Predicting Growth Conditions from Internal Metabolic Fluxes in an In-Silico Model of E. coli

A widely studied problem in systems biology is to predict bacterial phenotype from growth conditions, using mechanistic models such as flux balance analysis (FBA). However, the inverse prediction of growth conditions from phenotype is rarely considered. Here we develop a computational framework to carry out this inverse prediction on a computational model of bacterial metabolism. We use FBA to calculate bacterial phenotypes from growth conditions in E. coli, and then we assess how accurately we can predict the original growth conditions from the phenotypes. Prediction is carried out via regularized multinomial regression. Our analysis provides several important physiological and statistical insights. First, we show that by analyzing metabolic end products we can consistently predict growth conditions. Second, prediction is reliable even in the presence of small amounts of impurities. Third, flux through a relatively small number of reactions per growth source (∼10) is sufficient for accurate prediction. Fourth, combining the predictions from two separate models, one trained only on carbon sources and one only on nitrogen sources, performs better than models trained to perform joint prediction. Finally, that separate predictions perform better than a more sophisticated joint prediction scheme suggests that carbon and nitrogen utilization pathways, despite jointly affecting cellular growth, may be fairly decoupled in terms of their dependence on specific assortments of molecular precursors.     

The pathogenesis of simian varicella virus in cynomolgus monkeys.

The MLM herpesvirus is infectious for cynomolgus monkeys. The disease in this species, possibly modulated by preinoculation antibody resembles human varicella. Virus has been recovered from blood during the early incubation period, and from liver, lymph nodes, kidney, bladder and urine during the eruptive period of infection. The major target organs were skin and liver; specific pathological changes developed in both. Appropriate antibody responses, including those to Herpesvirus varicellae followed infections mounted by parenteral inoculation of cynomolgus monkeys.     

A collection of programs for one‐dimensional Ising analysis of linear repeat proteins with point substitutions

A collection of programs is presented to analyze the thermodynamics of folding of linear repeat proteins using a 1D Ising model to determine intrinsic folding and interfacial coupling free energies. Expressions for folding transitions are generated for a series of constructs with different repeat numbers and are globally fitted to transitions for these constructs. These programs are designed to analyze Ising parameters for capped homopolymeric consensus repeat constructs as well as heteropolymeric constructs that contain point substitutions, providing a rigorous framework for analysis of the effects of mutation on intrinsic and directional (i.e., N‐ vs. C‐terminal) interfacial coupling free‐energies. A bootstrap analysis is provided to estimate parameter uncertainty as well as correlations among fitted parameters. Rigorous statistical analysis is essential for interpreting fits using the complex models required for Ising analysis of repeat proteins, especially heteropolymeric repeat proteins. Programs described here are available at https://github.com/barricklab-at-jhu/Ising_programs .     

Time Series Analysis of Sexual Assault Case Characteristics and the 2007–2008 Period of Post-Election Violence in Kenya

Background

Following the declaration that President Mwai Kibaki was the winner of the Kenyan presidential election held on December 27, 2007, a period of post-election violence (PEV) took place. In this study, we aimed to identify whether the period of PEV in Kenya was associated with systematic changes in sexual assault case characteristics.

Methods and Findings

Medical records of 1,615 patients diagnosed with sexual assault between 2007 and 2011 at healthcare facilities in Eldoret (n = 569), Naivasha (n = 534), and Nakuru (n = 512) were retrospectively reviewed to examine characteristics of sexual assault cases over time. Time series and linear regression were used to examine temporal variation in case characteristics relative to the period of post-election violence in Kenya. Key informant interviews with healthcare workers at the sites were employed to triangulate findings. The time series of sexual assault case characteristics at these facilities were examined, with a specific focus on the December 2007–February 2008 period of post-election violence. Prais-Winsten estimates indicated that the three-month period of post-election violence was associated with a 22 percentage-point increase in cases where survivors did not know the perpetrator, a 20 percentage-point increase in cases with more than one perpetrator, and a 4 percentage-point increase in cases that had evidence of abdominal injury. The post-election violence period was also associated with an 18 percentage-point increase in survivors waiting >1 month to report to a healthcare facility. Sensitivity analyses confirmed that these characteristics were specific to the post-election violence time period.

Conclusion

These results demonstrate systematic patterns in sexual assault characteristics during the PEV period in Kenya.     

In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model

Imbalances in neurotrophins or their high-affinity Trk receptors have long been reported in neurodegenerative diseases. However, a molecular link between these gene products and neuronal cell death has not been established. In the trisomy 16 (Ts16) mouse there is increased apoptosis in the cortex, and hippocampal neurons undergo accelerated cell death that cannot be rescued by administration of brain-derived neurotrophic factor (BDNF). Ts16 neurons have normal levels of the TrkB tyrosine kinase receptor but an upregulation of the TrkB.T1 truncated receptor isoform. Here we show that restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death. Moreover, it corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling mediated by full-length TrkB in Ts16 hippocampal neurons. These data provide a direct link between neuronal cell death and abnormalities in Trk neurotrophin receptor levels.     

Contractile behavior of the forelimb digital flexors during steady-state locomotion in horses (Equus caballus): an initial test of muscle architectural hypotheses about in vivo function

The forelimb digital flexors of the horse display remarkable diversity in muscle architecture despite each muscle-tendon unit having a similar mechanical advantage across the fetlock joint. We focus on two distinct muscles of the digital flexor system: short compartment deep digital flexor (DDF(sc)) and the superficial digital flexor (SDF). The objectives were to investigate force-length behavior and work performance of these two muscles in vivo during locomotion, and to determine how muscle architecture contributes to in vivo function in this system. We directly recorded muscle force (via tendon strain gauges) and muscle fascicle length (via sonomicrometry crystals) as horses walked (1.7 m s(-1)), trotted (4.1 m s(-1)) and cantered (7.0 m s(-1)) on a motorized treadmill. Over the range of gaits and speeds, DDF(sc) fascicles shortened while producing relatively low force, generating modest positive net work. In contrast, SDF fascicles initially shortened, then lengthened while producing high force, resulting in substantial negative net work. These findings suggest the long fibered, unipennate DDF(sc) supplements mechanical work during running, whereas the short fibered, multipennate SDF is specialized for economical high force and enhanced elastic energy storage. Apparent in vivo functions match well with the distinct architectural features of each muscle.