Numerical solution of a class of random boundary value problems

AbstractThis paper deals with the nonlinear two point boundary value problem y″ = f(x, y, y′, R1,…, Rn), x0 < x < xf S1y(x0) + S2 y′(x0) = S3, S4 y(xf) + S5 y′(xf) = S6 where R1,…, Rn, S1,…, S6 are bounded continuous random variables. An approximate probability distribution function for y(x) is constructed by numerical integration of a set of related deterministic problems. Two distinct methods are described, and in each case convergence of the approximate distribution function to the actual distribution function is established. Primary attention is placed on problems with two random variables, but various generalizations are noted. As an example, a nonlinear one-dimensional heat conduction problem containing one or two random variables is studied in some detail

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

SummaryBiotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

SummaryBiotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required

Non-Visual Effects of Light on Melatonin, Alertness and Cognitive Performance: Can Blue-Enriched Light Keep Us Alert?

Light exposure can cascade numerous effects on the human circadian process via the non-imaging forming system, whose spectral relevance is highest in the short-wavelength range. Here we investigated if commercially available compact fluorescent lamps with different colour temperatures can impact on alertness and cognitive performance

Tracing the migration of mantle CO2 in gas fields and mineral water springs in south-east Australia using noble gas and stable isotopes

Geochemical monitoring of CO2 storage requires understanding of both innate and introduced fluids in the crust as well as the subsurface processes that can change the geochemical fingerprint of CO2 during injection, storage and any subsequent migration. Here, we analyse a natural analogue of CO2 storage, migration and leakage to the atmosphere, using noble gas and stable isotopes to constrain the effect of these processes on the geochemical fingerprint of the CO2. We present the most comprehensive evidence to date for mantle-sourced CO2 in south-east Australia, including well gas and CO2-rich mineral spring samples from the Otway Basin and Central Victorian Highlands (CVH). 3He/4He ratios in well gases and CO2 springs range from 1.21 to 3.07 RA and 1.23 – 3.65 RC/RA, respectively. We present chemical fractionation models to explain the observed range of 3He/4He ratios, He, Ne, Ar, Kr, Xe concentrations and δ13C(CO2) values in the springs and the well gases. The variability of 3He/4He in the well gases is controlled by the gas residence time in the reservoir and associated radiogenic 4He accumulation. 3He/4He in CO2 springs decrease 29 away from the main mantle fluid supply conduit. We identify one main pathway for CO2 supply to the surface in the CVH, located near a major fault zone. Solubility fractionation during phase separation is proposed to explain the range in noble gas concentrations and δ13C(CO2) values measured in the mineral spring samples. This process is also responsible for low 3He concentrations and associated high CO2/3He, which are commonly interpreted as evidence for mixing with crustal CO2. The elevated CO2/3He can be explained solely by solubility fractionation without the need to invoke other CO2 sources. The noble gases in the springs and well gases can be traced back to a single end-member which has suffered varying degrees of radiogenic helium accumulation and late stage degassing. This work shows that combined stable and noble gas isotopes in natural gases provide a robust tool for identifying the migration of injected CO2 to the shallow subsurface

Newly rare or newly common: evolutionary feedbacks through changes in population density and relative species abundance, and their management implications

Environmental management typically seeks to increase or maintain the population sizes of desirable species and to decrease population sizes of undesirable pests, pathogens, or invaders. With changes in population size come long-recognized changes in ecological processes that act in a density-dependent fashion. While the ecological effects of density dependence have been well studied, the evolutionary effects of changes in population size, via changes in ecological interactions with community members, are underappreciated. Here, we provide examples of changing selective pressures on, or evolution in, species as a result of changes in either density of conspecifics or changes in the frequency of heterospecific versus conspecific interactions. We also discuss the management implications of such evolutionary responses in species that have experienced rapid increases or decreases in density caused by human actions