The choice of hydrological model structure, that is, a model's selection of states and fluxes and the equations used to describe them, strongly controls model performance and realism. This work ...investigates differences in performance of 36 lumped conceptual model structures calibrated to and evaluated on daily streamflow data in 559 catchments across the United States. Model performance is compared against a benchmark that accounts for the seasonality of flows in each catchment. We find that our model ensemble struggles to beat the benchmark in snow‐dominated catchments. In most other catchments model structure equifinality (i.e., cases where different models achieve similar high efficiency scores) can be very high. We find no relation between the number of model parameters and performance during either calibration or evaluation periods nor evidence of increased risk of overfitting for models with more parameters. Instead, the choice of model parametrization (i.e., which equations are used and how parameters are used within them) dictates the model's strengths and weaknesses. Results suggest that certain model structures are inherently better suited for certain objective functions and thus for certain study purposes. We find no clear relationships between the catchments where any model performs well and descriptors of those catchments' geology, topography, soil, and vegetation characteristics. Instead, model suitability seems to relate strongest to the streamflow regime each catchment generates, and we have formulated several tentative hypotheses that relate commonalities in model structure to similarities in model performance. Modeling results are made publicly available for further investigation.
Key Points
Conceptual model structure uncertainty is high across different catchments and objective functions
There is no evidence of systematic overfitting for models with up to 15 calibrated parameters
Model performance relates more to streamflow signatures than to climate or catchment descriptors
During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become ...a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant ...clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with
and
mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of
mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
Highlights • Breathomics is an upcoming bioanalytical area transforming point-of-care diagnostics. • Volatile organic compounds (VOCs) are an important source of potential diagnostic information. • ...Current technologies bridge the gap from large analytical systems to portable sensor platforms.
Human epithelial tissues accumulate cancer-driver mutations with age
, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness ...of proliferating cells
. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours
. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.
•Semiconductor fabs need efficient & effective operations to remain competitive.•Deterministic scheduling strategies employed to improve photolithography operations.•An IP model and a heuristic ...developed to schedule photolithography machines.•The IP model primed with the heuristic improved the performance of the IP.•IP model primed with a heuristic adds value to practitioners.
This paper considers a dual resource constrained scheduling problem prevalent in high-capital cost manufacturing industry such as the photolithography area in the semiconductor industry. Specifically, the problem consists of assigning jobs to parallel machines that use common and constrained auxiliary resources such as lithography lens. Very often these auxiliary resources require heavy capital investment and setup times further complicates an already complex dual resource constrained scheduling problem. This paper advocates for the use of deterministic scheduling theory for the design and development of more efficient scheduling strategies. An Integer Programming (IP) model, a heuristic and a hybrid model were developed to schedule identical parallel machines with shared, constrained, auxiliary resources, with sequence-dependent setups, and job release dates with the goal of minimizing the sum of completion times.
An IP model primed with a heuristic can add value to practitioners looking to solve real world resource constrained parallel machine scheduling problems with sequence-dependent setups. It is extremely important to control problem instance size and time horizon in order to obtain near-optimal or efficient solutions within acceptable run times. The proposed heuristic provides an initial feasible solution for the IP model which reduces the space search by decreasing the time horizon and eliminates the time needed to find an initial feasible solution. A tighter formulation is also proposed by reducing the time horizon formulation.
Inferential models have long been used to determine pollutant dry deposition to ecosystems from measurements of air concentrations and as part of national and regional atmospheric chemistry and ...transport models, and yet models still suffer very large uncertainties. An inferential network of 55 sites throughout Europe for atmospheric reactive nitrogen (Nr) was established in 2007, providing ambient concentrations of gaseous NH3, NO2, HNO3 and HONO and aerosol NH4+ and NO3− as part of the NitroEurope Integrated Project. Network results providing modelled inorganic Nr dry deposition to the 55 monitoring sites are presented, using four existing dry deposition routines, revealing inter-model differences and providing ensemble average deposition estimates. Dry deposition is generally largest over forests in regions with large ambient NH3 concentrations, exceeding 30–40 kg N ha−1 yr−1 over parts of the Netherlands and Belgium, while some remote forests in Scandinavia receive less than 2 kg N ha−1 yr−1. Turbulent Nr deposition to short vegetation ecosystems is generally smaller than to forests due to reduced turbulent exchange, but also because NH3 inputs to fertilised, agricultural systems are limited by the presence of a substantial NH3 source in the vegetation, leading to periods of emission as well as deposition. Differences between models reach a factor 2–3 and are often greater than differences between monitoring sites. For soluble Nr gases such as NH3 and HNO3, the non-stomatal pathways are responsible for most of the annual uptake over many surfaces, especially the non-agricultural land uses, but parameterisations of the sink strength vary considerably among models. For aerosol NH4+ and NO3− discrepancies between theoretical models and field flux measurements lead to much uncertainty in dry deposition rates for fine particles (0.1–0.5 μm). The validation of inferential models at the ecosystem scale is best achieved by comparison with direct long-term micrometeorological Nr flux measurements, but too few such datasets are available, especially for HNO3 and aerosol NH4+ and NO3−.
The use of electronic cigarettes (e-cigs) is increasing and there is widespread perception that e-cigs are safe. E-cigs contain harmful chemicals; more research is needed to evaluate the safety of ...e-cig use. Our aim was to investigate the effects of e-cigs on the inflammatory response of human neutrophils.
Neutrophils were exposed to e-cig vapour extract (ECVE) and the expression of CD11b and CD66b was measured by flow cytometry and MMP-9 and CXCL8 by ELISA. We also measured the activity of neutrophil elastase (NE) and MMP-9, along with the activation of inflammatory signalling pathways. Finally we analysed the biochemical composition of ECVE by ultra-high performance liquid chromatography mass spectrometry.
ECVE caused an increase in the expression of CD11b and CD66b, and increased the release of MMP-9 and CXCL8. Furthermore, there was an increase in NE and MMP-9 activity and an increase in p38 MAPK activation. We also identified several harmful chemicals in ECVE, including known carcinogens.
ECVE causes a pro-inflammatory response from human neutrophils. This raises concerns over the safety of e-cig use.
The global nitrogen (N) cycle at the beginning of the 21st century has been shown to be strongly influenced by the inputs of reactive nitrogen (Nr) from human activities, including combustion-related ...NOx, industrial and agricultural N fixation, estimated to be 220 Tg N yr-1 in 2010, which is approximately equal to the sum of biological N fixation in unmanaged terrestrial and marine ecosystems. According to current projections, changes in climate and land use during the 21st century will increase both biological and anthropogenic fixation, bringing the total to approximately 600 Tg N yr-1 by around 2100. The fraction contributed directly by human activities is unlikely to increase substantially if increases in nitrogen use efficiency in agriculture are achieved and control measures on combustion-related emissions implemented. Some N-cycling processes emerge as particularly sensitive to climate change. One of the largest responses to climate in the processing of Nr is the emission to the atmosphere of NH3, which is estimated to increase from 65 Tg N yr-1 in 2008 to 93 Tg N yr-1 in 2100 assuming a change in global surface temperature of 5 degree C in the absence of increased anthropogenic activity. With changes in emissions in response to increased demand for animal products the combined effect would be to increase NH3 emissions to 135 Tg N yr-1. Another major change is the effect of climate changes on aerosol composition and specifically the increased sublimation of NH4NO3 close to the ground to form HNO3 and NH3 in a warmer climate, which deposit more rapidly to terrestrial surfaces than aerosols. Inorganic aerosols over the polluted regions especially in Europe and North America were dominated by (NH4)2SO4 in the 1970s to 1980s, and large reductions in emissions of SO2 have removed most of the SO42- from the atmosphere in these regions. Inorganic aerosols from anthropogenic emissions are now dominated by NH4NO3, a volatile aerosol which contributes substantially to PM10 and human health effects globally as well as eutrophication and climate effects. The volatility of NH4NO3 and rapid dry deposition of the vapour phase dissociation products, HNO3 and NH3, is estimated to be reducing the transport distances, deposition footprints and inter-country exchange of Nr in these regions. There have been important policy initiatives on components of the global N cycle. These have been regional or country-based and have delivered substantial reductions of inputs of Nr to sensitive soils, waters and the atmosphere. To date there have been no attempts to develop a global strategy to regulate human inputs to the nitrogen cycle. However, considering the magnitude of global Nr use, potential future increases, and the very large leakage of Nr in many forms to soils, waters and the atmosphere, international action is required. Current legislation will not deliver the scale of reductions globally for recovery from the effects of Nr deposition on sensitive ecosystems, or a decline in N2O emissions to the global atmosphere. Such changes would require substantial improvements in nitrogen use efficiency across the global economy combined with optimization of transport and food consumption patterns. This would allow reductions in Nr use, inputs to the atmosphere and deposition to sensitive ecosystems. Such changes would offer substantial economic and environmental co-benefits which could help motivate the necessary actions.
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