that Lion and Pig-tailed simplex viruses (vs core herpes B strains) were well over the distance species cutoff. In conclusion, we propose designating Lion and Pig-tailed simplex viruses as separate, individual viral species, and that this may be the first identification of viral cryptic species.

Representation of the QM Subsystem for Long-Range Electrostatic Interaction in Non-Periodic Ab Initio QM/MM Calculations

In QM/MM calculations, it is essential to handle electrostatic interactions between the QM and MM subsystems accurately and efficiently. To achieve maximal efficiency, it is convenient to adopt a hybrid scheme, where the QM electron density is used explicitly in the evaluation of short-range QM/MM electrostatic interactions, while a multipolar representation for the QM electron density is employed to account for the long-range QM/MM electrostatic interactions. In order to avoid energy discontinuity at the cutoffs, which separate the short- and long-range QM/MM electrostatic interactions, a switching function should be utilized to ensure a smooth potential energy surface. In this study, we benchmarked the accuracy of such hybrid embedding schemes for QM/MM electrostatic interactions using different multipolar representations, switching functions and cutoff distances. For test systems (neutral and anionic oxyluciferin in MM (aqueous and enzyme) environments), the best accuracy was acquired with a combination of QM electrostatic potential (ESP) charges and dipoles and two switching functions (long-range electrostatic corrections (LREC) and Switch) in the treatment of long-range QM/MM electrostatics. It allowed us to apply a 10Å distance cutoff and still obtain QM/MM electrostatics/polarization energies within 0.1 kcal/mol and time-dependent density functional theory (TDDFT)/MM vertical excitation energies within 10−3 eV from theoretical reference values.

Brian Greene: The Speculative Sublime

Charles Dodgson warned a child correspondent of the dangers of living in the looking-glass world of mathematicians like himself, the high price of consistently believing “six impossible things before breakfast”: . . . Don’t be in such a hurry to believe next time—I’ll tell you why—If you set to work to believe everything you will tire out the muscles of the mind, and then you’ll be so weak you won’t be able to believe the simplest true things. Only last week a friend of mine set to work to believe Jack-the-giant-killer. He managed to do it, but he was so exhausted by it that when I told him it was raining (which was true) he couldn’t believe it, but rushed out into the street without his umbrella, the consequence of which was his hair got seriously damp, and one curl didn’t recover its right shape for nearly two days. . . . In all his books, Brian Greene is our tour guide on a journey into his particular looking-glass world—string theory, an exercise in the speculative sublime, a sublime only for aficionados, certainly not for you and me. Here is the abstract of an article cited a respectable 201 times: . . . We show that a string-inspired Planck scale modification of general relativity can have observable cosmological effects. Specifically, we present a complete analysis of the inflationary perturbation spectrum produced by a phenomenological Lagrangian that has a standard form on large scales but incorporates a string-inspired short distance cutoff, and find a deviation from the standard result. We use the de Sitter calculation as the basis of a qualitative analysis of other inflationary backgrounds, arguing that in these cases the cutoff could have a more pronounced effect, changing the shape of the spectrum. Moreover, the computational approach developed here can be used to provide unambiguous calculations of the perturbation spectrum in other heuristic models that modify trans-Planckian physics and thereby determine their impact on the inflationary perturbation spectrum. Finally, we argue that this model may provide an exception to constraints, recently proposed by Tanaka and Starobinsky, on the ability of Planck-scale physics to modify the cosmological spectrum. . . .