Analyzing Machupo virus-receptor binding by molecular dynamics simulations

In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein-protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non-alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host-virus protein-protein interface. We use steered molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second, although the static co-crystal structure shows two large hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate that one of them may not be important for tight binding. Third, one viral site known to be critical for infection may mark an important evolutionary suppressor site for infection-resistant hTfR1 mutants. Finally, our approach provides a framework to compare the effects of multiple mutations, individually and jointly, on protein-protein interactions.Comment: 33 pages, 8 figures, 5 table

A Toy Model of Flying Snake's Glide

We have developed a toy model of flying snake's glide [J.J. Socha, Nature vol. 418 (2002) 603.] by modifying a model for a falling paper. We have found that asymmetric oscillation is a key about why snake can glide. Further investigation for snake's glide will provide us details about how it can glide without a wing.Comment: 6 pages, to be submitted to J. Phys. Soc. Jpn. Revised Version submitted to the abov

Fertility intentions following testing for a BRCA1 gene mutation

Journal ArticleObjective: To test whether fertility intentions differed among persons who tested positive, tested negative, or did not know their genetic status for a mutation of the BRCA1 gene. Method: Participants were members of a large Utah-based kindred with an identified mutation at the BRCA1 locus. Participants received genetic counseling prior to testing and were interviewed at baseline before testing and at three points after receiving test results from a genetic counselor. The sample included men and women who completed all interviews, were between ages 18 and 45, and were fertile, resulting in a sample of 101 respondents. The primary dependent variable measured whether a subject indicated that they were moderately or very sure at all three post-testing interviews that they intended to have additional children. Effects of BRCA1 mutation status on fertility intentions were estimated using multivariate logistic regressions where we controlled for gender, age, marital status, and baseline fertility intentions. Results: Female carriers were less likely to want additional children in relation to female noncarriers (odds ratio 0.12, 95% confidence interval 0.01-1.23; P = 0.074). No differences were found among men. There was a significant difference in the effect of mutation status on fertility intentions between males and females (Gender _x0001_ Carrier status interaction; P = 0.009). Persons who did not know their mutation status were less likely to want more children than noncarriers (odds ratio 0.09, 95% confidence interval 0.01-0.75; P = 0.027). Conclusion: Predictive genetic testing for late-onset cancer susceptibility affects family planning decision-making. Persons contemplating predictive testing should be informed about possible effects such testing may have on their plans for future fertility

In Washington State, Open Courts Jurisprudence Consists Mainly of Open Questions

Issues of public trial and the open administration of justice have been an intense focus of the Washington State Supreme Court in recent years. In its December issue, the Washington Law Review surveyed U.S. and Washington State public trial and public access jurisprudence, and made recommendations for clarifying the constitutional issues involved when a courtroom “closure” occurs. Just before that issue went to press, the Washington State Supreme Court decided four important public trial cases: State v. Sublett, State v. Wise, State v. Paumier, and In re Morris. The court issued fourteen separate opinions, clearly demonstrating deep divisions among the justices. This follow-up article examines the principal arguments of the new opinions, identifies what areas appear settled, and discusses the important questions that remain unresolved

Enhanced flight performance by genetic manipulation of wing shape in Drosophila

Insect wing shapes are remarkably diverse and the combination of shape and kinematics determines both aerial capabilities and power requirements. However, the contribution of any specific morphological feature to performance is not known. Using targeted RNA interference to modify wing shape far beyond the natural variation found within the population of a single species, we show a direct effect on flight performance that can be explained by physical modelling of the novel wing geometry. Our data show that altering the expression of a single gene can significantly enhance aerial agility and that the Drosophila wing shape is not, therefore, optimized for certain flight performance characteristics that are known to be important. Our technique points in a new direction for experiments on the evolution of performance specialities in animals

Georgia\u27s New Battleground: Five Georgia Law Professors Examine the State\u27s New Tort Legislation

In February, after several years of debate, the Georgia General Assembly enacted a comprehensive set of tort reform provisions. This fairly complex body of legislation contains 16 separate sections dealing with procedure, evidence and substantive tort issues. Shortly after it was signed into law, five Georgia Law professors sat down with alumni and students to describe parts of the new legislation, to identify some issues that are likely to arise as the new laws go into effect and to speculate about what they think the likely impact will be on litigation

A Raman spectroscopic and computational study of new aromatic pyrimidine-based halogen bond acceptors

© 2019 by the authors. Two new aromatic pyrimidine-based derivatives designed specifically for halogen bond directed self-assembly are investigated through a combination of high-resolution Raman spectroscopy, X-ray crystallography, and computational quantum chemistry. The vibrational frequencies of these new molecular building blocks, pyrimidine capped with furan (PrmF) and thiophene (PrmT), are compared to those previously assigned for pyrimidine (Prm). The modifications affect only a select few of the normal modes of Prm, most noticeably its signature ring breathing mode, ν1. Structural analyses afforded by X-ray crystallography, and computed interaction energies from density functional theory computations indicate that, although weak hydrogen bonding (C-H...O or C-H...N interactions) is present in these pyrimidine-based solid-state co-crystals, halogen bonding and π-stacking interactions play more dominant roles in driving their molecular-assembly

Age Is Not a Barrier: Older Adults With Cancer Derive Similar Benefit in a Randomized Controlled Trial of a Remote Symptom Monitoring Intervention Compared With Younger Adults

This study investigated a remote symptom monitoring intervention to examine if older participants with cancer received a similar magnitude of benefit compared with younger adults with cancer. We analyzed a longitudinal symptom monitoring intervention for 358 participants beginning a new course of chemotherapy treatment in community and academic oncology practices. The study design was a randomized control trial; participants were randomized to the intervention or usual care, the intervention was delivered during daily automated coaching. Older adults with moderate and severe symptoms derived similar benefit as those adults younger than 60 years of age, adherence to the study protocol which involved daily calls was high. There was no significant difference between the 2 age categories; on average, older adult participants made 88% of expected daily calls and younger adult participants made 90% of expected daily calls. Our results challenge the perception that older adults are unwilling or unable to use a technological tool such as interactive voice response and suggest that patient utilization may be guided by other factors, such as ease of use and perceived benefit from the intervention

Modelling amorphous computations with transcription networks

The power of electronic computation is due in part to the development of modular gate structures that can be coupled to carry out sophisticated logical operations and whose performance can be readily modelled. However, the equivalences between electronic and biochemical operations are far from obvious. In order to help cross between these disciplines, we develop an analogy between complementary metal oxide semiconductor and transcriptional logic gates. We surmise that these transcriptional logic gates might prove to be useful in amorphous computations and model the abilities of immobilized gates to form patterns. Finally, to begin to implement these computations, we design unique hairpin transcriptional gates and then characterize these gates in a binary latch similar to that already demonstrated by Kim et al. (Kim, White & Winfree 2006 Mol. Syst. Biol. 2, 68 (doi:10.1038/msb4100099)). The hairpin transcriptional gates are uniquely suited to the design of a complementary NAND gate that can serve as an underlying basis of molecular computing that can output matter rather than electronic information