Multivariate emulation of computer simulators: model selection and diagnostics with application to a humanitarian relief model

We present a common framework for Bayesian emulation methodologies for multivariate-output simulators, or computer models, that employ either parametric linear models or nonparametric Gaussian processes. Novel diagnostics suitable for multivariate covariance-separable emulators are developed and techniques to improve the adequacy of an emulator are discussed and implemented. A variety of emulators are compared for a humanitarian relief simulator, modelling aid missions to Sicily after a volcanic eruption and earthquake, and a sensitivity analysis is conducted to determine the sensitivity of the simulator output to changes in the input variables. The results from parametric and nonparametric emulators are compared in terms of prediction accuracy, uncertainty quantification and scientific interpretability

Deletion mutants in COP9/Signalosome subunits in fission yeast Schizosaccharomyces pombe display distinct phenotypes

The COP9/signalosome complex is highly conserved in evolution and possesses significant structural similarity to the 19S regulatory lid complex of the proteasome. It also shares limited similarity to the translation initiation factor eIF3. The signalosome interacts with multiple cullins in mammalian cells. In the fission yeast Schizosaccharomyces pombe, the Csn1 subunit is required for the removal of covalently attached Nedd8 from Pcu1, one of three S. pombe cullins. It remains unclear whether this activity is required for all the functions ascribed to the signalosome. We previously identified Csn1 and Csn2 as signalosome subunits in S. pombe. csn1 and csn2 null mutants are DNA damage sensitive and exhibit slow DNA replication. Two further putative subunits, Csn4 and Csn5, were identified from the S. pombe genome database. Herein, we characterize null mutations of csn4 and csn5 and demonstrate that both genes are required for removal of Nedd8 from the S. pombe cullin Pcu1 and that their protein products associate with Csn1 and Csn2. However, neither csn4 nor csn5 null mutants share the csn1 and csn2 mutant phenotypes. Our data suggest that the subunits of the signalosome cannot be considered as a distinct functional unit and imply that different subunits of the signalosome mediate distinct functions

Chromatin Structure in the Cellular Slime Mold Dictyostelium discoideum

The structure of Dictyostelium discoideum chromatin has been studied by the following techniques: electron microscopy, staphylococcal nuclease digestion, acrylamide gel electrophoresis, sucrose gradient centrifugation, and melting. The basic unit of chromatin is the nucleosome, which is a particle 98.6 angstrom in diameter. Approximately 50% of the chromatin is protected from nuclease digestion, but this decreases when protease activity is not inhibited. The nucleosome contains 187 base pairs of DNA, including a 137-base-pair core and a 50-base-pair linker. The monomer nucleosome has an s20,w value of 11.5 S on isokinetic sucrose gradients. When the chromatin is melted, four transitions are observed, at 54.5 degrees, 66.7 degrees, 74.9 degrees, and 79.7 degrees. The structure of Dictyostelium chromatin is very similar to that seen in higher eukaryotes

Bayesian Optimal Design for Ordinary Differential Equation Models

Bayesian optimal design is considered for experiments where it is hypothesised that the responses are described by the intractable solution to a system of non-linear ordinary differential equations (ODEs). Bayesian optimal design is based on the minimisation of an expected loss function where the expectation is with respect to all unknown quantities (responses and parameters). This expectation is typically intractable even for simple models before even considering the intractability of the ODE solution. New methodology is developed for this problem that involves minimising a smoothed stochastic approximation to the expected loss and using a state-of-the-art stochastic solution to the ODEs, by treating the ODE solution as an unknown quantity. The methodology is demonstrated on three illustrative examples and a real application involving estimating the properties of human placentas

In situ correction of liquid meniscus in cell culture imaging system based on parallel Fourier ptychographic microscopy (96 Eyes)

We collaborated with Amgen and spent five years in designing and fabricating next generation multi-well plate imagers based on Fourier ptychographic microscopy (FPM). A 6-well imager (Emsight) and a low-cost parallel microscopic system (96 Eyes) based on parallel FPM were reported in our previous work. However, the effect of liquid meniscus on the image quality is much stronger than anticipated, introducing obvious wavevector misalignment and additional image aberration. To this end, an adaptive wavevector correction (AWC-FPM) algorithm and a pupil recovery improvement strategy are presented to solve these challenges in situ. In addition, dual-channel fluorescence excitation is added to obtain structural information for microbiologists. Experiments are demonstrated to verify their performances. The accuracy of angular resolution with our algorithm is within 0.003 rad. Our algorithms would make the FPM algorithm more robust and practical and can be extended to other FPM-based applications to overcome similar challenges

Evidence for potential underestimation of clinical folate deficiency in resource-limited countries using blood tests

Although a low serum folate concentration is a useful biomarker of pure folate deficiency, the presence of vitamin B12 deficiency or hemolysis or both in individuals with low folate status predictably raises serum folate levels. Therefore, in resource-limited settings where dietary folate deficiency can coexist with vitamin B12 deficiency or malaria or both, the serum folate concentration can range from normal to high, leading to serious underestimation of tissue folate status. This review traces the genesis of an inappropriate overreliance on the serum folate concentration to rule out folate deficiency in vulnerable populations of women and children. Of significance, without due consideration of a chronically inadequate dietary folate intake, authors of influential studies have likely wrongly judged these populations to have an adequate folate status. Through repetition, this error has led to a dangerous entry into the contemporary medical literature that folate deficiency is rare in women and children. As a consequence, many millions of under-resourced women and children with mild to moderate tissue folate deficiency may have been deprived of folate replacement. This review uses historical documents to challenge earlier conclusions and re-emphasizes the need for contextual integration of clinical information in resource-limited settings