Uncertainty quantification in atomistic simulations of silicon using interatomic potentials.

Atomistic simulations often rely on interatomic potentials to access greater time and length scales than those accessible to first-principles methods, such as density functional theory. However, since a parameterized potential typically cannot reproduce the true potential energy surface of a given system, we should expect a decrease in accuracy and increase in error in quantities of interest calculated from these simulations. Quantifying the uncertainty on the outputs of atomistic simulations is thus an important, necessary step so that there is confidence in the results and available metrics to explore improvements in said simulations. Here, we address this research question by forming ensembles of atomic cluster expansion potentials, and using conformal prediction with ab initio training data to provide meaningful, calibrated error bars on several quantities of interest for silicon: the bulk modulus, elastic constants, relaxed vacancy formation energy, and the vacancy migration barrier. We evaluate the effects on uncertainty bounds using a range of different potentials and training sets.

Genetic Covariation Between the Vertically Transmitted Endophyte Epichloë canadensis and Its Host Canada Wildrye.

Symbiotic mutualisms are thought to be stabilized by correlations between the interacting genotypes which may be strengthened via vertical transmission and/or reduced genetic variability within each species. Vertical transmission, however, may weaken interactions over time as the endosymbionts would acquire mutations that could not be purged. Additionally, temporal variation in a conditional mutualism could create genetic variation and increased variation in the interaction outcome. In this study, we assessed genetic variation in both members of a symbiosis, the endosymbiotic fungal endophyte Epichloë canadensis and its grass host Canada wildrye (Elymus canadensis). Both species exhibited comparable levels of diversity, mostly within populations rather than between. There were significant differences between populations, although not in the same pattern for the two species, and the differences were not correlated with geographic distance for either species. Interindividual genetic distance matrices for the two species were significantly correlated, although all combinations of discriminant analysis of principle components (DAPC) defined multilocus genotype groups were found suggesting that strict genotype matching is not necessary. Variation in interaction outcome is common in grass/endophyte interactions, and our results suggest that the accumulation of mutations overtime combined with temporal variation in selection pressures increasing genetic variation in the symbiosis may be the cause.

Modeled Vegetation Community Trajectories: Effects from Climate Change, Atmospheric Nitrogen Deposition, and Soil Acidification Recovery.

Forest understory plant communities in the United States harbor most of the vegetation diversity of forests and are often sensitive to changes in climate and atmospheric deposition of nitrogen (N). As temperature increases from human-caused climate change and soils recover from long term atmospheric deposition of N and sulfur (S), it is unclear how these important ecosystem components will respond. We used the newly developed US-PROPS model - based on species response functions for over 1,500 species - to evaluate the potential impacts of atmospheric N deposition and climate change on species occurrence probability for a case study in the forested ecosystems of the Great Smoky Mountains National Park (GRSM), an iconic park in the southeastern United States. We evaluated six future scenarios from various combinations of two potential recoveries of soil pH (no change, +0.5 pH units) and three climate futures (no change, +1.5, +3.0 deg C). Species critical loads (CLs) of N deposition and projected responses for each scenario were determined. Critical loads were estimated to be low (< 2 kg N/ha/yr) to protect all species under current and expected future conditions across broad regions of GRSM and these CLs were exceeded at large spatial extents among scenarios. Northern hardwood, yellow pine, and chestnut oak forests were among the most N-sensitive vegetation map classes found within GRSM. Potential future air temperature conditions generally led to decreases in the maximum occurrence probability for species. Therefore, CLs were considered "unattainable" in these situations because the specified level of protection used for CL determination (i.e., maximum occurrence probability under ambient conditions) was not attainable. Although some species showed decreases in maximum occurrence probability with simulated increases in soil pH, most species were favored by increased pH. The importance of our study is rooted in the methodology described here for establishing regional CLs and for evaluating future conditions, which is transferable to other national parks in the U.S. and in Europe where the original PROPS model was developed.

Regional target loads of atmospheric nitrogen and sulfur deposition for the protection of stream and watershed soil resources of the Adirondack Mountains, USA.

Acidic deposition contributes to a range of environmental impacts across forested landscapes, including acidification of soil and drainage water, toxic aluminum mobilization, depletion of available soil nutrient cations, and impacts to forest and aquatic species health and biodiversity. In response to decreasing levels of acidic deposition, soils and drainage waters in some regions of North America have become gradually less acidic. Thresholds of atmospheric deposition at which adverse ecological effects are manifested are called critical loads (CLs) and/or target loads (TLs). Target loads are developed based on approaches that account for spatial and temporal aspects of acidification and recovery. Exceedance represents the extent to which current or projected future levels of acidic deposition exceed the level expected to cause ecological harm. We report TLs of sulfur (S) and nitrogen (N) deposition and the potential for ecosystem recovery of watershed soils and streams in the Adirondack region of New York State, resources that have been less thoroughly investigated than lakes. Regional TLs were calculated by statistical extrapolation of hindcast and forecast simulations of 25 watersheds using the process-based model PnET-BGC coupled with empirical observations of stream hydrology and established sensitivity of sugar maple (Acer saccharum) to soil base saturation and brook trout (Salvelinus fontinalis) to stream acid neutralizing capacity (ANC). Historical impacts and the expected recovery timeline of regional soil and stream chemistry and fish community condition within the Adirondack Park were evaluated. Analysis suggests that many low-order Adirondack streams and associated watershed soils have low TLs (<40 meq/m2/yr of N + S deposition) to achieve specified benchmarks for recovery of soil base saturation or stream ANC. Acid-sensitive headwater and low-order streams and watershed soils in the region are expected to experience continued adverse effects from N and S deposition well into the future even under aggressive emissions reductions. Watershed soils and streams in the western Adirondack Park are particularly vulnerable to acidic deposition and currently in exceedance of TLs. The methods used for linking statistical and process-based models to consider chemical and biological response under varying flow conditions at the regional scale in this study can be applied to other areas of concern.

Convergence rates of Gaussian ODE filters.

A recently introduced class of probabilistic (uncertainty-aware) solvers for ordinary differential equations (ODEs) applies Gaussian (Kalman) filtering to initial value problems. These methods model the true solution x and its first q derivatives a priori as a Gauss-Markov process X , which is then iteratively conditioned on information about x ˙ . This article establishes worst-case local convergence rates of order q + 1 for a wide range of versions of this Gaussian ODE filter, as well as global convergence rates of order q in the case of q = 1 and an integrated Brownian motion prior, and analyses how inaccurate information on x ˙ coming from approximate evaluations of f affects these rates. Moreover, we show that, in the globally convergent case, the posterior credible intervals are well calibrated in the sense that they globally contract at the same rate as the truncation error. We illustrate these theoretical results by numerical experiments which might indicate their generalizability to q ∈ { 2 , 3 , … } .

Threshold effects of air pollution and climate change on understory plant communities at forested sites in the eastern United States.

Forest understory plant communities in the eastern United States are often diverse and are potentially sensitive to changes in climate and atmospheric inputs of nitrogen caused by air pollution. In recent years, empirical and processed-based mathematical models have been developed to investigate such changes in plant communities. In the study reported here, a robust set of understory vegetation response functions (expressed as version 2 of the Probability of Occurrence of Plant Species model for the United States [US-PROPS v2]) was developed based on observations of forest understory and grassland plant species presence/absence and associated abiotic characteristics derived from spatial datasets. Improvements to the US-PROPS model, relative to version 1, were mostly focused on inclusion of additional input data, development of custom species-level input datasets, and implementation of methods to address uncertainty. We investigated the application of US-PROPS v2 to evaluate the potential impacts of atmospheric nitrogen (N) and sulfur (S) deposition, and climate change on forest ecosystems at three forested sites located in New Hampshire, Virginia, and Tennessee in the eastern United States. Species-level N and S critical loads (CLs) were determined under ambient deposition at all three modeled sites. The lowest species-level CLs of N deposition at each site were between 2 and 11 kg N/ha/yr. Similarly, the lowest CLs of S deposition, based on the predicted soil pH response, were less than 2 kg S/ha/yr among the three sites. Critical load exceedance was found at all three model sites. The New Hampshire site included the largest percentage of species in exceedance. Simulated warming air temperature typically resulted in lower maximum occurrence probability, which contributed to lower CLs of N and S deposition. The US-PROPS v2 model, together with the PROPS-CLF model to derive CL functions, can be used to develop site-specific CLs for understory plants within broad regions of the United States. This study demonstrates that species-level CLs of N and S deposition are spatially variable according to the climate, light availability, and soil characteristics at a given location. Although the species niche models generally performed well in predicting occurrence probability, there remains uncertainty with respect to the accuracy of reported CLs. As such, the specific CLs reported here should be considered as preliminary estimates.

Vismodegib for periocular basal cell carcinoma: an international multicentre case series.

INTRODUCTION: Vismodegib (Erivedge, Genentech) is a first-in-class inhibitor of the hedgehog (Hh) pathway, which is licensed for use in locally advanced basal cell carcinoma (BCC) and metastatic BCC. The National Institute for Health and Care Excellence withdrew recommendation for use of vismodegib secondary to a lack of data comparing vismodegib to standard supportive care. The purpose of this multicentre, international case series is to report outcomes of patients with locally advanced periocular BCC who have been treated with vismodegib. METHODS: The medical records of all patients treated with vismodegib were retrospectively reviewed across seven institutions in the United Kingdom, Australia, and New Zealand. RESULTS: Thirteen patients were identified. Seven (54%) patients were male. All BCCs were ill-defined, with seven (58%) having orbital involvement at presentation. Median treatment time was 7 months (range 2-36 months). Eleven out of 13 patients developed side effects, the most common being fatigue in six patients (46%). Median follow-up was 24 months (range 12-48 months). Complete response was found in 5/13 patients (38%) and a partial response in 8/13 patients (62%). Six patients had further surgery after vismodegib, with three classed as globe-sparing operations. Three patients developed recurrence (23%). Three patients (23%) ultimately underwent exenteration. DISCUSSION: This study demonstrates vismodegib to be a well-tolerated treatment which may, in some cases, facilitate globe-sparing surgery and hence avoid disfiguring operations such as exenteration. Uncertainty does remain regarding the long-term outcomes of patients treated with vismodegib.

Vegetation dynamics associated with changes in atmospheric nitrogen deposition and climate in hardwood forests of Shenandoah and Great Smoky Mountains National Parks, USA.

Ecological effects of atmospheric nitrogen (N) and sulfur (S) deposition on two hardwood forest sites in the eastern United States were simulated in the context of a changing climate using the dynamic coupled biogeochemical/ecological model chain ForSAFE-Veg. The sites are a mixed oak forest in Shenandoah National Park, Virginia (Piney River) and a mixed oak-sugar maple forest in Great Smoky Mountains National Park, Tennessee (Cosby Creek). The sites have received relatively high levels of both S and N deposition and the climate has warmed over the past half century or longer. The model was used to evaluate the composition of the understory plant communities, the alignment between plant species niche preferences and ambient conditions, and estimate changes in relative species abundances as reflected by plant cover under various scenarios of future atmospheric N and S deposition and climate change. The main driver of ecological effects was soil solution N concentration. Results of this research suggested that future climate change might compromise the capacity for the forests to sustain habitat suitability. However, vegetation results should be considered preliminary until further model validation can be performed. With expected future climate change, preliminary estimates suggest that sustained future N deposition above 7.4 and 5.0 kg N/ha/yr is expected to decrease contemporary habitat suitability for indicator plant species located at Piney River and Cosby Creek, respectively.

Feasibility of coupled empirical and dynamic modeling to assess climate change and air pollution impacts on temperate forest vegetation of the eastern United States.

Changes in climate and atmospheric nitrogen (N) deposition caused pronounced changes in soil conditions and habitat suitability for many plant species over the latter half of the previous century. Such changes are expected to continue in the future with anticipated further changing air temperature and precipitation that will likely influence the effects of N deposition. To investigate the potential long-term impacts of atmospheric N deposition on hardwood forest ecosystems in the eastern United States in the context of climate change, application of the coupled biogeochemical and vegetation community model VSD+PROPS was explored at three sites in New Hampshire, Virginia, and Tennessee. This represents the first application of VSD+PROPS to forest ecosystems in the United States. Climate change and elevated (above mid-19th century) N deposition were simulated to be important factors for determining habitat suitability. Although simulation results suggested that the suitability of these forests to support the continued presence of their characteristic understory plant species might decline by the year 2100, low data availability for building vegetation response models with PROPS resulted in uncertain results at the extremes of simulated N deposition. Future PROPS model development in the United States should focus on inclusion of additional foundational data or alternate candidate predictor variables to reduce these uncertainties.

Population genetic structure and comparative diversity of smallmouth bass Micropterus dolomieu: congruent patterns from two genomes.

Genetic diversity and divergence patterns of smallmouth bass Micropterus dolomieu spawning groups are analysed across its northern native range with mtDNA cytochrome b gene sequences and eight unlinked nuclear DNA microsatellite loci. Results reveal high levels of genetic variability and significant differences in allelic representation among populations (mtDNA: mean ± s.e., HD = 0·50 ± 0·06, mean ± s.e., θST = 0·41 ± 0·02 and microsatellites: mean ± s.e. HO = 0·46 ± 0·03, mean ± s.e. θST = 0·25 ± 0·01). The distributions of 28 variant mtDNA haplotypes, which differ by an average of 3·94 nucleotides (range = 1-8), denote divergent representation among geographic areas. Microsatellite data support nine primary population groups, whose high self-assignment probabilities likewise display marked divergence. Genetic patterns demonstrate: (1) high genetic diversity in both genomes, (2) significant divergence among populations, probably resulting from natal site homing and low lifetime migration, (3) support for three post-glacial refugia that variously contributed to the current northern populations, which remain evident today despite waterway connectivity and (4) a weak yet significant genetic isolation by geographic distance pattern, indicating that other processes affect the differences among populations, such as territoriality and site fidelity.

Downstream Warming and Headwater Acidity May Diminish Coldwater Habitat in Southern Appalachian Mountain Streams.

Stream-dwelling species in the U.S. southern Appalachian Mountains region are particularly vulnerable to climate change and acidification. The objectives of this study were to quantify the spatial extent of contemporary suitable habitat for acid- and thermally sensitive aquatic species and to forecast future habitat loss resulting from expected temperature increases on national forest lands in the southern Appalachian Mountain region. The goal of this study was to help watershed managers identify and assess stream reaches that are potentially vulnerable to warming, acidification, or both. To our knowledge, these results represent the first regional assessment of aquatic habitat suitability with respect to the combined effects of stream water temperature and acid-base status in the United States. Statistical models were developed to predict July mean daily maximum water temperatures and air-water temperature relations to determine potential changes in future stream water temperatures. The length of stream considered suitable habitat for acid- and thermally sensitive species, based on temperature and acid neutralizing capacity thresholds of 20°C and 50 µeq/L, was variable throughout the national forests considered. Stream length displaying temperature above 20°C was generally more than five times greater than the length predicted to have acid neutralizing capacity below 50 µeq/L. It was uncommon for these two stressors to occur within the same stream segment. Results suggested that species' distributional shifts to colder, higher elevation habitats under a warming climate can be constrained by acidification of headwater streams. The approach used in this study can be applied to evaluate climate change impacts to stream water resources in other regions.

Modeled subalpine plant community response to climate change and atmospheric nitrogen deposition in Rocky Mountain National Park, USA.

To evaluate potential long-term effects of climate change and atmospheric nitrogen (N) deposition on subalpine ecosystems, the coupled biogeochemical and vegetation community competition model ForSAFE-Veg was applied to a site at the Loch Vale watershed of Rocky Mountain National Park, Colorado. Changes in climate and N deposition since 1900 resulted in pronounced changes in simulated plant species cover as compared with ambient and estimated future community composition. The estimated critical load (CL) of N deposition to protect against an average future (2010-2100) change in biodiversity of 10% was between 1.9 and 3.5 kg N ha(-1) yr(-1). Results suggest that the CL has been exceeded and vegetation at the study site has already undergone a change of more than 10% as a result of N deposition. Future increases in air temperature are forecast to cause further changes in plant community composition, exacerbating changes in response to N deposition alone.

Effects of acidic deposition and soil acidification on sugar maple trees in the Adirondack Mountains, New York.

We documented the effects of acidic atmospheric deposition and soil acidification on the canopy health, basal area increment, and regeneration of sugar maple (SM) trees across the Adirondack region of New York State, in the northeastern United States, where SM are plentiful but not well studied and where widespread depletion of soil calcium (Ca) has been documented. Sugar maple is a dominant canopy species in the Adirondack Mountain ecoregion, and it has a high demand for Ca. Trees in this region growing on soils with poor acid-base chemistry (low exchangeable Ca and % base saturation [BS]) that receive relatively high levels of atmospheric sulfur and nitrogen deposition exhibited a near absence of SM seedling regeneration and lower crown vigor compared with study plots with relatively high exchangeable Ca and BS and lower levels of acidic deposition. Basal area increment averaged over the 20th century was correlated (p < 0.1) with acid-base chemistry of the Oa, A, and upper B soil horizons. A lack of Adirondack SM regeneration, reduced canopy condition, and possibly decreased basal area growth over recent decades are associated with low concentrations of nutrient base cations in this region that has undergone soil Ca depletion from acidic deposition.

Genetic and morphometric differences demonstrate fine-scale population substructure of the yellow perch Perca flavescens: need for redefined management units.

Whole-body morphometrics and 15 nuclear DNA microsatellite loci were analysed for 158 Perca flavescens collected during the spawning season from four spawning locations in central Lake Erie, two along the northern shore and two along the southern shore, to evaluate fine-scale variation (spanning 17-94 km). Results showed significant morphological and genetic differences among P. flavescens from the four locations. The magnitudes of differences were unrelated to geographic distance, demonstrating spatially heterogeneous levels of genetic divergence. These results linked morphometric and genetic variation, showing a discontinuity of scale between currently defined management units and population structure of P. flavescens in Lake Erie, and support that P. flavescens might exist as one or more metapopulations. Findings demonstrate the value of using complementary techniques for evaluating population structure.

Regionalization of soil base cation weathering for evaluating stream water acidification in the Appalachian Mountains, USA.

Estimation of base cation supply from mineral weathering (BC(w)) is useful for watershed research and management. Existing regional approaches for estimating BC(w) require generalized assumptions and availability of stream chemistry data. We developed an approach for estimating BC(w) using regionally specific empirical relationships. The dynamic model MAGIC was used to calibrate BC(w) in 92 watersheds distributed across three ecoregions. Empirical relationships between MAGIC-simulated BC(w) and watershed characteristics were developed to provide the basis for regionalization of BC(w) throughout the entire study region. BC(w) estimates extracted from MAGIC calibrations compared reasonably well with BC(w) estimated by regression based on landscape characteristics. Approximately one-third of the study region was predicted to exhibit BC(w) rates less than 100 meq/m(2)/yr. Estimates were especially low for some locations within national park and wilderness areas. The regional BC(w) results are discussed in the context of critical loads (CLs) of acidic deposition for aquatic ecosystem protection.

Photodynamic therapy against common bacteria causing wound and skin infections.

Photodynamic therapy (PDT) uses the combination of a photosensitising (PS) agent and visible light. Historically, various injectable PS agents have been used with medical grade lasers to treat neoplasia. The objective of this in vitro study was to determine whether PDT using topical aminolevulinic acid (ALA) with a non-coherent light source would kill common wound infecting bacteria, namely, Staphylococcus intermedius, Streptococcus canis, Pseudomonas aeruginosa, and Escherichia coli. Bacterial strains were sensitised to light with ALA before exposing to the non-coherent light source. Colony counts were performed in triplicate and compared to controls. When compared with controls there was a significant decrease in bacterial survival following PDT for all organisms except E. coli. A single treatment required 2-3h of light exposure. These data suggest that PDT may be a possible treatment option for wound infections but repeated treatments or alterations in the PS or its carrier will be needed to decrease treatment times.

Do Botanophila flies provide reproductive isolation between two species of Epichloë fungi? A field test.

Epichloë spp., fungal endophytes of cool season grasses, produce collars of mycelium (stromata) on host stems that Botanophila flies visit for egg laying. Flies transfer fungal gametes among stromata and thereby serve to cross-fertilize fungi. Hence, the interaction is analogous to insect pollination in angiosperms. While most Epichloë species are not interfertile, Epichloë typhina and Epichloë clarkii can hybridize. We investigated whether Botanophila flies play a role in the reproductive isolation of the two Epichloë species at a field site in southwestern Switzerland. We estimated the density of stromata and collected fly larvae and stromata occurring on plants. While most ascospores collected from both species indicated intraspecific mating, 9.3% of fungal fruiting bodies contained spores of hybrid origin. Two species of Botanophila larvae occurred on stromata and both preferred E. typhina. Yet, both fly species laid eggs on both fungal species. While preferences by Botanophila flies should influence reproductive isolation between the fungi, other mechanisms are likely more important. Our data, which show hybrid ascospores are produced, suggest postzygotic isolating mechanisms are an important means of reproductive isolation.

Comparison among model estimates of critical loads of acidic deposition using different sources and scales of input data.

The critical load (CL) of acidic atmospheric deposition represents the load of acidity deposited from the atmosphere to the earth's surface at which harmful acidification effects on sensitive biological receptors are thought to occur. In this study, the CL for forest soils was estimated for 27 watersheds throughout the United States using a steady-state mass balance approach based on both national and site-specific data and using different approaches for estimating base cation weathering. Results suggested that the scale and source of input data can have large effects on the calculated CL and that the most important parameter in the steady-state model used to estimate CL is base cation weathering. These results suggest that the data and approach used to estimate weathering must be robust if the calculated CL is to be useful for its intended purpose.

Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism.

Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate haematopoetic cell movement are implicated in the metastatic process of malignant tumours, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. In vitro, activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo, systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited the implantation and the growth of human and mouse CRC cells within lung without affecting that in the liver. In addition, we measured increased levels of CXCR3 and ligands expression within lung nodules compared with liver tumours. Altogether, our findings indicate that activation of CXCR3 receptors by its cognate ligands facilitates the implantation and the progression of CRC cells within lung tissues and that inhibition of this axis decreases pulmonary metastasis of CRC in two murine tumour models.

Effects of methyl jasmonate and an endophytic fungus on plant resistance to insect herbivores.

Tall fescue (Lolium arundinaceum) forms a mutualistic relationship with the fungal endophyte Neotyphodium coenophialum. The endophyte provides constitutive resistance to herbivores through its production of alkaloid compounds. Moreover, herbivore attack induces elevated synthesis of loline alkaloids, that is, the fungus also provides wound-inducible resistance for its host. Jasmonic acid and its conjugates are key signaling compounds in many plant species and play a role systemically in the upregulation of defensive compounds within plants following attack by herbivores. The purpose of our study was to determine if and how the plant and fungus respond to methyl jasmonate (MJ) exposure and if these responses interact in antagonistic or synergistic ways. Plants were exposed to MJ via gaseous diffusion within a controlled environment chamber. Response to MJ was assessed with an herbivore bioassay, gas chromatography-mass spectrometry to quantify alkaloids, and real-time reverse transcriptase-polymerase chain reaction to quantify mRNA from a loline alkaloid biosynthesis gene. We found that MJ hindered endophyte-infected tall fescue's resistance against aphids by downregulating transcription of the LolC gene. The opposite pattern was observed for endophyte-free tall fescue; its exposure to MJ resulted in a significant increase in resistance to aphids, apparently through stimulating defense compounds produced by the plant. These results indicate that, when tall fescue lacks fungal infection, MJ induces the plant to produce its own defensive compounds. In contrast, while endophyte-infected plants are defended from herbivores by fungally produced lolines, this defense is compromised by MJ.