The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient ...multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization‐deprotection reaction sequence, used in the synthesis of a precursor for 1‐methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in‐depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.
An autonomous continuous flow platform for the rapid development of multistep synthetic pathways is reported. New multipoint sampling and Bayesian optimization techniques were combined, enabling simultaneous identification of optimum reaction conditions within a pharmaceutical process. The short optimization times achieved are promising for development of telescoped reactions in the future.
With social policies increasingly directed toward enhancing equity through health programs, it is important that methods for estimating the health and economic benefits of these programs by ...subpopulation be developed, to assess both equity concerns and the programs' total impact. We estimated the differential health impact (measured as the number of deaths averted) and household economic impact (measured as the number of cases of medical impoverishment averted) of ten antigens and their corresponding vaccines across income quintiles for forty-one low- and middle-income countries. Our analysis indicated that benefits across these vaccines would accrue predominantly in the lowest income quintiles. Policy makers should be informed about the large health and economic distributional impact that vaccines could have, and they should view vaccination policies as potentially important channels for improving health equity. Our results provide insight into the distribution of vaccine-preventable diseases and the health benefits associated with their prevention.
The ELUM Software Package spatially predicts the net soil greenhouse gas balance of land-use change to grow energy crops in the UK up to 2050. It is able to support a range of analyses of bioenergy, ...and was developed in consultation with anticipated users. Results can be obtained according to specific interests, viewed in the graphical interface and exported for a variety of purposes. The functionality of the software is demonstrated through different case studies, which show an array of applications.
•ELUM models soil greenhouse gas balance of bioenergy land-use change in UK to 2050.•It is based on the ECOSSE model, but quick and easy to use, with added features.•It is able to support life-cycle assessments and policy making for bioenergy.•Consultation with anticipated users guided usability and functionality.•Greenhouse gas balance is highly dependent on initial land use and new energy crop.
Hosts are often infected by a variety of different parasites, leading to competition for hosts and coevolution between parasite species. There is increasing evidence that some vertically transmitted ...parasitic symbionts may protect their hosts from further infection and that this protection may be an important reason for their persistence in nature. Here, we examine theoretically when protection is likely to evolve and its selective effects on other parasites. Our key result is that protection is most likely to evolve in response to horizontally transmitted parasites that cause a significant reduction in host fecundity. The preponderance of sterilizing horizontally transmitted parasites found in arthropods may therefore explain the evolution of protection seen by their symbionts. We also find that protection is more likely to evolve in response to highly transmissible parasites that cause intermediate, rather than high, virulence (increased death rate when infected). Furthermore, intermediate levels of protection select for faster, more virulent horizontally transmitted parasites, suggesting that protective symbionts may lead to the evolution of more virulent parasites in nature. When we allow for coevolution between the symbiont and the parasite, more protection is likely to evolve in the vertically transmitted symbionts of longer lived hosts. Therefore, if protection is found to be common in nature, it has the potential to be a major selective force on host–parasite interactions.
ABSTRACT
Skeletal muscle adapts to endurance exercise with an increase in mitochondria. Muscle contractions generate numerous potential signals. To determine which of these stimulates mitochondrial ...biogenesis, we are using L6 myotubes. Using this model we have found that raising cytosolic Ca2+ induces an increase in mitochondria. In this study, we tested the hypothesis that raising cytosolic Ca2+ in L6 myotubes induces increased expression of PGC‐1, NRF‐1, NRF‐2, and mtTFA, factors that have been implicated in mitochondrial biogenesis and in the adaptation of muscle to exercise. Raising cytosolic Ca2+ by exposing L6 myotubes to caffeine for 5 h induced significant increases in PGC‐1 and mtTFA protein expression and in NRF‐1 and NRF‐2 binding to DNA. These adaptations were prevented by dantrolene, which blocks Ca2+ release from the SR. Exposure of L6 myotubes to caffeine for 5 h per day for 5 days induced significant increases in mitochondrial marker enzyme proteins. Our results show that the adaptive response of L6 myotubes to an increase in cytosolic Ca2+ mimics the stimulation of mitochondrial biogenesis by exercise. They support the hypothesis that an increase in cytosolic Ca2+ is one of the signals that mediate increased mitochondrial biogenesis in muscle.
•We used a Hierarchical Bayesian method to calibrate the nitrogen process model.•Parameters of NO module could be considered constant for model extrapolation.•Parameters of denitrification are highly ...variable compared with nitrification.•Parameters in denitrification are highly dependent on soil texture.•Spatial variability of parameters for soil taxonomy could deal with model extrapolation.
With the position of nitrous oxide (N2O) being the greenhouse gas with the highest global warming potential and its long atmospheric lifetime, the anthropogenic production of N2O is of major concern. The process-based model, ECOSSE, was partly developed to quantify emissions of greenhouse gases with an input data requirement that is readily available at regional scale. Hierarchical Bayesian (HB) methods are potentially used to reduce the uncertainty and to explain the spatial variability of estimated parameters. Here, we used a Hierarchical Bayesian method to calibrate the parameters of the N2O and nitrogen monoxide (NO) sub-model of ECOSSE and to quantify the uncertainty of model simulations and to investigate the model extrapolation using soil information. The sub model simulated N2O emission from nitrification and denitrification, while the simulated NO from nitrification. The HB calibration reduced the uncertainty in the N2O and NO simulations. The model's root mean square error (RMSE) was decreased by 18% and 29% for N2O and NO across field sites compared to an uncalibrated model. Parameters for nitrification could be considered universal, while parameters for denitrification challenged the assumption that these parameters may be considered universal constant values across sites. Parameters of the NO module could be considered constant for model extrapolation to regional scale. The calibrated parameters derived from soil-specific calibration could be served as default values for the N2O module extrapolation for similar soil types. Otherwise, the mean value of posterior distribution of calibration parameters in multi-dataset could be served as the parameter for model up scaling at regional scale.
Decreasing trends in measles mortality have been reported in recent years. However, such estimates of measles mortality have depended heavily on assumed regional measles case fatality risks (CFRs) ...and made little use of mortality data from low- and middle-income countries in general and India, the country with the highest measles burden globally, in particular.
We constructed a dynamic model of measles transmission in India with parameters that were empirically inferred using spectral analysis from a time series of measles mortality extracted from the Million Death Study, an ongoing longitudinal study recording deaths across 2.4 million Indian households and attributing causes of death using verbal autopsy. The model was then used to estimate the measles CFR, the number of measles deaths, and the impact of vaccination in 2000-2015 among under-five children in India and in the states of Bihar and Uttar Pradesh (UP), two states with large populations and the highest numbers of measles deaths in India.
We obtained the following estimated CFRs among under-five children for the year 2005: 0.63% (95% confidence interval (CI): 0.40-1.00%) for India as a whole, 0.62% (0.38-1.00%) for Bihar, and 1.19% (0.80-1.75%) for UP. During 2000-2015, we estimated that 607,000 (95% CI: 383,000-958,000) under-five deaths attributed to measles occurred in India as a whole. If no routine vaccination or supplemental immunization activities had occurred from 2000 to 2015, an additional 1.6 (1.0-2.6) million deaths for under-five children would have occurred across India.
We developed a data- and model-driven estimation of the historical measles dynamics, CFR, and vaccination impact in India, extracting the periodicity of epidemics using spectral and coherence analysis, which allowed us to infer key parameters driving measles transmission dynamics and mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Soil C sequestration in croplands is deemed to be one of the most promising greenhouse gas mitigation options for agriculture. We have used crop-level yields, modeled heterotrophic respiration (Rh) ...and land use data to estimate spatio-temporal changes in regional scale net primary productivity (NPP), plant C inputs, and net biome productivity (NBP) in northern Japan's arable croplands and grasslands for the period of 1959–2011. We compared the changes in C stocks derived from estimated NBP and using repeated inventory datasets for each individual land use type from 2005 to 2011. For the entire study region of 2193ha, overall annual plant C inputs to the soil constituted 37% of total region NPP. Plant C inputs in upland areas (excluding bush/fallow) could be predicted by climate variables. Overall NBP for all land use types increased from −1.26MgCha−1yr−1 in 1959–0.26MgCha−1yr−1 in 2011. However, upland and paddy fields showed a decreased in NBP over the period of 1959–2011, under the current C input scenario. From 1988, an increase in agricultural abandonment (bush/fallow) and grassland cover caused a slow increase in the regional C pools. The comparison of carbon budgets using the NBP estimation method and the soil inventory method indicated no significant difference between the two methods. Our results showed C loss in upland crops, paddy fields and sites that underwent land use change from paddy field to upland sites. We also show C gain in grassland from 2005 to 2011. An underestimation of NBP or an overestimation of repeated C inventories cannot be excluded, but either method may be suitable for tracking absolute changes in soil C, considering the uncertainty associated with these methods.
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•We compared C stocks change by two methods: (i) net biome productivity (NBP) and (ii) soil inventory.•Variation in net primary productivity (NPP), plant C input, NBP can be predicted by climate conditions.•NBP decreased in upland and paddy fields under the recent C input scenario.•In the case of land use change, the regional C pools slowly start to build up.•There is no significant difference in two methods (NBP & soil inventory).
Understanding the processes that shape the evolution of parasites is a key challenge for evolutionary biology. It is well understood that different parasites may often infect the same host and that ...this may have important implications to the evolutionary behavior.Here we examine the evolutionary implications of the conflict that arises when two parasite species, one vertically transmitted and the other horizontally transmitted, infect the same host. We show that the presence of a vertically transmitted parasite (VTP) often leads to the evolution of higher virulence in horizontally transmitted parasites (HTPs), particularly if the VTPs are feminizing.The high virulence in some HTPs may therefore result from coinfection with cryptic VTPs. The impact of an HTP on a VTP evolution depends crucially on the nature of the life-history trade-offs. Fast virulent HTPs select for intermediate feminization and virulence in VTPs. Coevolutionary models show similar insights, but emphasize the importance of host life span to the outcome, with higher virulence in both types of parasite in short-lived hosts. Overall, our models emphasize the interplay of host and parasite characteristics in the evolutionary outcome and point the way for further empirical study.
Category:
Hindfoot; Midfoot/Forefoot
Introduction/ Purpose:
Peritalar subluxation (PTS) is a crucial feature of Progressive Collapsing Foot Deformity (PCFD). Surrounding structures assume distinct ...behaviors, contributing to different disease deformities (classes). One of its most traditional aspects is the midfoot abduction (class B), usually noted by a lateral deviation of distal structures at the talonavicular joint. This finding commonly leads surgeons to perform a lateral column lengthening osteotomy for abduction correction, a complex surgery with potential complications. The first ray's ability to reestablish the tripod and restore the hindfoot by derotating structures under the talus was previously theorized. This study aimed to test the capability of the Lapidus and the Cotton procedures in conjunction with a calcaneus displacement osteotomy (MDCO) to improve midfoot abduction in the setting of a collapsed foot.
Methods:
In this IRB-approved, prospective cohort study, we analyzed patients undergoing medial column instability surgery and evaluated preoperatively with a weight-bearing CT (WBCT). We included individuals receiving a Lapidus bone block procedure or a Cotton for PCFD or Hallux Valgus (HV). Patients having a lateral column lengthening procedure of any type were excluded.
Talonavicular coverage angle (TNCA) was measured as a marker of midfoot abduction. Medial arch collapse and forefoot varus were evaluated by the sagittal talus-first metatarsal angle (TFMA), and the forefoot arch angle (FFA) was measured. Associated procedures and the correction amount (displacement or wedge size) were recorded. Normality was estimated by the Shapiro- Wilk test and comparison among timelines by the one-way ANOVA. A multivariate regression analysis was executed to evaluate which of the measurements influenced abduction improvement. Statistical significance was considered for p-values of less than 0.05.
Results:
A total of 20 patients (age: 43.85 19-72, BMI 30.98 SD: 5.95) were included, 11 PCFD (55%) and 9 HV (45%) with a mean follow-up of 7.5 months (3-12). Bone block Lapidus was performed in most subjects (90%), and the median wedge used was 9mm (5-12mm). MDCO occurred in 55% of patients. All measured variables had improvement with surgery (TNCA: 23.74 to 10.66, p< 0.0001; FFA: 6.27 to 12.67, p< 0.0001; TFMA: 11.73 to 4.22, p=0.0003). A correlation was found between TNCA improvement and FFA improvement (rs=0.46, p=0.0407), but not among TNCA improvement and TFMA improvement (rs=0.43, p=0.06). The size of the wedge did not strongly influence the TNCA correction (R2=0.016, p=0.0036), an improvement moderately explained by the MDCO amount (R2=0.186, p< 0.0001).
Conclusion:
This study demonstrated correction of midfoot abduction, translated by the TNCA, in the absence of lateral column lengthening procedures. When evaluating patients submitted to first ray procedures (bone block Lapidus and Cotton) in conjunction with MDCO, an enhancement on the talar head coverage was noted. Variables associated with arch height and forefoot varus (FFA and TFMA) were correlated with the TNCA improvement. Nevertheless, only the MDCO displacement amount and not the size of the used allograft wedge could explain changes in TNCA. The provided data might support surgeons when planning treatment in the PCFD scenario.
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