Fast sensitivity analysis methods for computationally expensive models with multi-dimensional output

© Author(s) 2018. Global sensitivity analysis (GSA) is a powerful approach in identifying which inputs or parameters most affect a model's output. This determines which inputs to include when performing model calibration or uncertainty analysis. GSA allows quantification of the sensitivity index (SI) of a particular input - the percentage of the total variability in the output attributed to the changes in that input - by averaging over the other inputs rather than fixing them at specific values. Traditional methods of computing the SIs using the Sobol and extended Fourier Amplitude Sensitivity Test (eFAST) methods involve running a model thousands of times, but this may not be feasible for computationally expensive Earth system models. GSA methods that use a statistical emulator in place of the expensive model are popular, as they require far fewer model runs. We performed an eight-input GSA, using the Sobol and eFAST methods, on two computationally expensive atmospheric chemical transport models using emulators that were trained with 80 runs of the models. We considered two methods to further reduce the computational cost of GSA: (1) a dimension reduction approach and (2) an emulator-free approach. When the output of a model is multi-dimensional, it is common practice to build a separate emulator for each dimension of the output space. Here, we used principal component analysis (PCA) to reduce the output dimension, built an emulator for each of the transformed outputs, and then computed SIs of the reconstructed output using the Sobol method. We considered the global distribution of the annual column mean lifetime of atmospheric methane, which requires ∼ 2000 emulators without PCA but only 5-40 emulators with PCA. We also applied an emulator-free method using a generalised additive model (GAM) to estimate the SIs using only the training runs. Compared to the emulator-only methods, the emulator-PCA and GAM methods accurately estimated the SIs of the ∼ 2000 methane lifetime outputs but were on average 24 and 37 times faster, respectively

The Influence of Motion and Stress on Optical Fibers

We report on extensive testing carried out on the optical fibers for the VIRUS instrument. The primary result of this work explores how 10+ years of simulated wear on a VIRUS fiber bundle affects both transmission and focal ratio degradation (FRD) of the optical fibers. During the accelerated lifetime tests we continuously monitored the fibers for signs of FRD. We find that transient FRD events were common during the portions of the tests when motion was at telescope slew rates, but dropped to negligible levels during rates of motion typical for science observation. Tests of fiber transmission and FRD conducted both before and after the lifetime tests reveal that while transmission values do not change over the 10+ years of simulated wear, a clear increase in FRD is seen in all 18 fibers tested. This increase in FRD is likely due to microfractures that develop over time from repeated flexure of the fiber bundle, and stands in contrast to the transient FRD events that stem from localized stress and subsequent modal diffusion of light within the fibers. There was no measurable wavelength dependence on the increase in FRD over 350 nm to 600 nm. We also report on bend radius tests conducted on individual fibers and find the 266 microns VIRUS fibers to be immune to bending-induced FRD at bend radii of R > 10cm. Below this bend radius FRD increases slightly with decreasing radius. Lastly, we give details of a degradation seen in the fiber bundle currently deployed on the Mitchell Spectrograph (formally VIRUS-P) at McDonald Observatory. The degradation is shown to be caused by a localized shear in a select number of optical fibers that leads to an explosive form of FRD. In a few fibers, the overall transmission loss through the instrument can exceed 80%.Comment: 19 pages, 22 figure

High-temperature weak ferromagnetism on the verge of a metallic state: Impact of dilute Sr-doping on BaIrO3

The 5d-electron based BaIrO3 is a nonmetallic weak ferromagnet with a Curie temperature at Tc=175 K. Its largely extended orbitals generate strong electron-lattice coupling, and magnetism and electronic structure are thus critically linked to the lattice degree of freedom. Here we report results of our transport and magnetic study on slightly Sr doped BaIrO3. It is found that dilute Sr-doping drastically suppresses Tc, and instantaneously leads to a nonmetal-metal transition at high temperatures. All results highlight the instability of the ground state and the subtle relation between magnetic ordering and electron mobility. It is clear that BaIrO3 along with very few other systems represents a class of materials where the magnetic and transport properties can effectively be tuned by slight alterations in lattice parameters

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF

Protection of White Leghorn chickens by recombinant fowlpox vector vaccine with an updated H5 insert against Mexican H5N2 avian influenza viruses

Despite decades of vaccination, surveillance, and biosecurity measures, H5N2 low pathogenicity avian influenza (LPAI) virus infections continue in Mexico and neighboring countries. One explanation for tenacity of H5N2 LPAI in Mexico is the antigenic divergence of circulating field viruses compared to licensed vaccines due to antigenic drift. Our phylogenetic analysis indicates that the H5N2 LPAI viruses circulating in Mexico and neighboring countries since 1994 have undergone antigenic drift away from vaccine seed strains. Here we evaluated the efficacy of a new recombinant fowlpox virus vector containing an updated H5 insert (rFPV-H5/2016), more relevant to the current strains circulating in Mexico. We tested the vaccine efficacy against a closely related subcluster 4 Mexican H5N2 LPAI (2010 H5/LP) virus and the historic H5N2 HPAI (1995 H5/HP) virus in White Leghorn chickens. The rFPV-H5/2016 vaccine provided hemagglutinin inhibition (HI) titers pre-challenge against viral antigens from both challenge viruses in almost 100% of the immunized birds, with no differences in number of birds seroconverting or HI titers among all tested doses (1.5, 2.0, and 3.1 log10 mean tissue culture infectious doses/bird). The vaccine conferred 100% clinical protection and a significant decrease in oral and cloacal virus shedding from 1995 H5/HP virus challenged birds when compared to the sham controls at all tested doses. Virus shedding titers from vaccinated 2010 H5/LP virus challenged birds significantly decreased compared to sham birds especially at earlier time points. Our results confirm the efficacy of the new rFPV-H5/2016 against antigenic drift of LPAI virus in Mexico and suggest that this vaccine would be a good candidate, likely as a primer in a prime-boostinfo:eu-repo/semantics/publishedVersio

Can an Off-Nominal Landing by an MMRTG-Powered Spacecraft Induce a Special Region on Mars When No Ice Is Present?

This work aims at addressing whether a catastrophic failure of an entry, descent, and landing event of a Multimission Radioisotope Thermoelectric Generator-based lander could embed the heat sources into the martian subsurface and create a local environment that (1) would temporarily satisfy the conditions for a martian Special Region and (2) could establish a transport mechanism through which introduced terrestrial organisms could be mobilized to naturally occurring Special Regions elsewhere on Mars. Two models were run, a primary model by researchers at the Lawrence Berkeley National Laboratory and a secondary model by researchers at the Jet Propulsion Laboratory, both of which were based on selected starting conditions for various surface composition cases that establish the worst-case scenario, including geological data collected by the Mars Science Laboratory at Gale Crater. The summary outputs of both modeling efforts showed similar results: that the introduction of the modeled heat source could temporarily create the conditions established for a Special Region, but that there would be no transport mechanism by which an introduced terrestrial microbe, even if it was active during the temporarily induced Special Region conditions, could be transported to a naturally occurring Special Region of Mars

Efficacy of recombinant Marek’s disease virus vectored vaccines with computationally optimized broadly reactive antigen (COBRA) hemagglutinin insert against genetically diverse H5 high pathogenicity avian influenza viruses

The genetic and antigenic drift associated with the high pathogenicity avian influenza (HPAI) viruses of Goose/Guangdong (Gs/GD) lineage and the emergence of vaccine-resistant field viruses underscores the need for a broadly protective H5 influenza A vaccine. Here, we tested experimental vector herpesvirus of turkey (vHVT)-H5 vaccines containing either wild-type clade 2.3.4.4A-derived H5 inserts or computationally optimized broadly reactive antigen (COBRA) inserts with challenge by homologous and genetically divergent H5 HPAI Gs/GD lineage viruses in chickens. Direct assessment of protection was confirmed for all the tested constructs, which provided clinical protection against the homologous and heterologous H5 HPAI Gs/GD challenge viruses and significantly decreased oropharyngeal shedding titers compared to the sham vaccine. The cross reactivity was assessed by hemagglutinin inhibition (HI) and focus reduction assay against a panel of phylogenetically and antigenically diverse H5 strains. The COBRA-derived H5 inserts elicited antibody responses against antigenically diverse strains, while the wild-type-derived H5 vaccines elicited protection mostly against close antigenically related clades 2.3.4.4A and 2.3.4.4D viruses. In conclusion, the HVT vector, a widely used replicating vaccine platform in poultry, with H5 insert provides clinical protection and significant reduction of viral shedding against homologous and heterologous challenge. In addition, the COBRA-derived inserts have the potential to be used against antigenically distinct co-circulating viruses and future drift variants.info:eu-repo/semantics/publishedVersio

Efficacy of novel recombinant fowlpox vaccine against recent Mexican H7N3 highly pathogenic avian influenza virus

Since 2012, H7N3 highly pathogenic avian influenza (HPAI) has produced negative economic and animal welfare impacts on poultry in central Mexico. In the present study, chickens were vaccinated with two different recombinant fowlpox virus vaccines (rFPV-H7/3002 with 2015 H7 hemagglutinin [HA] gene insert, and rFPV-H7/2155 with 2002 H7 HA gene insert), and were then challenged three weeks later with H7N3 HPAI virus (A/chicken/Jalisco/CPA-37905/2015). The rFPV-H7/3002 vaccine conferred 100% protection against mortality and morbidity, and significantly reduced virus shed titers from the respiratory and gastrointestinal tracts. In contrast, 100% of sham and rFPV-H7/2155 vaccinated birds shed virus at higher titers and died within 4 days. Pre- (15/20) and post- (20/20) challenge serum of birds vaccinated with rFPV-H7/3002 had antibodies detectable by hemagglutination inhibition (HI) assay using challenge virus antigen. However, only a few birds (3/20) in the rFPV-H7/2155 vaccinated group had antibodies that reacted against the challenge strain but all birds had antibodies that reacted against the homologous vaccine antigen (A/turkey/Virginia/SEP-66/2002) (20/20). One possible explanation for differences in vaccines efficacy is the antigenic drift between circulating viruses and vaccines. Molecular analysis demonstrated that the Mexican H7N3 strains have continued to rapidly evolve since 2012. In addition, we identified in silico three potential new N-glycosylation sites on the globular head of the H7 HA of A/chicken/Jalisco/CPA-37905/2015 challenge virus, which were absent in 2012 H7N3 outbreak virus. Our results suggested that mutations in the HA antigenic sites including increased glycosylation sites, accumulated in the new circulating Mexican H7 HPAIV strains, altered the recognition of neutralizing antibodies from the older vaccine strain rFPV-H7/2155. Therefore, the protective efficacy of novel rFPV-H7/3002 against recent outbreak Mexican H7N3 HPAIV confirms the importance of frequent updating of vaccines seed strains for long-term effective control of H7 HPAI virus.info:eu-repo/semantics/publishedVersio