Showing papers by "University of Rennes published in 2013"

Ground water and climate change

Abstract: As the world's largest distributed store of fresh water, ground water plays a central part in sustaining ecosystems and enabling human adaptation to climate variability and change. The strategic importance of ground water for global water and food security will probably intensify under climate change as more frequent and intense climate extremes (droughts and floods) increase variability in precipitation, soil moisture and surface water. Here we critically review recent research assessing the impacts of climate on ground water through natural and human-induced processes as well as through groundwater-driven feedbacks on the climate system. Furthermore, we examine the possible opportunities and challenges of using and sustaining groundwater resources in climate adaptation strategies, and highlight the lack of groundwater observations, which, at present, limits our understanding of the dynamic relationship between ground water and climate.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 10 × 10(-4)) In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 50 × 10(-8)), 3 of which we found after conditioning on previously identified variants Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals

Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The Frailty Operative Definition-Consensus Conference Project

Abstract: BACKGROUND: There is no consensus regarding the definition of frailty for clinical uses. METHODS: A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted. RESULTS: Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis. CONCLUSIONS: There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.

Accurate 3D comparison of complex topography with terrestrial laser scanner: Application to the Rangitikei canyon (N-Z)

Abstract: Surveying techniques such as terrestrial laser scanner have recently been used to measure surface changes via 3D point cloud (PC) comparison. Two types of approaches have been pursued: 3D tracking of homologous parts of the surface to compute a displacement field, and distance calculation between two point clouds when homologous parts cannot be defined. This study deals with the second approach, typical of natural surfaces altered by erosion, sedimentation or vegetation between surveys. Current comparison methods are based on a closest point distance or require at least one of the PC to be meshed with severe limitations when surfaces present roughness elements at all scales. To solve these issues, we introduce a new algorithm performing a direct comparison of point clouds in 3D. The method has two steps: (1) surface normal estimation and orientation in 3D at a scale consistent with the local surface roughness; (2) measurement of the mean surface change along the normal direction with explicit calculation of a local confidence interval. Comparison with existing methods demonstrates the higher accuracy of our approach, as well as an easier workflow due to the absence of surface meshing or Digital Elevation Model (DEM) generation. Application of the method in a rapidly eroding, meandering bedrock river (Rangitikei River canyon) illustrates its ability to handle 3D differences in complex situations (flat and vertical surfaces on the same scene), to reduce uncertainty related to point cloud roughness by local averaging and to generate 3D maps of uncertainty levels. We also demonstrate that for high precision survey scanners, the total error budget on change detection is dominated by the point clouds registration error and the surface roughness. Combined with mm-range local georeferencing of the point clouds, levels of detection down to 6 mm (defined at 95% confidence) can be routinely attained in situ over ranges of 50 m. We provide evidence for the self-affine behaviour of different surfaces. We show how this impacts the calculation of normal vectors and demonstrate the scaling behaviour of the level of change detection. The algorithm has been implemented in a freely available open source software package. It operates in complex 3D cases and can also be used as a simpler and more robust alternative to DEM differencing for the 2D cases.

A review of earthworm impact on soil function and ecosystem services

Abstract: Summary Biodiversity is responsible for the provision of many ecosystem services; human well-being is based on these services, and consequently on biodiversity. In soil, earthworms represent the largest component of the animal biomass and are commonly termed ‘ecosystem engineers’. This review considers the contribution of earthworms to ecosystem services through pedogenesis, development of soil structure, water regulation, nutrient cycling, primary production, climate regulation, pollution remediation and cultural services. Although there has been much research into the role of earthworms in soil ecology, this review demonstrates substantial gaps in our knowledge related in particular to difficulties in identifying the effects of species, land use and climate. The review aims to assist people involved in all aspects of land management, including conservation, agriculture, mining or other industries, to obtain a broad knowledge of earthworms and ecosystem services.

Eosinophilic granulomatosis with polyangiitis (Churg‐Strauss): Clinical characteristics and long‐term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort

Abstract: OBJECTIVE: Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes. METHODS: A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis. RESULTS: We identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean±SD of 66.8±62.5 months. At diagnosis, their mean±SD age was 50.3±15.7 years, and 91.1% had asthma (duration 9.3±10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA-negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8-74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse. CONCLUSION: The characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.

Will climate change promote future invasions

Abstract: Biological invasion is increasingly recognized as one of the greatest threats to biodiversity. Using ensemble forecasts from species distribution models to project future suitable areas of the 100 of the world's worst invasive species defined by the International Union for the Conservation of Nature, we show that both climate and land use changes will likely cause drastic species range shifts. Looking at potential spatial aggregation of invasive species, we identify three future hotspots of invasion in Europe, northeastern North America, and Oceania. We also emphasize that some regions could lose a significant number of invasive alien species, creating opportunities for ecosystem restoration. From the list of 100, scenarios of potential range distributions show a consistent shrinking for invasive amphibians and birds, while for aquatic and terrestrial invertebrates distributions are projected to substantially increase in most cases. Given the harmful impacts these invasive species currently have on ecosystems, these species will likely dramatically influence the future of biodiversity.

sp2 C–H bond activation in water and catalytic cross-coupling reactions

Abstract: The metal-catalysed successive activation and functionalisation of sp2 C–H bonds is the at heart of synthetic innovations for the development of C–C bond cross-coupling processes. Against expectation catalytic C–H bond transformations can be performed in water as an available, renewable, safe solvent but most importantly as a partner improving the catalyst activity. The objective of the review is to present the catalytic successes for C–H bond transformations in water, discovered mainly during the last six years and involving mostly palladium and ruthenium catalysts, often with the help of a carboxylate partner for the initial key C–H bond deprotonation. Water is beneficial for the direct catalytic arylation with (hetero)aryl halides of functional arene ortho C–H bonds with pyridine, pyrazole, oxazoline, imine, urea, amide… directing groups leading to functional biaryl derivatives, polyheterocycles and polydentate ligands. Metal-catalysed activation of the sp2 C–H bond in water also allows the cross-coupling reaction of two different C–H bonds in the presence of an oxidant and regioselective alkenylations of arenes, heterocycles and functional alkenes are now controlled. Annulation reactions via insertion of alkynes into both activated C–H and heteroatom–hydrogen bonds in water constitute new routes to heterocycles.

Digital game-based learning: Impact of instructions and feedback on motivation and learning effectiveness

Abstract: Although many studies have investigated the effects of digital game-based learning (DGBL) on learning and motivation, its benefits have never been systematically demonstrated. In our first experiment, we sought to identify the conditions under which DGBL is most effective, by analyzing the effects of two different types of instructions (learning instruction vs. entertainment instruction). Results showed that the learning instruction elicited deeper learning than the entertainment one, without impacting negatively on motivation. In our second experiment, we showed that if learners are given regular feedback about their performance, the entertainment instruction results in deep learning. These two experiments demonstrate that a serious game environment can promote learning and motivation, providing it includes features that prompt learners to actively process the educational content. We examined the effects of two types of instructions on digital game-based learning.Experiment 1 showed that learning is deeper with a learning instruction.Experiment 2 showed that an entertainment instruction with feedback is beneficial.These results are discussed in terms of motivation and learning processes.

Color image database TID2013: Peculiarities and preliminary results

Abstract: Visual quality of color images is an important aspect in various applications of digital image processing and multimedia. A large number of visual quality metrics (indices) has been proposed recently. In order to assess their reliability, several databases of color images with various sets of distortions have been exploited. Here we present a new database called TID2013 that contains a larger number of images. Compared to its predecessor TID2008, seven new types and one more level of distortions are included. The need for considering these new types of distortions is briefly described. Besides, preliminary results of experiments with a large number of volunteers for determining the mean opinion score (MOS) are presented. Spearman and Kendall rank order correlation factors between MOS and a set of popular metrics are calculated and presented. Their analysis shows that adequateness of the existing metrics is worth improving. Special attention is to be paid to accounting for color information and observers focus of attention to locally active areas in images.

The MLL recombinome of acute leukemias in 2013

Abstract: Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case–control study of 410 patients with 8 years post-operative follow-up

Abstract: Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Achieving few-femtosecond time-sorting at hard X-ray free-electron lasers

Abstract: Recently, few-femtosecond pulses have become available at hard X-ray free-electron lasers Coupled with the available sub-10 fs optical pulses, investigations into few-femtosecond dynamics are not far off However, achieving sufficient synchronization between optical lasers and X-ray pulses continues to be challenging We report a 'measure-and-sort' approach, which achieves sub-10 fs root-mean-squared (rms) error measurement at hard X-ray FELs, far beyond the 100-200 fs rms jitter limitations This timing diagnostic, now routinely available at the Linac Coherent Light Source (LCLS), is based on ultrafast free-carrier generation in optically transparent materials Correlation between two independent measurements enables unambiguous demonstration of ~6 fs rms error in reporting the optical/X-ray delay, with single shot error suggesting the possibility of reaching few-femtosecond resolution

GRACE satellite monitoring of large depletion in water storage in response to the 2011 drought in Texas

Abstract: [1] Texas experienced the most extreme one-year drought on record in 2011 with precipitation at 40% of long-term mean and agricultural losses of ~$7.6 billion. We assess the value of Gravity Recovery and Climate Experiment (GRACE) satellite-derived total water storage (TWS) change as an alternative remote sensing-based drought indicator, independent of traditional drought indicators based on in situ monitoring. GRACE shows depletion in TWS of 62.3 ± 17.7 km3 during the 2011 drought. Large uncertainties in simulated soil moisture storage depletion (14–83 km3) from six land surface models indicate that GRACE TWS is a more reliable drought indicator than disaggregated soil moisture or groundwater storage. Groundwater use and groundwater level data indicate that depletion is dominated by changes in soil moisture storage, consistent with high correlation between GRACE TWS and the Palmer Drought Severity Index. GRACE provides a valuable tool for monitoring statewide water storage depletion, linking meteorological and hydrological droughts.

Methods for comparing scanpaths and saliency maps: strengths and weaknesses.

Abstract: In this article, we are interested in the computational modeling of visual attention. We report methods commonly used to assess the performance of these kinds of models. We survey the strengths and weaknesses of common assessment methods based on diachronic eye-tracking data. We then illustrate the use of some methods to benchmark computational models of visual attention.

Genome structure and metabolic features in the red seaweed Chondrus crispus shed light on evolution of the Archaeplastida.

Abstract: Red seaweeds are key components of coastal ecosystems and are economically important as food and as a source of gelling agents, but their genes and genomes have received little attention. Here we report the sequencing of the 105-Mbp genome of the florideophyte Chondrus crispus (Irish moss) and the annotation of the 9,606 genes. The genome features an unusual structure characterized by gene-dense regions surrounded by repeat-rich regions dominated by transposable elements. Despite its fairly large size, this genome shows features typical of compact genomes, e.g., on average only 0.3 introns per gene, short introns, low median distance between genes, small gene families, and no indication of large-scale genome duplication. The genome also gives insights into the metabolism of marine red algae and adaptations to the marine environment, including genes related to halogen metabolism, oxylipins, and multicellularity (microRNA processing and transcription factors). Particularly interesting are features related to carbohydrate metabolism, which include a minimalistic gene set for starch biosynthesis, the presence of cellulose synthases acquired before the primary endosymbiosis showing the polyphyly of cellulose synthesis in Archaeplastida, and cellulases absent in terrestrial plants as well as the occurrence of a mannosylglycerate synthase potentially originating from a marine bacterium. To explain the observations on genome structure and gene content, we propose an evolutionary scenario involving an ancestral red alga that was driven by early ecological forces to lose genes, introns, and intergenetic DNA; this loss was followed by an expansion of genome size as a consequence of activity of transposable elements.

Seismic diagnostics for transport of angular momentum in stars. I. Rotational splittings from the pre-main sequence to the red-giant branch.

Abstract: Context. Rotational splittings are currently measured for several main sequence stars and a large number of red giants with the space mission Kepler. This will provide stringent constraints on rotation profiles. Aims: Our aim is to obtain seismic constraints on the internal transport and surface loss of the angular momentum of oscillating solar-like stars. To this end, we study the evolution of rotational splittings from the pre-main sequence to the red-giant branch for stochastically excited oscillation modes. Methods: We modified the evolutionary code CESAM2K to take rotationally induced transport in radiative zones into account. Linear rotational splittings were computed for a sequence of 1.3 Ms models. Rotation profiles were derived from our evolutionary models and eigenfunctions from linear adiabatic oscillation calculations. Results: We find that transport by meridional circulation and shear turbulence yields far too high a core rotation rate for red-giant models compared with recent seismic observations. We discuss several uncertainties in the physical description of stars that could have an impact on the rotation profiles. For instance, we find that the Goldreich-Schubert-Fricke instability does not extract enough angular momentum from the core to account for the discrepancy. In contrast, an increase of the horizontal turbulent viscosity by 2 orders of magnitude is able to significantly decrease the central rotation rate on the red-giant branch. Conclusions: Our results indicate that it is possible that the prescription for the horizontal turbulent viscosity largely underestimates its actual value or else a mechanism not included in current stellar models of low mass stars is needed to slow down the rotation in the radiative core of red-giant stars.

Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels

Abstract: Dehydrated hereditary stomatocytosis is a genetic condition with defective red blood cell membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations in the mechanically activated PIEZO1 (FAM38A) ion channel were associated with dehydrated hereditary stomatocytosis. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated dehydrated hereditary stomatocytosis cases, we identify three novel missense mutations and one recurrent duplication in PIEZO1, demonstrating that it is the major gene for dehydrated hereditary stomatocytosis. All the dehydrated hereditary stomatocytosis-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in red blood cells of dehydrated hereditary stomatocytosis patients. Our findings also suggest a new role for mechanotransduction in red blood cell biology and pathophysiology.

Space partitioning without territoriality in gannets.

Abstract: Colonial breeding is widespread among animals. Some, such as eusocial insects, may use agonistic behavior to partition available foraging habitat into mutually exclusive territories; others, such as breeding seabirds, do not. We found that northern gannets, satellite-tracked from 12 neighboring colonies, nonetheless forage in largely mutually exclusive areas and that these colony-specific home ranges are determined by density-dependent competition. This segregation may be enhanced by individual-level public information transfer, leading to cultural evolution and divergence among colonies.

Effects of high vs. moderate exercise intensity during interval training on lipids and adiponectin levels in obese young females

Abstract: We investigate the effects of 12-week interval training of moderate- or high-intensity exercise on blood lipids and plasma levels of adiponectin. Thirty-four obese adolescent females [age = 15.9 ± 0.3 years; BMI and BMI-Z-score = 30.8 ± 1.6 kg/m2 and 3 ± 0.3, respectively], were randomized to high-intensity interval training (HIIT, n = 11), moderate-intensity interval training (MIIT, n = 11), or a control group (CG, n = 12). Maximal oxygen uptake ( $$\mathop V\limits^{.} {\text{O}}_{{2{\text{peak}}}}$$ ), maximal aerobic speed (MAS), plasma lipids and adiponectin levels were measured in all subjects before and after training. Following the training program, in both training groups, body mass, BMI-Z-score, and percentage body fat (% BF) decreased, while $$\mathop V\limits^{.} {\text{O}}_{{2{\text{peak}}}}$$ and MAS increased. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and adiponectin levels were positively altered (−12.6 and −7.4 %; 6.3 and 8.0 %; 35.8 and 16.2 %; high to moderate training program, respectively). Waist circumference, triglyceride and total cholesterol decreased only in HIIT group (−3.5; −5.3 and −7.0 %, respectively, in all P < 0.05). Significant decrease in the usual index of insulin resistance (HOMA-IR) occurred in HIIT and MIIT groups (−29.2 ± 5.3 and −18.4 ± 8.6 %, respectively; P < 0.01). The results show that HIIT positively changes blood lipids and adiponectin variables in obese adolescent girls, resulting in improved insulin sensitivity, as attested by a lower HOMA-IR, and achieving better results compared to moderate-intensity exercise.

Follow me cloud: interworking federated clouds and distributed mobile networks

Abstract: This article introduces the Follow-Me Cloud concept and proposes its framework. The proposed framework is aimed at smooth migration of all or only a required portion of an ongoing IP service between a data center and user equipment of a 3GPP mobile network to another optimal DC with no service disruption. The service migration and continuity is supported by replacing IP addressing with service identification. Indeed, an FMC service/application is identified, upon establishment, by a session/service ID, dynamically changing along with the service being delivered over the session; it consists of a unique identifier of UE within the 3GPP mobile network, an identifier of the cloud service, and dynamically changing characteristics of the cloud service. Service migration in FMC is triggered by change in the IP address of the UE due to a change of data anchor gateway in the mobile network, in turn due to UE mobility and/or for load balancing. An optimal DC is then selected based on the features of the new data anchor gateway. Smooth service migration and continuity are supported thanks to logic installed at UE and DCs that maps features of IP flows to the session/service ID.

Wideband 400-Element Electronically Reconfigurable Transmitarray in X Band

Abstract: A fully electronically reconfigurable 400-element transmitarray is studied numerically and experimentally in X-band. The array operates in linear polarization and consists of 20 × 20 unit-cells. A 1-bit phase resolution has been selected for the unit-cell in order to reduce the complexity of the biasing network and steering logic, the insertion loss and the overall cost of the antenna system. The unit-cell stack-up is simple and is made of four metal layers: active side, biasing lines, ground plane and passive side. Two p-i-n diodes are integrated on the active side of each cell in order to control its transmission phase. The active array contains 800 diodes in total. It demonstrates experimentally pencil beam scanning over a 140 × 80-degree window over a 15.8% fractional bandwidth, with a maximum gain of 22.7 dBi at broadside. We also show that the same antenna array can be used for beam shaping applications (flat-top beam). The experimental results presented between 8 and 12 GHz are in good agreement with the theoretical performance calculated using full-wave electromagnetic simulations and an in-house CAD tool based on analytical modeling.