Novel observation techniques (e.g., smart tracers) for characterizing coupled hydrological and biogeochemical processes are improving understanding of stream network transport and transformation ...dynamics. In turn, these observations are thought to enable increasingly sophisticated representations within transient storage models (TSMs). However, TSM parameter estimation is prone to issues with insensitivity and equifinality, which grow as parameters are added to model formulations. Currently, it is unclear whether (or not) observations from different tracers may lead to greater process inference and reduced parameter uncertainty in the context of TSM. Herein, we aim to unravel the role of in‐stream processes alongside metabolically active (MATS) and inactive storage zones (MITS) using variable TSM formulations. Models with one (1SZ) and two storage zones (2SZ) and with and without reactivity were applied to simulate conservative and smart tracer observations obtained experimentally for two reaches with differing morphologies. As we show, smart tracers are unsurprisingly superior to conservative tracers when it comes to partitioning MITS and MATS. However, when transient storage is lumped within a 1SZ formulation, little improvement in parameter uncertainty is gained by using a smart tracer, suggesting the addition of observations should scale with model complexity. Importantly, our work identifies several inconsistencies and open questions related to reconciling time scales of tracer observation with conceptual processes (parameters) estimated within TSM. Approaching TSM with multiple models and tracer observations may be key to gaining improved insight into transient storage simulation as well as advancing feedback loops between models and observations within hydrologic science.
Plain Language Summary
Solute experiments and transport models, called commonly tracer experiments, are used to understand the relative importance of different stream processes, especially those that influence water, solutes, and nutrients as they move through a stream network. Within these tracer experiments, there are processes that exchange mass beyond the main stream channel to other parts of the river valley bottom environment. Sometimes, there are single or multiple types of tracers used and modeled to try to understand this exchange. There are also multiple models with different equations and structures to simulate these tracers. This study shows that what you can learn about these stream processes depends on experiment choices and which model you use. Hence, refining future multiple tracer experiments and models is needed to determine how we best obtain consistent measurements of key stream processes.
Key Points
TSM interpretation improved with analysis of multiple tracers but results in increased parameter uncertainty for a more complex model
Nonconservative tracers enabled interpretation of parameters that were highly uncertain when estimated by conservative tracers alone
Achieving reliable parameter estimates depends on choice of tracers and model framework and should be coupled with uncertainty assessment
The governments of high-income countries and private organizations provide billions of dollars to developing countries for health. This type of development assistance can have a critical role in ...ensuring that life-saving health interventions reach populations in need.
To identify the amount of development assistance that countries and organizations provided for health and to determine the health areas that received these funds.
Budget, revenue, and expenditure data on the primary agencies and organizations (n = 38) that provided resources to developing countries (n = 146-183, depending on the year) for health from 1990 through 2014 were collected. For each channel (the international agency or organization that directed the resources toward the implementing institution or government), the source and recipient of the development assistance were determined and redundant accounting of the same dollar, which occurs when channels transfer funds among each other, was removed. This research derived the flow of resources from source to intermediary channel to recipient. Development assistance for health (DAH) was divided into 11 mutually exclusive health focus areas, such that every dollar of development assistance was assigned only 1 health focus area.
Since 1990, $458.0 billion of development assistance has been provided to maintain or improve health in developing countries. The largest source of funding was the US government, which provided $143.1 billion between 1990 and 2014, including $12.4 billion in 2014. Of resources that originated with the US government, 70.6% were provided through US government agencies, and 41.0% were allocated for human immunodeficiency virus (HIV)/AIDS. The second largest source of development assistance for health was private philanthropic donors, including the Bill and Melinda Gates Foundation and other private foundations, which provided $69.9 billion between 1990 and 2014, including $6.2 billion in 2014. These resources were provided primarily through private foundations and nongovernmental organizations and were allocated for a diverse set of health focus areas. Since 1990, 28.0% of all DAH was allocated for maternal health and newborn and child health; 23.2% for HIV/AIDS, 4.3% for malaria, 2.8% for tuberculosis, and 1.5% for noncommunicable diseases. Between 2000 and 2010, DAH increased 11.3% annually. However, since 2010, total DAH has not increased as substantially.
Funding for health in developing countries has increased substantially since 1990, with a focus on HIV/AIDS, maternal health, and newborn and child health. Funding from the US government has played a substantial role in this expansion. Funding for noncommunicable diseases has been limited. Understanding how funding patterns have changed across time and the priorities of sources of international funding across distinct channels, recipients, and health focus areas may help identify where funding gaps persist and where cost-effective interventions could save lives.
Grape marc (the skins, seeds, stalk, and stems remaining after grapes have been pressed to make wine) is currently a by-product used as a feed supplement by the dairy and beef industries. Grape marc ...contains condensed tannins and has high concentrations of crude fat; both these substances can reduce enteric methane (CH4) production when fed to ruminants. This experiment examined the effects of dietary supplementation with either dried, pelleted grape marc or ensiled grape marc on yield and composition of milk, enteric CH4 emissions, and ruminal microbiota in dairy cows. Thirty-two Holstein dairy cows in late lactation were offered 1 of 3 diets: a control (CON) diet; a diet containing dried, pelleted grape marc (DGM); and a diet containing ensiled grape marc (EGM). The diet offered to cows in the CON group contained 14.0kg of alfalfa hay dry matter (DM)/d and 4.3kg of concentrate mix DM/d. Diets offered to cows in the DGM and EGM groups contained 9.0kg of alfalfa hay DM/d, 4.3kg of concentrate mix DM/d, and 5.0kg of dried or ensiled grape marc DM/d, respectively. These diets were offered individually to cows for 18d. Individual cow feed intake and milk yield were measured daily and milk composition measured on 4d/wk. Individual cow CH4 emissions were measured by the SF6 tracer technique on 2d at the end of the experiment. Ruminal bacterial, archaeal, fungal, and protozoan communities were quantified on the last day of the experiment. Cows offered the CON, DGM, and EGM diets, ate 95, 98, and 96%, respectively, of the DM offered. The mean milk yield of cows fed the EGM diet was 12.8kg/cow per day and was less than that of cows fed either the CON diet (14.6kg/cow per day) or the DGM diet (15.4kg/cow per day). Feeding DGM and EGM diets was associated with decreased milk fat yields, lower concentrations of saturated fatty acids, and enhanced concentrations of mono- and polyunsaturated fatty acids, in particular cis-9,trans-11 linoleic acid. The mean CH4 emissions were 470, 375, and 389g of CH4/cow per day for cows fed the CON, DGM, and EGM diets, respectively. Methane yields were 26.1, 20.2, and 21.5g of CH4/kg of DMI for cows fed the CON, DGM, and EGM diets, respectively. The ruminal bacterial and archaeal communities were altered by dietary supplementation with grape marc, but ruminal fungal and protozoan communities were not. Decreases of approximately 20% in CH4 emissions and CH4 yield indicate that feeding DGM and EGM could play a role in CH4 abatement.
Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF ...diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
PROTAC linker design remains mostly an empirical task. We employed the PRosettaC computational software in the design of sulfonyl‐fluoride‐based PROTACs targeting acyl protein thioesterase 1 (APT1). ...The software efficiently generated ternary complex models from empirically‐designed PROTACs and suggested alkyl linkers to be the preferred type of linker to target APT1. Western blotting analysis revealed efficient degradation of APT1 and activity‐based protein profiling showed remarkable selectivity of an alkyl linker‐based PROTAC amongst serine hydrolases. Collectively, our data suggests that combining PRosettaC and chemoproteomics can effectively assist in triaging PROTACs for synthesis and providing early data on their potency and selectivity.
PROTAC linker design remains mostly an empirical task. The PRosettaC software successfully generated ternary complex models for empirically designed sulfonyl‐fluoride‐based PROTACs targeting Acyl Protein Thioesterase 1 (APT1). Western blotting analysis and activity‐based protein profiling (ABPP) revealed efficient degradation of APT1 with selected alkyl linker‐based PROTACs showing remarkable selectivity for APT1 within serine hydrolases.
Objectives
Long‐term outcomes of endoscopic ultrasound‐guided choledochoduodenostomy (EUS‐CDS) performed with lumen apposing metal stents (LAMS) have been poorly evaluated in small or retrospective ...series, leading to an underestimation of LAMS dysfunction.
Methods
All consecutive EUS‐CDS performed in three academic referral centers were included in prospectively maintained databases. Technical/clinical success, adverse events (AEs), and dysfunction during follow‐up were retrospectively analyzed. Kaplan–Meier analysis was used to estimate dysfunction‐free survival (DFS), with Cox proportional hazard regression to evaluate independent predictors of dysfunction.
Results
Ninety‐three patients were included (male 56%; mean age, 70 years 95% confidence interval (CI) 68–72; pancreatic cancer 81%, metastatic disease 47%). In 67% of procedures, 6 mm LAMS were used. Technical and clinical success were achieved in 97.8% and 93.4% of patients, respectively, with AEs occurring in 9.7% (78% mild/moderate). Dysfunction occurred in 31.8% of patients after a mean of 166 days (95% CI 91–241), with an estimated 6 month and 12 month DFS of 75% and 52%, respectively; mean DFS of 394 (95% CI 307–482) days. Almost all dysfunctions (96%) were successfully managed by endoscopic reintervention. Duodenal invasion (hazard ratio 2.7 95% CI 1.1–6.8) was the only independent predictor of dysfunction.
Conclusions
Endoscopic ultrasound‐guided choledochoduodenostomy shows excellent initial efficacy and safety, although stent dysfunctions occurs frequently during long‐term follow‐up. Almost all stent dysfunctions can be managed successfully by endoscopic reinterventions. We propose a comprehensive classification of the different types of dysfunction that may be encountered and rescue procedures that may be employed under these circumstances. Duodenal invasion seems to increase the risk of developing EUS‐CDS dysfunction, potentially representing a relative contraindication for this technique.
Climate change may affect the ability of hunters to harvest wildlife and, hence, threaten food security of local people. However, few studies have investigated the relative influence of environmental ...conditions on wildlife harvest rates. We harnessed a 24-year dataset of harvest dates for a boreal ungulate in a region where climate change is having pronounced impacts on snow depth, precipitation, and temperatures to investigate the effect of weather on harvest rates. We used generalized linear models and a model selection framework to examine the influence of weather covariates (snow depth, mean daily temperature, precipitation) and socio-economic factors (gasoline and red meat prices, employment rates, and moose Alces americanus harvest) on harvest rates of bison (Bison bison) in Yukon, Canada, at two temporal scales: annual and daily. At an annual scale, snow depth was the only covariate that was important in explaining bison harvest. No socioeconomic variables improved our model beyond the null. At the daily scale, snow depth and mean daily temperature influenced bison harvest rates, with a 1 SD increase resulting in a 14 % and 9 % increase in daily harvest rates, respectively. Increased snow depth facilitates ease of travel in remote, roadless areas by snowmobile to locate bison and truncates movements of bison, resulting in increased harvest rates. Decreased snow depth due to climate change will impact hunter access to boreal ungulates and food security for northern people. More broadly, our data suggests that in some socioecological systems, environmental covariates have a greater influence on wildlife harvest rates than socioeconomic factors and need to be considered in future studies to better understand and predict harvest rates.
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•We examined socioeconomic and winter climate drivers of boreal bison hunter harvest.•Climate covariates influenced harvest rates more than socioeconomic factors.•Snow depth increased hunter access and boosted annual and daily harvest rates.•Climate change may impact wildlife harvest and food security in the boreal forest.
Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic ...tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.
Summary Background China has experienced a remarkable epidemiological and demographic transition during the past three decades. Far less is known about this transition at the subnational level. ...Timely and accurate assessment of the provincial burden of disease is needed for evidence-based priority setting at the local level in China. Methods Following the methods of the Global Burden of Disease Study 2013 (GBD 2013), we have systematically analysed all available demographic and epidemiological data sources for China at the provincial level. We developed methods to aggregate county-level surveillance data to inform provincial-level analysis, and we used local data to develop specific garbage code redistribution procedures for China. We assessed levels of and trends in all-cause mortality, causes of death, and years of life lost (YLL) in all 33 province-level administrative units in mainland China, all of which we refer to as provinces, for the years between 1990 and 2013. Findings All provinces in mainland China have made substantial strides to improve life expectancy at birth between 1990 and 2013. Increases ranged from 4·0 years in Hebei province to 14·2 years in Tibet. Improvements in female life expectancy exceeded those in male life expectancy in all provinces except Shanghai, Macao, and Hong Kong. We saw significant heterogeneity among provinces in life expectancy at birth and probability of death at ages 0–14, 15–49, and 50–74 years. Such heterogeneity is also present in cause of death structures between sexes and provinces. From 1990 to 2013, leading causes of YLLs changed substantially. In 1990, 16 of 33 provinces had lower respiratory infections or preterm birth complications as the leading causes of YLLs. 15 provinces had cerebrovascular disease and two (Hong Kong and Macao) had ischaemic heart disease. By 2013, 27 provinces had cerebrovascular disease as the leading cause, five had ischaemic heart disease, and one had lung cancer (Hong Kong). Road injuries have become a top ten cause of death in all provinces in mainland China. The most common non-communicable diseases, including ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and cancers (liver, stomach, and lung), contributed much more to YLLs in 2013 compared with 1990. Interpretation Rapid transitions are occurring across China, but the leading health problems and the challenges imposed on the health system by epidemiological and demographic change differ between groups of Chinese provinces. Localised health policies need to be implemented to tackle the diverse challenges faced by local health-care systems. Funding China National Science & Technology Pillar Program 2013 (2013BAI04B02) and Bill & Melinda Gates Foundation.
Antigenic exposures at epithelial sites in infancy and early childhood are thought to influence the maturation of humoral immunity and modulate the risk of developing immunoglobulin E (IgE)-mediated ...allergic disease. How different kinds of environmental exposures influence B cell isotype switching to IgE, IgG, or IgA, and the somatic mutation maturation of these antibody pools, is not fully understood. We sequenced antibody repertoires in longitudinal blood samples in a birth cohort from infancy through the first 3 years of life and found that, whereas IgG and IgA show linear increases in mutational maturation with age, IgM and IgD mutations are more closely tied to pathogen exposure. IgE mutation frequencies are primarily increased in children with impaired skin barrier conditions such as eczema, suggesting that IgE affinity maturation could provide a mechanistic link between epithelial barrier failure and allergy development.
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