Solute Partitioning Research Articles

SWORD2: hierarchical analysis of protein 3D structures.

Understanding the functions and origins of proteins requires splitting these macromolecules into fragments that could be independent in terms of folding, activity, or evolution. For that purpose, structural domains are the typical level of analysis, but shorter segments, such as subdomains and supersecondary structures, are insightful as well. Here, we propose SWORD2, a web server for exploring how an input protein structure may be decomposed into ‘Protein Units’ that can be hierarchically assembled to delimit structural domains. For each partitioning solution, the relevance of the identified substructures is estimated through different measures. This multilevel analysis is achieved by integrating our previous work on domain delineation, ‘protein peeling’ and model quality assessment. We hope that SWORD2 will be useful to biologists searching for key regions in their proteins of interest and to bioinformaticians building datasets of protein structures. The web server is freely available online: https://www.dsimb.inserm.fr/SWORD2.

Nucleic acid partitioning in PEG-Ficoll protocells.

The phase separation of aqueous polymer solutions is a widely used method for producing self-assembled, membraneless droplet protocells. Non-ionic synthetic polymers forming an aqueous two-phase system (ATPS) have been shown to reliably form protocells that, when equipped with biological materials, are useful for applications such as analyte detection. Previous characterization of an ATPS-templated protocell did not investigate the effects of its biological components on phase stability. Here we report the phase diagram of a PEG 35k-Ficoll 400k-water ATPS at baseline and in the presence of necessary protocell components. Because the stability of an ATPS can be sensitive to small changes in composition, which in turn impacts solute partitioning, we present partitioning data of a variety of nucleic acids in response to protocell additives. The results show that the additives-particularly a mixture of salts and small organic molecules-have profound positive effects on ATPS stability and nucleic acid partitioning, both of which significantly contribute to protocell function. Our data uncovers several new areas of optimization for future protocell engineering.

Genesis of plasticity-induced serrated metal flow in medium-Mn steel

Serration is a complex issue in medium-Mn steel, associated with a jerky metal flow and deformation banding. The problem has been well debated over the decades. In order to investigate the reason, a medium-Mn steel is prepared by hot-rolling in the austenitic domain, followed by air cooling. This results in martensitic microstructure due to high hardenability provided by adequate austenite stabilizers (C, Mn, Ni) in the steel. The intercritical annealing was performed for martensite to austenite reversion at 650 °C for different durations. From solute partitioning kinetics estimated by Dictra simulation, it appears that martensite released C-atoms, but the product austenite could not occupy them into octahedral under thermodynamic and kinetic constraints. This leads to an undissolved state of C, disowned by both martensite and austenite. With an enhanced diffusivity by intercritical annealing at 650 °C, those undissolved C-atoms without a bonding restriction repeatedly interact with sample dislocations, acquired from the rolling process and martensite. The interaction minimizes elastic energy by forming numerous C-dislocation aggregates into clusters, as the building block of Cottrell atmospheres. In metal plasticity theory, the Cottrell atmosphere usually dictates at room temperature. This work suggests it at an elevated temperature to enlighten hitherto unexplored mechanism of the dynamical C-dislocation interaction behind serrations. Additionally, austenite inhomogeneity by a lack of redistribution of Ni and Mn at 650 °C is found to be responsible for a staircase-wise propagation of the jerky metal flow.

Tissue Drug Concentration.

Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues. However, the concentrations of the drug are not homogeneous throughout the tissues, and they rarely reflect the free drug concentration in the blood. This heterogeneity is due to differences in the blood flow fraction delivered to the tissues and membrane transporters, efflux pumps, and metabolic enzymes. The rate of drug elimination from the body (systemic elimination) depends more on the driving force of drug elimination than on the free concentration of the drug at the site from which the drug is being eliminated. In fact, the actual free drug concentration in the tissues results from the balance between the input and output rates. In the present paper, we develop a theoretical concept regarding solute partition between intravascular and extravascular spaces; discuss experimental research on aqueous/non-aqueous solute partitioning and clinical research on microdialysis; present hypotheses to predict in-vivo elimination using parameters of in-vitro metabolism.

Tutorial review of reverse osmosis and electrodialysis

Reverse osmosis (RO) and electrodialysis (ED) are the two most important membrane technologies for water desalination and treatment. Their desalination and transport mechanisms are very different, but on a closer look also have many similarities. In this tutorial review, we describe state-of-the-art theory for both processes, focusing on simple examples that are helpful for the non-specialist and for classroom teaching. We describe relevant theory for ion and water transport and the coupling with theory for chemical and mechanical equilibrium on membrane/solution interfaces. For RO of neutral solutes, we explain the solution-friction (SF) model which is closely related to the classical sieving or pore flow model. The SF model includes advection, diffusion, and solute partitioning, and leads to simple relationships for the coupled fluxes of water and solutes (and thus for solute retention as well), also when a diffusion boundary (or concentration polarization) layer is included in the model. Subsequently this theory is extended to describe RO for symmetric salt solutions with charged membranes. For the desalination of salt solutions, both for RO and ED we present two-dimensional module-scale calculations which lead to a characteristic curve that determines optimum operational conditions based on a simple cost calculation that offsets energy and material costs. We discuss the two-fluid model (TFM) that comprehensively describes ion and water flow both in RO and ED, and we explain how this theory also accurately describes osmosis experiments where water and ions are transported in opposite directions through a membrane. Finally, we present results of optimization studies of the combination of multiple modules for RO and ED, and we evaluate the relevance of concentration polarization by using a 3D model for cross-current flow in an ED module.

Evaluation of Two Cosolvency Models to Predict Solute Partitioning between Polymers (LDPE) and Water - Ethanol Simulating Solvent Mixtures

Binary water - ethanol mixtures, by mimicking a clinically relevant medium's polarity-driven extraction strength, facilitate experimental modeling of patient exposure to chemicals which can potentially leach from a plastic material for pharmaceutical applications. Estimates of patient exposure could consequently benefit from a quantitative concept for tailoring the extraction strength of the simulating solvent mixture towards the one of the clinically relevant medium. The hypothetical partition coefficient based upon the differential solubility between water-ethanol mixtures and water, [Formula: see text], has been calculated by the log-linear model from Yalkowsky and coworkers and a cosolvency model based on Abraham-type linear solvation energy relationships (LSERs). Then, by applying a thermodynamic cycle using the partition coefficient LDPE/water, [Formula: see text], partitioning between LDPE and the ethanol in water mixture was calculated and experimentally verified for a wide array of chemically diverse solutes. The partition coefficients between LDPE and volume fractions of 0.1, 0.2, 0.35 and 0.5 of ethanol in water calculated by this approach correlated well with experimentally obtained values. The LSER based model was found slightly superior over the log-linear cosolvency model. Solubilization strength projection by means of cosolvency models in combination with LSER predicted partition coefficients LDPE/water enable the tailored preparation of water-ethanol simulating solvent mixtures when input parameters from the clinically relevant medium are available. This approach can increase the reliability of patient exposure estimations and avoid overly complex extraction profiles, thus minimizing time and resources for chemical safety risk assessments on plastic materials used in pharmaceutical applications.

Theoretical method for additional horizontal stress of isolation piles due to adjacent loading

AbstractIsolation piles are widely used to increase the horizontal resistance of high‐speed railway under adjacent loading in soft soils. This study proposes a theoretical model for horizontal additional stress of pile‐reinforced area subjected to adjacent loading. The isolation piles and the soil between piles in the reinforcement area are equivalent to a uniform medium in the proposed model. The Heaviside function is introduced to avoid the partition solution problem of pile‐reinforced area and the foundation soils. A combined method with the inverse Fourier transform, Gauss integral, Lagrange quadratic interpolation, and Simpson quadrature formula is employed in the calculation process. The theoretical model is validated by the finite element method. According to the calculated results, the distribution of horizontal additional stress is obtained. The horizontal soil displacements at the location of the railway increases in the depth range of 0–2.5 m and then gradually decreases. The proposed model with engineering significance is available for preliminary design of isolation piles.

An Effective Task Offloading Method for Separable Complex Mobile Terminal Tasks

Due to limited energy and computing power of IoT devices, they cannot handle complex tasks. Edge computing technology effectively solves the requirements of computing power and response delay for complex tasks in devices by migrating computing power to the vicinity of IoT devices. For a separable complex task on IoT terminal, we focus on the effects of data distribution, dependencies, and offloading sequence of subtasks on its total delay when it is offloaded to edge servers. Through comprehensively considering these factors, we study the slicing and choreographing method during the offloading process of a complex task. Firstly, a task slicing method based on hierarchical clustering is presented and an improved hierarchical clustering algorithm is used to obtain the optimal solution of task partitioning. Secondly, a task choreographing method based on overlapping the longest path is presented. Finally, through the simulation experiments of complex tasks with different structures and loads, the effectiveness of our method is verified.

Microfluidic Control of Coexisting Chemical Microenvironments within Multiphase Water-in-Fluorocarbon Droplets.

The use of aqueous polymer-based phase separation within water-in-oil emulsion droplets provides a powerful platform for exploring the impact of compartmentalization and preferential partitioning on biologically relevant solutes. By forming an emulsion, a bulk solution is converted into a large number of chemically isolated microscale droplets. Microfluidic techniques provide an additional level of control over the formation of such systems. This enables the selective production of multiphase droplets with desired solution compositions and specific characteristics, such as solute partitioning. Here, we demonstrate control over the chemical microenvironment by adjusting the composition to increase tie line length for poly(ethylene glycol) (PEG)-dextran aqueous two-phase systems (ATPS) encapsulated within multiphase water-in-fluorocarbon oil emulsion droplets. Through rational adjustment of microfluidic parameters alone, ATPS droplets containing differing compositions could be produced during the course of a single experiment, with the produced droplets demonstrating a controllable range of tie line lengths. This provided control over partitioning behavior for biologically relevant macromolecules such that the difference in local protein concentration between adjacent phases could be rationally tuned. This work illustrates a broadly applicable technique to rationally create emulsified multiphase aqueous systems of desired compositions through the adjustment of microfluidic parameters alone, allowing for easy and rapid screening of various chemical microenvironments.

Evolution of the mixed-mode character of solid-state phase transformations in metals involving solute partitioning

Abstract Partitioning phase transformations in the solid state are principally subjected to two processes that take place: the redistribution, through long-range diffusion, of the partitioning element, and the lattice transformation taking place at the interface. Consequently, the usual approximation to consider one of these two processes as controlling the rate of the phase transformation is of limited accuracy. For a more accurate description, the so-called mixed-mode character of partitioning phase transformations is to be taken into account. In the present study, it is shown that the mixed-mode character can be quantified and that it has a significant effect on the kinetics. By means of examples involving either substitutional (Mo in Ti) or interstitial (C in Fe) partitioning elements, it is shown that a gradual change of the character of the transformation occurs during the phase transformation, shifting from initially interface-controlled (which implies the largest interface velocity) towards more diffusion-controlled.

Calculating the closest approach parameter for ethyl lactate-based ATPS

Aqueous Two-Phase Systems (ATPS) is a powerful separation technique for biotechnological compounds, such as pigments, proteins and flavonoids. Nowadays, ATPS generally include dissolved salts, which cause phase immiscibility and promote solute partition. Therefore, to accurately model the liquid-liquid equilibria (LLE) of these systems, specific terms for the long-range interactions in thermodynamic models are needed. A well-known hypothesis for this purpose is the Pitzer-Debye-Hückel (PDH) term, which requires the knowledge of the closest approach parameter (ρ), i.e., an adjustable parameter. The aim of this work was calculating this parameter supposing total dissociation of the salts in ethyl lactate-based ATPS. In this new approach, ρ became specific for each chemical species and its physical meaning (related to the distance between ions of different charges) was preserved. This method was applied in the LLE modelling of 7 ethyl lactate + organic or inorganic salts + water systems measured by the group, using the PDH term coupled with the UNIversal QUAsi-Chemical (UNIQUAC) model, whose junction is generally known as PDH+UNIQUAC, and compared with classical UNIQUAC and with previous works. The new approach accurately described the experimental liquid-liquid equilibria (LLE) data and presented smaller composition deviations than UNIQUAC.

Early stages of discontinuous precipitation reaction in an advanced Cr-Fe-Ni alloy isothermally aged at 800 °C

The initiation mechanism of the discontinuous precipitation (DP) reaction driven by migrating grain boundaries (GBs) in Alloy 33 (Cr-Fe-Ni-N) isothermally aged at 800 °C has been studied using analytical electron microscopy, which includes scanning/transmission electron microscopy (STEM/TEM), X-ray energy-dispersive spectroscopy (XEDS), and electron diffraction. Precipitation products including both the types of precipitated phases (FCC M23C6 and M6N with diamond-cubic structure) and the GB morphology generated in the early stages of the aging process have been investigated in detail to correlate the experimental findings of the present work with the DP initiation mechanisms reported in the literature. STEM-XEDS elemental maps and electron diffraction data confirmed the FCC M23C6 was the first precipitated phase at the GBs, generating a Cr-depleted zone along the boundary and around the intergranular precipitates. The most remarkable characteristic in the initiation of DP reaction observed in this alloy system refers to the consistent evidence that the GB migration occurred to a significant extent while the M23C6 precipitates remain at the original GB position. In all observations, GB migration occurred against the capillarity force of the concave-forward boundary curvature, thereby suggesting a strong chemical force acting on the GB. Micro and nano-scale analytical STEM-XEDS results corroborated the existence of a compositional gradient of Cr across all migrating GB, confirming that a chemical driving force is responsible for the displacement of the GB. It is concluded that in the overall precipitation phenomenon the necessary solute partitioning is operated by interface diffusion mechanism through the moving GB acting as reaction front. Extensive STEM-XEDS analyses of the precipitation products observed in this investigation have confirmed that diffusion-induced grain boundary migration (DIGM) plays a major role as precursor to the initiation of DP reaction in Alloy 33.

Effect of multiphase flux with BaO addition on phosphorus partition

It is important to clarify the effect of BaO in phosphorus partition of multiphase flux. In current work, the slag CaO-SiO2-FetO-P2O5 with different contents of BaO was cooled from 1873 K to 1673 K to investigate the effect of BaO on phosphorus partition of solid solution. The phosphorous partition between the solid solution phase and liquid phase was obtained. In order to further inspect the effect of BaO on phosphorus partition, the experiment of reaction between 2CaO · SiO2 (C2S)-FetO/Fe2O3-BaO slag and hot metal was carried out. Furthermore, the CaO-FetO slag was also studied to compare the dephosphorization effect to C2S-FetO/Fe2O3-BaO slag. The phosphorus partition ratios Lp between the slag and hot metal were obtained. The result showed that when the slag CaO-SiO2-FetO-P2O5-BaO with various BaO content was cooled down from 1873 K to 1673 K, the solid solution was precipitated, and the enrichment of phosphorus in solid solution phase was improved with the addition of BaO. The phosphorus element content in solid solution increased from 4.16% to 5.27% with the increasing of BaO content in slag from 0 to 15% at the interval of 5%. Based on the experiment of reaction between slag and hot metal, the phosphorus content in hot metal showed that the barium ion was more beneficial to enrichment of phosphorus and the function of BaO was promoted by the addition of Fe2O3. The phosphorus partition ratio Lp between the slag C2S-FetO-BaO and hot metal was 295.38, which was higher than 208.24 that without BaO. The phosphorus partition ratio Lp between the slag CaO-FetO and hot metal was 217.50. The phosphorus partition ratio Lp between the slag C2S-Fe2O3-BaO and hot metal was 418.75, higher than that of the slag C2S-FetO-BaO.

POSSMs: a parsimonious speciation model for metals in soils

Environmental context Predicting the chemistry of metals is important for understanding their movement and impacts in the environment. Metal chemistry models are generally complex and difficult to apply, but a simpler model, which does not need large amounts of input data, can also provide good results. A simpler model can be more easily included in large-scale models of metal transport and impacts in the environment. Abstract Mechanistic geochemical models are useful for detailed study of the speciation of metals in well-characterised soils, but can be challenging to apply when driving soil compositional data are sparse, for example, at large scales. Empirical models, using minimal driving data, have been developed either for prediction of solid–solution partitioning or for the computation of the free metal ion from the total or geochemically active metal. This work presents an empirical speciation model, POSSMs (ParsimOniouS Speciation of Metals in soils), which predicts the free, solution-bound and sorbed metal in a soil in a single calculation, using a minimal set of soil parameters. The model has been parameterised for Ni, Cu, Zn, Cd and Pb using datasets of geochemically active soil metal and solution phase composition. The parameterised model can also be used to compute the free metal ion from the solution metal. The model was tested by applying it to literature datasets on the speciation of metals in soil solutions and extracts, and on the metal solid–solution partitioning. The performance of the model was comparable to other empirical models of similar complexity. Some test datasets produced biased predictions, particularly in the underestimation of measured free ion at circumneutral and alkaline pH, where the model predicted low free ion concentrations. The model is not a replacement for mechanistic geochemical models, but is a useful tool for soil metal speciation where comprehensive driving data are not available.

Carbohydrate-based aqueous biphasic systems for biomolecules extraction

Any potential of new biotechnological processes would be assuredly canceled in the absence of efficient separation strategies. This work comprehensively addresses the solutes partitioning behavior in biocompatible carbohydrate-polymer aqueous biphasic systems (ABSs) to explore the separation performance of these systems. The complete liquid–liquid phase diagrams were determined for sucrose/glucose-polypropylene glycol (PPG) ABSs at 25 °C and atmospheric pressure. Then, the partitioning pattern of four biomolecules, including caffeine, codeine, vanillin, and curcumin, was investigated in the carbohydrate-PPG ABSs. The obtained results show that caffeine, vanillin, and curcumin are mostly electrically neutral in the medium of the studied ABSs and preferentially concentrate in the more hydrophobic PPG-rich phase with the maximum partition coefficients (K) of 2.05, 19.75, and 246.37, respectively. However, codeine, being present mainly in the cationic form in the ABSs investigated, has a high tendency for the more hydrophilic carbohydrate-rich phase with the highest K−1 = 16.85. The magnitude of log K values for all the target biomolecules linearly increases by decreasing the water content ratio of the coexisting phases. The maximum value of the caffeine/codeine selectivity index was estimated to be 34.5 at optimum conditions. The best value of K did not necessarily correspond to the maximum recovery percentage (R) because the volume ratio of phases is another factor that can affect the R values. The curcumin partitioning behavior in carbohydrate-propanol ABSs was also investigated to provide a competitive platform. The gathered results indicate that although both carbohydrate-PPG and carbohydrate-propanol ABSs provide satisfactory partitioning performance for vanillin and curcumin, carbohydrate-PPG ABSs own a higher selectivity index for the alkaloids studied.

Paper Chromatographic Separation of Plant Pigments a New Approach by using Akshya-Swagatika Solvent and Mobile Chromatogram Detection System (MCDS)

Chromatography is a term that refers to a group of laboratory techniques for separating mixtures. Chromatography works on the premise of solute partitioning between two phases or solvents. The technique of paper chromatography is commonly used to separate plant pigments based on their molecular weight. Plant pigments include chlorophyll-b, chlorophyll-a, carotenoid, and xanthophyll, which all have various molecular weights, colours, and absorption maxima. In this study, an attempt was made to see how a new solvent (Akshya-Swagatika solvent) can be used to separate plant pigments using paper chromatography, as well as a new detection method developed by us known as Mobile chromatogram detection system (MCDS) that can be used for compound identification and photographing. As shown in the table and photograph, pigments are separated by molecular weight and band colour, with carotenoid having the highest RF value and chlorophyll-b having the lowest. It was obvious that the Akshya-Swagatika solution could be used to separate plant pigments in paper chromatography. Photograph taken with a mobile chromatogram detection system that is much clearer than normal one. In developing countries, both solvent and detection systems are useful in explaining paper chromatography in a cost-effective manner. The MCDS detection system is cost-effective fast method which replaces traditional sophisticated detection procedures.

Effect of composition and phase diagram features on printability and microstructure in laser powder bed fusion: Development and comparison of processing maps across alloy systems

Additive manufacturing (AM) has gained considerable academic and industrial interest due to its ability to produce parts with complex geometries with the potential for local microstructural control. However, due to the large number of material and process variables associated with AM, optimization of alloying compositions and process parameters to achieve desired properties is an arduous task. There is a fundamental gap in understanding how changes in process variables and alloy composition and thermodynamics affect additively manufactured parts. The present systematic study sheds light on the effects of alloying composition and corresponding phase diagram features on the printability and solidification microstructures of four binary nickel-based alloys, namely, Ni-20 at% Cu, Ni-5 at% Al, Ni-5 at% Zr, and Ni-8.8 at% Zr. These compositions are selected to represent binary isomorphous, weak solute partitioning, strong solute partitioning, and eutectic alloying conditions, respectively. Single track and bulk experiments are conducted to quantify the effects of varying material thermodynamic properties such as solidification temperature ranges, alloy melting temperatures, and other solidification conditions on resultant microstructures across the laser powder bed fusion (L-PBF) parameter space. A simple framework for developing processing maps detailing porosity formation and microsegregation across the laser power – scan speed parameter space is established and validated for each of these alloys to determine how material properties affect printability and microstructure in L-PBF. This knowledge will be vital in optimizing alloy chemistry and process parameters to design alloys specifically for additive manufacturing, as well as to provide a path toward local microstructure control.

Phase-field modeling of dendritic growth of magnesium alloys with a parallel-adaptive mesh refinement algorithm

A two-dimensional phase field (PF) model was developed to simulate the dendritic solidification in magnesium alloy with hcp crystal structure. By applying a parallel-adaptive mesh refinement (Para-AMR) algorithm, the computational efficiency of the numerical model was greatly improved. Based on the PF model, a series of simulation cases were conducted and the results showed that the anisotropy coefficient and coupling coefficient had a great influence on the dendritic morphology of magnesium alloy. The dendritic growth kinetics was determined by the undercooling and equilibrium solute partition coefficient. A significant finding is acquired that with a large undercooling, the maximum solute concentration is located on both sides of the dendrite tip in the liquid, whereas the maximum solute concentration gradient is located right ahead of the dendrite tip in the liquid. The dendrite tip growth velocity decreases with the increase of the equilibrium solute partition coefficient, while the variation trend of the dendrite tip radius is the opposite. Quantitative analysis was carried out relating to the dendritic morphology and growth kinetics, and the simulated results are consistent with the theoretical models proposed in the previously published works.

Phase constitution and microstructure of the NbTiVZr refractory high-entropy alloy solidified upon different processing

Time- and temperature-resolved phase formation in the equiatomic NbTiVZr refractory high-entropy alloy has been studied in situ using high-energy synchrotron X-ray diffraction and high-speed video imaging during non-equilibrium solidification. Phase formation is shown to be dependent on the solidification conditions. When the melt is undercooled over 80 K it crystallizes as a bcc single-phase solid solution despite solute partitioning between dendrites and interdendritic regions. When the sample is for some time kept in the semisolid state, two additional bcc phases form in the interdendritic regions. The crystal growth velocity for the NbTiVZr alloy, as estimated from the high-speed videos, shows pronounced sluggish kinetics.

Context-aware Adaptive Surgery

Deep Neural Networks (DNNs) have made massive progress in many fields and deploying DNNs on end devices has become an emerging trend to make intelligence closer to users. However, it is challenging to deploy large-scale and computation-intensive DNNs on resource-constrained end devices due to their small size and lightweight. To this end, model partition, which aims to partition DNNs into multiple parts to realize the collaborative computing of multiple devices, has received extensive research attention. To find the optimal partition, most existing approaches need to run from scratch under given resource constraints. However, they ignore that resources of devices (e.g., storage, battery power), and performance requirements (e.g., inference latency), are often continuously changing, making the optimal partition solution change constantly during processing. Therefore, it is very important to reduce the tuning latency of model partition to realize the real-time adaption under the changing processing context. To address these problems, we propose the Context-aware Adaptive Surgery (CAS) framework to actively perceive the changing processing context, and adaptively find the appropriate partition solution in real-time. Specifically, we construct the partition state graph to comprehensively model different partition solutions of DNNs by import context resources. Then "the neighbor effect" is proposed, which provides the heuristic rule for the search process. When the processing context changes, CAS adopts the runtime search algorithm, Graph-based Adaptive DNN Surgery (GADS), to quickly find the appropriate partition that satisfies resource constraints under the guidance of the neighbor effect. The experimental results show that CAS realizes adaptively rapid tuning of the model partition solutions in 10ms scale even for large DNNs (2.25x to 221.7x search time improvement than the state-of-the-art researches), and the total inference latency still keeps the same level with baselines.