To investigate the predictive role of meaning in life on the general health among medical sciences students.A cross‐sectional study.Four‐hundred medical sciences students were selected by proportional to size sampling. The general health questionnaire and the personal meaning profile were administrated to identify the predictive role of meaning in life on the student's general health. Descriptive statistics and linear regression were administrated.SD of the total score of general health and meaning in life among students was 16.34 ± 6.73 and 71.50 ± 9.78, respectively. In the multiple linear regression model, factors such as father's educational level, and meaning in life can predict a 20% variance of general health among university students. As meaning in life thus emerges as a variable worth further in the health of university students, implementing interventional studies to assess the effect of meaning in life on students' general health is recommended.The mean ±  Over the recent decades, GH assessments are considered an important issue in educational settings  and concern of specific professional careers in the future. So they may be at higher risk of GH problems  is one of the most complex issues which occupies the minds of many theorists. Despite numerous definitions in the field of MIL by philosophers and often anthropologist and existentialist psychologists; however, there is no universal comprehensive accepted definition , north of Iran, were recruited based on the proportional to size sampling method.The inclusion criteria were inclination to participate in the study and have no self‐reported psychiatric disorders such as depression and anxiety and no consumption of psychiatric drugs since last year. Cases with failure to complete a maximum of 20% of the questionnaires were excluded from the study.3.2For data collection, at first, the total number of all the students studying at bachelor of science degree or professional doctorate degree and the total number of students in each major were extracted by assistance of the educational office of the MAZUMS. Then, according to total sample size and by dividing the number of the students in each major  per the total number of students in the MAZUMS, the required sample size in each major was calculated. Finally, 400 volunteers' students in the campus of the MAZUMS completed the self‐administrated questionnaires. For all participants, a brief explanation about the objectives of the study and instructions for completing the questionnaires was given. Also, all students were provided written informed consent at the beginning of the study and were assured of the confidentiality of the data.According to a similar study in Iranian context which stated that approximately 45% of students had favourable GH status  and also to describe qualitative variables , frequency and percentage were applied. To assess the predictors of GH among students, linear regression was used. In linear regression, the relationship between demographic characteristics and MIL as independent variables and GH as dependent was assessed separately. Variables with p‐value <.05 in linear regression were entered into the adjusted multivariate linear regression model.Data analysis was performed by SPSS Statistics 24 , and to identify missing data, data were checked and cleaned before analysis. To describe quantitative variables such as age descriptive analysis such as mean ± standard deviation . All procedures in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.4The mean age of the participants was 21.35 ± 1.94 years and 53% of them were female. Paramedical and medical students were involved in approximately more than half of participants (50.3%) and the majority (55.7%) of the students was in bachelor of science degree. The characteristics of the participants are shown in Table SD of GH and MIL scores is described in Table The mean ± p < .05). These significant factors were entered into the adjusted multivariate linear regression model. In this way, factors such as father's educational level, and the total MIL score were significant predictors of GH score . The results showed that students whose father had academic educational level compared to the others had significantly higher GH status . Also, the total score of MIL had a positive significant effect on GH status . The regression model analysis showed that the total score of MIL was the most important predictors of GH among students in this current study .As shown in Table 5The aim of this study was to investigate the predictive role of MIL on the GH among medical sciences students. The health status of students is considered one of the most important public health issues worldwide and an increased level of student's health significantly associated with the high quality of life and subjective life satisfaction (Sreeramareddy et al., This study considered four domains of GH including physical symptoms, anxiety and insomnia, social dysfunction and severe depression. Based on the results of the current study, approximately two‐thirds of students had favourable GH status based on the GHQ‐28 questionnaire. The result of a study in Iran also showed that more than 50% of students had a healthy GH status (Hashemian et al., In the current study, there was a significant relationship between the score of MIL and GH among students. There is growing evidence of a positive relation between MIL and health status in adolescence and youth population (Nielsen & Hansson, Recent studies also revealed the link between MIL with different indicators of physical health and several studies reporting a positive relationship between MIL and self‐reported GH (Brassai et al., Adolescents who have positive expectations for the future are more likely to report high levels of satisfaction in the different life domains (Ho et al., 5.1The present studies had some limitations and strengthen. This study is one of the limited published studies about the MIL and its role on GH status of medical science students. The limitation of this study was the cross‐sectional design of the study and the self‐report methods to assess the student's GH so the depression domain of GHQ‐28 may not be reliable to evaluate the mental status of students. Also, generalization of the results from this sample to the general population of Iranian university students is limited due to conducting this project in medical sciences students.6Assessment of the GH is an important issue among medical sciences students since these students are responsible for maintaining and promoting the health status of the community in the future. Due to the lack of research about association of MIL and GH among university student in Iran, the findings of the current study make a new conceptual foundation regarding the role of MIL as an important predictor of the GH in this age group. As the importance of higher MIL and GH for meaningful and successful life in youth population, designing and implementing high‐quality studies regarding the evaluation of students' GH and also considering appropriate interventional studies regarding the role of MIL on students' health are important and effective action.The authors declare that they have no conflict of interest.ZSH designed the study and analysed the data; MA collected the data and contributed to the study design and wrote the paper. ZHG and RM contributed to the study design. All authors made a substantial contribution to the writing of the paper draft and met the four criteria for authorship recommended by the International Committee of Medical Journal Editors.


The configuration of proteins is critical for their biochemical behavior. Mechanical stresses that act on them can affect their behavior leading to the development of decease. The von Willebrand factor (vWF) protein circulating with the blood loses its efficacy when it undergoes non-physiological hemodynamic stresses. While often overlooked, extensional stresses can affect the structure of vWF at much lower stress levels than shear stresses. The statistical distribution of extensional stress as it applies on models of the vWF molecule within turbulent flow was examined here. The stress on the molecules of the protein was calculated with computations that utilized a Lagrangian approach for the determination of the molecule trajectories in the flow filed. The history of the stresses on the proteins was also calculated. Two different flow fields were considered as models of typical flows in cardiovascular mechanical devises, one was a Poiseuille flow and the other was a Poiseuille–Couette flow field. The data showed that the distribution of stresses is important for the design of blood flow devices because the average stress can be below the critical value for protein damage, but tails of the distribution can be outside the critical stress regime. This high molecular weight protein could unravel from globular to elongated conformation depending on changes in blood flow at the site of a vascular injury. The vWF initiates the formation of a hemostatic plug, which can adhere to the surface of a damaged blood vessel through a binding mechanism to collagen and simultaneous binding to platelets in the blood2. However, the functionality of vWF is either degrated or enhanced when its molecular structure is compromised because of mechanical stresses. The resulting disease is known as the acquired von Willebrand syndrome (AcWS), which can cause blood clotting irregularities and sometimes internal bleeding, especially to patients with cardiovascular implants4. Blood pumps, ventricular assist devices (VADs) and even heart valves generate blood flow conditions that are not typical for blood flow in the cardiovascular system8. The non-physiological conditions generated as blood flows through mechanical devices (including the generation of turbulence) lead to red blood cell (RBC) damage, known as hemolysis, because of shear and extensional stresses14 and to changes of the vWF protein20.The blood multimeric protein Von Willebrand factor (vWF) plays an important role in the primary hemostatis21. This process initiates the clotting. Further increase of stress leads to cleavage at the A2-A3 domain by ADAMTS-13. If stresses are applied during blood flow away from a wound, then the vWF conformation changes might lead to clotting. Such abnormal behavior can be observed in turbulent flows more than laminar flows21. While important, the extensional stresses are often not given equal treatment in the literature for vWF. The reason might be the fact that shear stresses are more predictable than extensional stresses in a turbulent flow field, especially the shear stress at the solid boundary of a pipe or duct that can be calculated from a force balance and knowing the pressure drop in the device. However, extensional stresses can be damaging to vWF molecules at levels that may be one order of magnitude smaller than shear stresses10. Further, the detailed measurement of stresses in a hemodynamic velocity field is difficult, especially in-situ for turbulent flow conditions, since it involves the measurement of derivatives of the blood velocity in all three space directions, and in every location of the flow . In such cases, the use of computational methods has become critical for both the probing of the hemodynamic conditions and for devise design22. Results of computations, however, might depend on the numerical approach. In fact, the Food and Drug Administration (FDA) has issued challenges to the computational fluid dynamics (CFD) community for the accurate prediction of blood flow in typical blood flow devices25. In these selected devises, experimental verification was made available through different laboratories across the US. High fidelity simulations, instead of turbulence modeling that is based on Reynolds Averaged Navier–Stokes (RANS) equation approaches, can provide detailed and accurate numerical predictions while avoiding empiricisms and approximations. Canonical flows that can be used as models for blood flow can be simulated with direct numerical simulations (DNS) that avoid any empiricisms, while flow in the complicated geometries of medical devices can be simulated with the less accurate RANS techniques.Both shear and extensional stresses can affect the configuration of a large molecule, like the vWF molecule. Strong shear stresses can even lead to cleavage of the protein. In equilibrium the vWF maintains a globular form, but under stresses, as blood flows through a wound or a cut, the A1 and A2 domains of the protein unfold to expose them to the platelets’ GPIB-α and integrin αIIbβ3 receptorsThe purpose of the present study is to investigate the magnitude of extensional stresses on vWF molecules using DNS in canonical flows. Using RANS for the calculation of extensional stresses locally in a turbulent flow field would not be feasible, since RANS provides the average velocity and not the fluctuating velocity field in 3D. In addition to the flow simulation, the trajectories of particles that serve as surrogates of the vWF protein were modeled, and the values of the extensional stress along the individual vWF trajectories were calculated as they traveled in the flow field. Two flows, a plane Poiseuille flow (PF) and a plane Poiseuille–Couette flow (PC) were examined. The choice of the PC flow was made in order to examine a flow regime that is relevant to VADs, where rotating parts contribute a Couette character of the flow and the pressure drop contributes a Poiseuille flow character to the flow. The structure of a Couette flow is such that larger coherent flow structures occur and it is different than the structure of a Poiseuille flow, which corresponds to flow in blood pumps with fully turbulent flow. The trajectories of 800,000 and 500,000 vWF molecules released at different locations in the PF and PC flow fields, respectively, were calculated. The history of the particles was thus computed, allowing the calculation not only of the average value of the stresses, but also of the statistical distribution of the stresses as a function of time and as a function of the location of vWF release, and of the history of the stresses as a function of time of exposure in the flow field. The contributions of this manuscript are (1) the development of a numerical methodology for obtaining the history of the stresses on vWF molecules as they move in a flow field; (2) the detailed calculation of extensional stress statistical distributions on the vWF molecules showcasing the importance of the tails of the distributions in addition to average values; and (3) the investigation of the importance of the flow field configuration and of the location of vWF injection on the distribution of stresses over time. The results are provided in dimensionless units, while typical flow parameters are provided to relate the dimensionless stresses to actual stresses in cardiovascular devises. A person who designs a devise can transform the dimensionless quantities to actual dimensional stresses.26. The critical value of shear stress for vWF deformation is around 5 Pa16. It has been found that the vWF is hemostatically active only under high shear rate, γ, and the value of the critical activation threshold is 28. In addition, there is a sharp, well-defined, large scale extension of vWF with end-to-end lengths up to 10 μm at shear rates > 5000 s−1 (corresponding to shear stress ∼4–5 Pa)29. Investigation of vWF in solution at shear stress of 6 Pa has showed that high shear stresses and long exposure times caused loss of high molecular weight multimers of vWF, resulting in poor binding to platelets and subendothelial collagen29.While there have been many papers focused on the effect of shear stress on vWF damage and blood cell trauma, the extensional components of the viscous stress also play a significant role in inducing cell damage31. Interestingly, RBCs deform at about 20 Pa in a simple shear flow, while in an extensional flow, the deformation is slightly higher (as measured by the deformation index) and occurs at much lower stress levels (about 6 Pa). Hence, the deformation of RBCs is more efficient in an extensional flow than in a simple shear flow10, and one could examine the hypothesis that this could be the case for proteins16. Further, the time of exposure of a cell in a stress field affects the level of cell trauma36. For RBC hemolysis, power law models are often used to quantify the expected hemolysis by considering both the stress level and the time of exposure,HI is the hemolysis index (a measure of hemolysis), τ is shear stress, t is length of exposure time to stress τ, and the constants α, β, and C are obtained through experiments.For blood cells, both the shear and the extensional stresses combine to act on the cell37. Other results have provided information to the extent that entomopathogenic nematodes were damaged during flow through an abrupt contraction, a predominately extensional flow regime38. In a combination of transient, extensional, and shear flow experimental studies, cultures of Chinese hamster ovary (CHO) showed cell damage above a critical value of turbulent kinetic energy dissipation rate39. Microfluidic sensing of the mechanical cell damage under an extensional stress field showed that the CHO cells were mechanically damaged when the extensional stress was greater than ∼250 Pa40. The use of a power law model to describe the vWF deformation appears to be justified because in these cases, where stresses affect the properties of a material, the effect depends on the duration of the stress application and the level of stress. In addition, prior research with vWF degradation with time, for example Zhussupbekov et al.41 and Kania et al.2, have indicated that a power law model applies for the unfolding of vWF under stress. Indirect evidence that a power law applies for the change in protein conformation vs time and shear rate is also offered in Heidari et al.42, where a normalized radius of gyration of the vWF was plotted as a function of the product of shear rate and a characteristic time. Even though the mechanisms of protein elongation and the mechanism of ADAMTS-13 cleavage are complex, applying a power law as a first order approximation to model the effects of exposure time on vWF deformation appears to make sense. The values of the exponential constants, however, are not known.Apart from RBCs, there have been other microparticles that are affected by extensional stress in a flow field, such as synthetic, liquid filled capsules that are suspended in hyperbolic extensional flow. Experimental results have demonstrated that capsule deformation is a function of the strain rate for an extensional flow generated in a four-roll mill16. Therefore, studying the behavior of vWF under extensional flow is quite necessary since there are strong indications that unraveling the multimer vWF is more impactful in extensional flow than in pure shear flow. Table Turning the focus back on vWF, when arterioles are cut, both the shear and elongational flow components increase with the elongational flow component selectively increasing at the site of rupture. After that, the flow would decrease with subsequent vasoconstriction that leads to a decrease of shear rate. Meanwhile, the elongational flow would increase precisely at the site of vasoconstriction hence it plays an utmost important role in hemostasisπh × 2h × 4πh and 16πh × 2h × 2πh, respectively, in the x (streamwise), y  and z (spanwise) directions. In the streamwise x and the spanwise z directions, the flow was assumed to be periodic and the no-slip boundary conditions were used at the channel walls. The algorithm used herein was developed by Lyons et al.43 to simulate flow in a channel by solving numerically the Navier–Stokes (N–S) equation. The code was for Newtonian fluids that have constant physical properties, and it has been modified by Papavassiliou44 to simulate Couette flow and has been extended by Kontomaris46 to simulate the transport of particles in the Lagrangian sense. The algorithm has been described in detail in45 and in the Dissertation by Lyons46. The results have been validated with experiments and with other DNS and experimental results for channel flow and plane Couette flow49, as well as for particle tracking in the DNS51. In this algorithm, the rotational form of the dimensionless N–S equations was solved. The equations were made dimensionless using the viscous wall parameters, i.e., the friction velocity u* (defined as ρ is the fluid density), the viscous length scale l* = (ν/u*) and the viscous time scale t* = l*/u*, where ν is the kinematic viscosity of the fluid. In the rotational form of the Navier–Stokes, the inertia term is replaced with the vector identityu is the velocity vector, and the vorticity vector is Blood flow in medical devices can be Poiseuille flow (PF) or Poiseuille–Couette flow (in certain parts of a VAD or a blood pump). Therefore, this study focuses on both kinds of flow in the canonical setting of a channel. We chose the dimensions for the computational box of PC flow and the fully turbulent PF as 3052 with a pressure step field correction suggested by Marcus53. The velocity field advanced from time step N to step N + 1 by three fractional steps: in the first, the non-linear convective term and the mean pressure gradient were calculated. The second fractional step calculated the dynamic pressure head and the third fractional step solved for the viscous terms of the N–S. The convective term and the mean pressure terms were advanced in time by a second order accurate semi-implicit Adams–Bashforth–Crank–Nicholson scheme. The dynamic pressure terms and the viscous term were advanced in time with a first order accurate Euler scheme. The convective (nonlinear) term was evaluated in physical space and, thus, aliasing errors occured, which were reduced by using the two-thirds truncation rule. The velocity field was expanded in terms of truncated Fourier series in the x and z directions and Chebyshev polynomial series in the wall normal direction. The periodic boundary conditions in x and z were thus satisfied with the use of Fourier series expansions. The number of Fourier modes depended on the simulation and it was equal to the number of mesh points in the x direction and the z direction. The number of Chebyshev nodes was equal to the number of mesh points in the wall-normal direction (direction y).The time integration was done using the pseudo-spectral fractional step method developed by Orszag and Kellsx direction and the top wall moved in the positive x direction. Both walls had the same velocity, equal in magnitude to 7.78 viscous wall units. The computational boxes of the PC flow and PF were divided into 512 × 128 × 128 and 1024 × 256 × 128 mesh points, respectively. The time step for simulations was Δt = 0.075 for the PC flow and Δt = 0.1 for PF. The blood was assumed to be a Newtonian fluid, given the high shear rate of the flow simulations55. In fact, calculations for non-Newtonian fluids for the FDA blood pump did not show significant differences in stress levels for that flow field25. Based on the data presented in Table 3 that indicate critical extensional shear rate between 300 s−1 and 400 s−1) the value of 350 s−1 for the shear rate was selected, which was combined with the blood viscosity value used here to provide the critical extensional stress value for vWF configurational changes to be 1.2 Pa. Therefore, the characteristic stress in this study is for the unraveling of the protein, and not for the ADAMTS-13 cleavage.In the PC channel, the bottom wall moved in the negative Reτ, for the PC flow and the fully turbulent PF was 80 and 300, respectively. In order to provide a sense of the dimensions of the simulation setups, the PC channel width was chosen to be 1.5 mm for Reτ = 80, the blood viscosity u* = 0.183 m/s,. This is a case of flow within the range of operation of VADs59. A typical flow field based on the FDA critical path initiative conditions for blood flow in the suction side of a centrifugal pump was chosen for the PF simulations63. For the case of Re = 3661 in a 1.5 mm diameter pipe and a flowrate of 7 lt/min, the corresponding mean velocity is 2.015 m/s. Comparing this velocity to the calculated dimensionless mean velocity of 16.68 in viscous wall units for the channel flow, the friction scales were calculated as u* = 0.1208 m/s and Reτ = 300. The DNS algorithm used was an in-house developed DNS that was based on the pseudo-spectral method of Lyons et al.43 which has been verified and used in our laboratory for PF, PC flow and plane Couette flow66.The friction Reynolds number 68. The markers were passive and were assumed to be massless , so one-way coupling between the flow and the motion of the particles was employed. For particles that are assumed to be surrogates of molecules, the main driving force for marker movement is the convection effect  and the Brownian motion that depends on the hydraulic diameter of these particles.The trajectories of each vWF molecule were modeled using a Lagrangian approach, i.e., Lagrangian scalar tracking (LST)V at the particle position and integrating in time. The Brownian motion was simulated by imposing a random jump at the end of each convection step70. This random jump took values from a normal probability density function that had a zero mean and a standard deviation that depends on the fluid properties and the molecular diffusivity of the particles. The equation of motion for each marker in each space direction x is given by71t + 1, x direction at position Z is a random number following a standard normal distribution.These markers were released into the simulated flow field from specified locations at one instant of the simulation (instantaneous source). The convective part of the marker motion was calculated assuming that using the fluid velocity is the same as the Lagrangian velocity 0, from the bottom wall of the computational channel. The values of Y0 were 0, 3, 5, 15 and 80 for the PC flow, and, Y0 = 0, 1.5, 3, 5, 10, 15, 75, 300 for the PF . These values were selected in order to observe the changes in the distribution of the extensional stresses for markers released at the center of the channel, at the channel wall, within the viscous wall sublayer and at the buffer region. At each Y0, markers were released from 20 lines spanning the x–z plane so that possible bias caused by the initial velocity field would be avoided. Starting at x = 0, these lines were uniformly spaced in x and were spanning the width of the channel in the z direction. We injected 100,000 markers uniformly in the z direction for each value of Y0 . Since the markers were passive, the presence of one did not affect the trajectory of any other marker. The x location for each marker was calculated by subtracting the initial position x0 of the marker, therefore (x- x0) was considered as the marker location in the streamwise direction. In vector form, the location of each marker in the Lagrangian sense, 0 = 0, and the corresponding Lagrangian velocity of the marker at that location was 72. The random molecular diffusion movement of each marker was calculated at the end of the convective motion, as seen in Eq. t is the time step of the simulation and Sc is the Schmidt number, Sc = ν/D. Finally, D is the molecular diffusivity of the vWF in blood. Assuming 1.8 × 10–8 m for the radius of a vWF molecule with molecular weight of 20,000KDa73 in a fluid with the dynamic viscosity of blood (0.0035 Pa s), the Stokes–Einstein relationship produced a diffusivity of 3.6119 × 10–12 m2/s for the vWF, and a Schmidt number of 914,000 (the blood kinematic viscosity was taken as ν = 3.30189 × 10–6 m2/s). This is a simplification of the vWF molecular behavior, since our algorithm does not account for different molecules that can interact and adhere to one another. However, a change in the mass marker due to molecular adhesion would only result in a change in its size, within the framework of the present calculations, leading to a change in the Sc that would change the trajectory of the new molecular cluster slightly, but not the stresses felt by it.A large number of mass markers were released in the flow field that was generated computationally by the DNS. The vWF markers were injected instantaneously at selected distances, Y29 and Sharifi and Bark74. It was treated implicitly as a sphere in Pushin et al.75, since the forces acting on the vWF were assumed there-in to be found as stress multiplied by the area of a circle. When the hydrodynamic and mechanical stresses are low, the multimers attain a compact (collapsed) conformation because of effective interdomain attractions76. Above a critical shear stress, the vWF free in flow would elongate and tumble, and it would extend in elongational flow74. Since such changes were not modeled in this study, the hydrodynamic radius was used for computations.In the above, the proteins were assumed to be in the globular shape. While the shape of vWF is dynamic and dependent on the type of flow, in general the vWF multimers have overall compact, bird’s nest shape. The behavior of the vWF as a sphere has been adopted by others, e.g., Gogia et al.u, v, and w are the fluid velocity components in the x, y and z directions respectively. This stress was calculated at the position of each vWF marker at each time step, based on interpolation of the Eulerian velocity field at the marker location. A sixth order Legendre interpolation scheme in the x and z directions and a Chebyshev polynomial interpolation in the wall-normal direction were implemented to obtain the velocity at the markers’ location67.The extensional stresses were calculated in dimensionless form as follows:α and β in a power law model for vWF degradation , but the variance of the statistical distribution of the stresses would be expected to grow with time.In Fig. y and z directions are larger than the critical extensional stress value (1.2 Pa). In general, the change of stress value followed the same trend in all directions. As expected, the vWF markers released close to the location of the Eulerian maximum (at Y0 = 15) started from a higher average value at t+  = 0, while those released closer to the wall were initially at smaller values. As time passed, the markers diffused away from their original location of release and eventually the average stress appeared to converge. For vWF released within the viscous sublayer (Y0 = 3 and 5) the stress value increased until t+ = 250 and then decreased gradually. The vWF markers released at the wall of the channel stayed in the wall region, since the molecular diffusion part of their motion was not enough to force them to leave the region very close to the wall. Considering the very high Sc for the vWF, the molecular diffusion part of the particle motion is dominated by convective effects, but close to the channel wall turbulence convection is not strong . The particles released at the channel center (at Y0 = 80) do not show significant change in the average stress over time. However, it is apparent from these figures, and specifically from the streamwise stress profile, that it is possible for vWF markers to experience lower than critical stresses as they travel in a region of the channel, and then at later times to be in regions where the stress is higher than the critical value. In that case, for small time, the proteins are functional, but at later times they might start to lose their functionality.The Lagrangian average of the extensional stresses over the vWF particles as a function of time is seen in Fig. 0 = 5), the buffer region and the center of the channel were selected for presentation. For release at Y0 = 5, the PDF of the stresses became wider as time passed. When the release position is farther from the wall, at Y0 = 15, the PDF becomes narrower with time, showing that the markers were experiencing a smaller variation of stresses with time. The stress distribution remained roughly the same as a function of time for release at the center of the channel. Moreover, the PDF was symmetric for that case. The critical extensional stress is also shown on the figure for the positive stress, and it is seen that those vWF molecules that experience the stress at the right and the left tail of the distribution would be damaged by extensional stress.In Fig. 78, the vWF molecule can undergo irreversible stretching or unfolding when it undergoes stresses even for small times. Therefore, the history of stresses on a molecule is important and can lead to an elongated or cleaved vWF as a result of a high stress experienced at earlier times, or as a result of low stress experienced over long times, even when the molecule at one particular snapshot in time is not stressed78. As time advanced, the distribution was displaced to larger values, since the particles experienced a stress for longer exposure times, but the variance of the distributions increased as well. The width of the distribution is an indication of the significant differences in the stress that particles underwent, and these differences seem to grow as time passed. At the release position Y0 = 0, the integrated stress values were much smaller when compared to the other release positions. At larger times, it appears that the stress distributions tended to be more symmetric and looked more similar to the PDF for particles released at the channel center. This is expected, since turbulent convection would mix and distribute the particles across the channel width as time passed.Figure yz plane in the channel was a plane of symmetry, so only the profile at the bottom half of the channel is shown. The stress profiles seen in Fig. + = 25 in the buffer layer. Farther out from the channel wall the stresses have lower values and reached a minimum at the center of the channel. The normal stress in the y direction, σyy, was larger than the extensional stress in the other two directions.The average of the absolute value of the extensional stresses in the three space directions as a function of the distance from the channel wall is presented in Fig. x direction, σxx, was smaller than the critical value for vWF deformation. In the y and z directions, however, particles released at the edge of the viscous sublayer and within the buffer region  appear to have experienced high stresses on average—higher than the critical value of 1.2 Pa. In general, the change of stress value followed the same trend in all directions. The average stress for vWF particles released at the center of the channel remained roughly constant, as expected based on the Eulerian stress profile and as discussed for the PC flow case. Particles released at the wall or very close to it (at Y0 = 0 and 1.5) did not have a chance to disperse away from the wall and experience high stresses. As the time after particle release increased, the particles dispersed more uniformly across the channel and the average stress was expected to reach the bulk average Eulerian value across the channel.Figure x, y, z the extensional stress distribution for particles released within the viscous sublayer and the buffer region changed the most with time. The most dramatic change was from t+ = 15 to t+ = 75. The variance of the PDF for the stress distribution increased as time elapsed, as indicated by the widening of the PDFs. When particles were released in the log-layer (Y0 = 75) and at the center of the channel the changes were moderate.After injecting particles, the full distribution of extensional stress was calculated at specific time instances and is presented in Fig. 0 = 1.5, 5, 15, 75, 300. It is clear that the integrated stress on particles at t+ = 150 shows a narrow distribution, roughly in the range from 0 to 10 for Y0 = 1.5 and 300 and from 0 to 25 for Y0 = 5, 15, 75. This observation can be interpreted when one considers the Eulerian stress profile depicted in Fig. Sc for the vWF particles. For particle release close to the wall of the channel one would expect that a high Sc particle would have small diffusion both by molecular means (the standard deviation of the Brownian motion displacement is very low) and by turbulent convection . At the channel center, as seen in Fig. + = 150) and the channel center at y+ = 300. For release at other locations, in the buffer layer and the viscous sublayer, the vWF particles could diffuse by molecular means and mostly by turbulent convection. In this way they could disperse in the wall-normal direction y and would experience a variety of stress values, leading to wider distributions of stress. At later times, as expected, the peaks of the stress history PDFs shifted to the right and the PDFs widened, while the stress distributions tended to be less skewed. As the time of exposure increased, the combined effect of time and stress would accumulate on the particles. As was the case for PC flow discussion for Fig. Figure 79 could be designed, to control the stress and exposure time to these stresses, but modifications of that apparatus would need to be made to control for elongational stress rather than shear stress 80.Experimental data for the validation of the PDF of the stresses experienced by the vWF surrogate particles in turbulent flow are not readily available. This type of measurement would be non-trivial, especially in a Lagrangian sense . Local extensional stresses depend on velocity derivatives that are very noisy to measure see Eq. . One cou82. In such computations the vWF was modeled taking into account the chain-like structure of the vWF and details of the unfolding of the A1 and A2 domains and the ADAMTS-13 cleavage could be observed, but the simulations were focused on the investigation of one vWF molecule. The approach herein has the advantage of providing the stresses in different flow fields, so that one could potentially use results such as those in refs81 to determine the critical stress for protein unfolding and to determine what percentage of the proteins in the flow are subject to that stress and for how long. Here, the protein was treated as a particle with a diffusivity that depends on its average radius. Having said this, the trajectories of modified proteins in our model could be calculated by updating the protein diffusivity. If the changes were small (within an order of magnitude), then the results that were obtained  would be expected to be affected very little. For example, the Sc for particles with twice the diameter would not generate significantly different Brownian motion effects, when the Sc is already as high as it is here (the Brownian motion is affected by the square root of the Sc). Prior work from our laboratory regarding the dispersion of high Sc particles in turbulent flow has shown that the behavior of particles with Sc > 2400 can be considered as very similar in the statistical sense . The trajectories of the particles tracked in the present work are representative of vWF particles only based on the diffusivity of these particles as calculated with the Stokes–Einstein relationship. Solid particles, or other protein molecules of the same diffusivity would follow (according to the modeling assumptions) similar trajectories and would undergo similar levels of stresses in the statistical sense, i.e., the distribution of stresses on any such particles released in these flow fields at the same locations would be subject to the same probability distributions for stresses. Blood cells could be tracked in the same way, but since blood cells are much larger than vWF the equation of motion would need to be modified to account for hydrodynamic drag forces and possibly for added mass terms.The goal of the present study is not to elucidate the molecular mechanism of protein unfolding, and the approach employed in our work cannot offer molecular level information, such as molecular dynamics simulations or coarse-grained simulations canIn this study, direct numerical simulations and Lagrangian scalar tracking methods were applied to compute the extensional stress of vWF surrogate particles in different flow configurations (plane Poiseuille–Couette and plane Poiseuille). The vWF particles were assumed to be spherical, in order to obtain a diffusion coefficient. The changes in the shape of the vWF under stress were not taken into account in the calculation of the diffusivity. The drag forces were assumed to be negligible, while Brownian motion was assumed to be the most dominant contributor to the vWF movement after convection. Following this approach, the three components of the extensional stress were monitored for individual vWF particles over time, enabling calculations of the detailed statistical distributions of the stresses. Such calculations are not trivial for either experimental approaches or computational approaches using turbulence modeling with other low-order numerical methods. On the other hand, these computations are not designed to provide structural information for the vWF or for vWF interactions, such as such as end-to-end-distance of the protein molecule or adherence and adsorption.The results of the simulation show that the distribution of stress was a function of both time and release position. It was found that both flow conditions lead to a percentage of vWF particles experiencing damaging stresses. The most unpredictable cases were the ones when the vWF was released in the viscous sublayer or in the buffer region of the turbulent flow field. In addition, it is highly probable that particles were exposed to different stresses as they dispersed in the flow field, and these stresses were potentially damaging for a portion of the time they spent in the flow. Injections at the center of the flow field, rather than closer to the wall, would be preferred, as they result in exposure to lower and more predictable stress.32, but the exponents of the power law model  similar trajectories and would undergo similar levels of stresses in the statistical sense, i.e., the distribution of stresses on any such particles released in these flow fields at the same locations would be subject to the same probability distributions for stresses.


One of the major concerns during the production of crude oil especially in tropical waters is the deposition of wax on to the walls of the pipeline. This is due to the low seabed temperatures which can be below the wax appearance temperature (WAT) which leads to wax depositing out through molecular diffusion. Currently, there are many methods to prevent and remedy wax deposition but most of these solutions pose a serious environmental threat and are expensive to produce. Hence, this research investigated the use of an organic and cheaper alternative by utilizing synthetic fatty acid esters such as oleic acid which has shown promising results in reducing the pour point of waxy crude oils. The solution that was used was of palm oil origin, crude palm oil (CPO) and crude palm kernel oil (CPKO) and was subsequently compared with the pour point depressant and wax inhibition efficiency of the current industry used inhibitors utilizing the SETA Pour Point and Cloud Point as well as the cold finger apparatus. It was observed that the palm oil inhibitors were highly effective at 1 wt.% due to the high composition of oleic acid present portraying a similar result to Triethanolamine (TEA) while Ethylene Vinyl Acetate (EVA) performed best at low concentration of 0.1 wt.% but deteriorates significantly as the concentration increases due to the polar end agglomerating among itself. With the current COVID 19 pandemic and significantly low demand of crude oil, the production of crude oil has decreased in order to reduce the loss due to the low oil price. However, demand remains for the production of crude oil due to the high energy density and versality as compared to other source of energy Agency . TherefoThere are a number of flow assurances issues that must be considered to prevent blockages and other difficulties during the production of crude oil. Among the flow assurance issues include hydrate formation, paraffin wax deposition, asphaltenes, erosion and corrosion  or when there is a temperature differential between the crude oil and the pipeline and palm kernel oil (CPKO) were obtained from United Plantation. The crude oil used from the Chenor oil field while the triethanolamine (TEA) and ethylene vinyl acetate (EVA) were purchased from Sigma Aldrich.The physical as well as the chemical properties of the crude oil are as shown in Table The pour point of the Malaysian crude oil was analyzed utilizing the ASTM D97-12 (SETA Cloud and Pour Point) Astm . The pouThere are two types of pour point, the upper pour point and the lower pour point: The upper pour point is obtained after the crude oil has undergone a procedure to enhance the wax crystal gelation as well as solidification. The lower pour point is obtained when the crude oil undergoes a procedure to delay the wax crystal gelation as well as solidification. The pour points depend on the wax content of the crude oil. As observed from the research performed by Sharma and et al., the higher the pour point temperature, the higher the wax content and vice versa  in a water bath that was maintained at a temperature of 12 °C above the expected pour point temperature (minimum 48 °C). The test jar was then placed in another water bath that is 0 °C. Also, the test jar was placed in a jacket and to avoid the test jar from touching the walls of the jacket, the use of gasket and disk is necessary. As the crude oil was allowed to cool, great care was taken to avoid any agitation to avoid low and erroneous reading. At every decrease in oil temperature by 3 °C, the test jar was removed, and the test jar was tilted to examine the movement of the crude oil. The presence of crude oil movement will lead to the test jar being immediately placed back in the jacket, and procedure is repeated until the absence of crude oil movement is observed. Once the crude oil movement has halted, the temperature was recorded, and the experiment is repeated to obtain a consistent reading.The experiment was then repeated in the presence of additives of TEA, EVA, CPO and CPKO at a concentration of 0.1 wt.%, 0.5 wt.%, 1 wt.%, 5 wt.% and 10 wt.%. The experiment was conducted to determine if the presence of additives aids in reducing the pour point of the crude oil.The oil tank was filled with 300 ml of the sample crude oil. The bulk oil temperature was maintained below the WAT of the crude oil at 25 °C. The cold finger was set at 5 °C to produce a temperature gradient in the sample. An overhead stirrer was used to induce sample mixing. After 2 h, the cold finger was removed, and the wax deposit was weighed. The experiment was conducted for 6 h and then extended time of 24 h to investigate the wax deposition of different ageing time. The experiment was then repeated using the crude oil in the presence of TEA, EVA, CPO and CPKO, respectively, at various concentration. Figure Wp = mass of deposited paraffin wax in the absence of inhibitors, g; Wa = mass of deposited paraffin wax in the presence of chemical additives, g.The Paraffin-Inhibition Efficiency (PIE) of each chemical additive was then determined using the following equation:The pour point of the crude oil as well as the pour point of the crude oil in the presence of various inhibitors were obtained after concluding that the crude oil did not flow after being tilted horizontally. Figure The results of the test are as shown in Table From Table In addition, when the pour point of the crude oil was tested in the presence of 0.1% CPO, the temperature when the crude oil stopped flowing was observed to be at − 4 °C. However, as the concentration of CPO increases, the pour point of the crude oil decreases as observed at 0.5% and 1% concentration of CPO where the pour point was observed to be at − 6 °C and − 8 °C, respectively. When the CPO concentration is further increased, the pour point of the crude oil can be seen to increase. Take instance, in the presence of 5% and 10% CPO concentration, the pour point was observed to be at − 4 °C and 0 °C, respectively. In terms of CPKO, at 0.1% concentration, the pour point of the crude oil was observed to be at − 2 °C and as the concentration of CPKO increased, the pour point decreased up to 1% concentration. At 0.5% and 1% concentration, the pour point of the crude oil was observed to be at − 6 °C and − 8 °C, respectively. As the concentration increased above 1% concentration, the pour point can be seen to increase to where at 5% concentration, the pour point was observed to be at − 4 °C while at 10% concentration, the pour point was observed to be at 0 °C.Thus, it can be concluded at low concentrations, all the inhibitors tested are able to reduce the pour point of the crude oil but a critical concentration exists where when the concentration used surpasses the critical concentration, the inhibitors losses their ability to reduce the pour point of the crude oil and may act as potential sites for crystallization and agglomeration to take place. This then causes the pour point of the crude oil to increase.As discussed in the experimental section, at the end of the experiments the PIE was obtained and plotted against the deposition time as illustrated from Figs. Wdep is the mass of wax deposited, Wb is the initial mass of the beaker, and Wt is the mass of the beaker and the scraped off deposited wax.The mass of the wax deposited under dynamic condition was obtained using Eq. From the results for the dynamic deposition test, it can be noticed that the initial mass of the deposited wax increases as the deposition time increases to the 6th hour and then the rate of wax deposition decreases as the experiment approaches the 24th hour both in the presence as well as the absence of additives. This deposition trend was is caused due to the time the cold finger is in contact with the crude oil, leading to an increase in heat loss as well as lowering the bulk oil temperature leading to wax precipitation and deposition. However, the deposition trend is not linear due to the depletion effect. It is important to comprehend that as the experiment was conducted at a laboratory set up, there is a constant amount of sample used, and no fresh sample was supplied after each reading, causing wax depletion to occur as time increases  tested. The wax deposited was much harder and denser which made it difficult to scrap off as compared to the brittle and easy to scrap wax deposited at the lower concentration.The paraffin inhibition efficiency (PIE) against deposition time in the presence of 5 wt.% additive under dynamic conditions is portrayed in Fig. According to Fig. In terms of the physical appearance of the deposited wax of CPO, CPKO and TEA throughout the 24 h experiment in the presence of 5 wt.% concentration of the additives was soft and easy to be remove but became more compact and stiffer as the deposition time increases. However, the wax deposited under dynamic conditions in the presence of 5 wt.% EVA was similar to the wax deposited in the presence of 1 wt.% EVA but harder and denser which were harder to scrap off.Figure Based on Fig. Furthermore, the physical appearance of the deposited wax of CPO, CPKO and TEA in the presence of 10 wt.% concentration was soft and easy to be removed as observed in 0.5 wt.%, 1 wt.% and 5 wt.% concentration. However, the wax deposited in the presence of 10 wt.% EVA was extremely hard and compact as compared to 5 wt.% EVA. To better understand, the effect of the additives in various concentration tested, the graph of average paraffin inhibition efficiency against time was plotted and is illustrated in Table Based on Table As the concentration increased, the average PIE of EVA under dynamic conditions decreased drastically especially above 1 wt.% concentration. This is due to the possibility that the EVA additives are behaving as supplementary suspended particles in the crude oil which deteriorates the efficiency of the polymer to inhibit wax deposition. This confirms that the increase in wax deposits is influenced by the concentration of wax inhibitor utilized and as the concentration reaches the optimum value, it alters the wax crystallization behavior by implementing more structures to disturb and reconcile with edge of the developing wax crystals , followed by 1% CPKO (Average PIE = 70.387%), then 1% TEA (Average PIE = 70.198%) and finally 0.1% EVA (Average PIE = 62.541%). The results not only illustrate that oleic acid or CPO and CPKO can be an excellent wax inhibitor in terms of efficiency but also portrays palm oil additives can be a potential substitute to the existing expensive and hazardous additives used in the industry. However, further investigation should be conducted on the effect of CPO and CPKO on the wax content analysis as well as the reduction of deposited wax using a flow loop apparatus before implementation in the field.


Rafiei and Rahnev (2021) presented an analysis of an experiment in which they manipulated speed-accuracy stress and stimulus contrast in an orientation discrimination task. They argued that the standard diffusion model could not account for the patterns of data their experiment produced. However, their experiment encouraged and produced fast guesses in the higher speed-stress conditions. These fast guesses are responses with chance accuracy and response times (RTs) less than 300 ms. We developed a simple mixture model in which fast guesses were represented by a simple normal distribution with fixed mean and standard deviation and other responses by the standard diffusion process. The model fit the whole pattern of accuracy and RTs as a function of speed/accuracy stress and stimulus contrast, including the sometimes bimodal shapes of RT distributions. In the model, speed-accuracy stress affected some model parameters while stimulus contrast affected a different one showing selective influence. Rafiei and Rahnev’s failure to fit the diffusion model was the result of driving subjects to fast guess in their experiment. They used five levels of speed-stress, varying from extremely high stress on speed to high stress on accuracy (“slow” stress in their terms). Our analyses of their data show that when speed was stressed, on some proportion of trials subjects randomly responded to the onset of the stimulus without waiting to make a decision based on stimulus orientation. The results produced bimodal response time (RT) distributions in the speed-stress conditions for some subjects and distributions with most RTs less than 300 ms for others. The accuracy of the responses with RTs less than 300 ms was chance.Would we want to apply a single-process model to a task in which on some proportion of the trials subjects try to make a decision about a stimulus while on other trials they close their eyes and hit a button randomly? Rafiei and RahnevTo demonstrate this, Fig. 4). Luce5 reviewed fast guess data and modeling from a range of experimental tasks including those from a study by Blough6 with pigeons performing a (light) wavelength discrimination task and a study by Swensson7 with humans performing a discrimination task judging the orientation of a rectangle. In both cases, the shape of RT distributions with RTs less than about 250 ms was unaffected by manipulations of difficulty. Discriminative responses had RTs greater than about 300 ms in Swensson’s study and in Blough’s study, and there were peaks in the RT distributions at 200 ms for fast guesses and at 350 ms for discriminative responses based on the stimulus.Rafiei and Rahnev’s research represents a rediscovery of fast guessing. Fast guessing was a major topic in the 1960’s and 1970’s with experiments with simple stimuli that examined the phenomenon and models that were developed to account for the data  from trial to trial with SD η and the starting point of the process is also assumed to vary from trial to trial with range sz. The time for processes outside the decision process  is assumed to have mean Ter and range st. .Rafiei and Rahnev’s article focussed on showing that the standard diffusion modeldel Fig. b, inform11 examined the effects of fast and slow outlier RTs on the power of analysis of variance and on measures such as skewness and kurtosis12. Ratcliff and Tuerlinckx13 discussed fast guesses in the context of parameter estimation for the diffusion model. The DMAT diffusion model fitting package14 has an explicit mechanism to detect the point in time at which accuracy begins to rise above chance which can be used as a cutoff to eliminate fast guesses. However, this outlier-elimination mechanism has not found much use as far as we know. Simen et al.15 conducted an optimality analysis of the diffusion model and found that in some cases in which one stimulus occurred with greater probability than the other, fast guesses were optimal to maximize reward rate. In these studies and others, it is generally agreed that if subjects are encouraged to respond extremely quickly, some subjects some proportion of the time will engage in fast guessing. Generally, a lot of diffusion modeling has used cutoffs  to eliminate fast guesses or has eliminated subjects with a large proportion of fast guesses.Fast guesses have been considered in some applications since the research described in Luce’s review. Ratcliff17.In many experiments, fast guessing has been minimized by instructions, monitoring subjects, and/or an extra long delay following a too-fast response to discourage such responses . Remaining too-fast responses have usually been eliminated from analyses and model fitting. However, recently, experiments are being published with results contaminated with fast guesses, and online tasks or those without close supervision of subjects are susceptible to fast guessespo of a fast guess and a probability 1 − po of a standard diffusion process. po differs as a function of the speed-accuracy condition, but is constant across levels of stimulus contrast. Fast guesses are assumed to be random with 50% accuracy and guessing times are normally distributed with mean mg and standard deviation (SD) sg that are fixed across all conditions. While the normal distribution is likely an oversimplification, a slightly skewed distribution such as an inverse Gaussian (e.g.19) would provide similar results at the expense of an additional parameter.To directly address Rafiei and Rahnev’s analyses of their data and the problems with them, we introduce a mixture model that adds a simple, explicit model of fast guessing to the standard diffusion process for stimulus-based discriminative decisions. In this model, there is some probability at each level of speed-stress that a trial is a fast guess. Figure The mixture model was fit to Rafiei and Rahnev’s data for each subject separately with all of its parameters estimated simultaneously for all of the experimental conditions. There were 25 conditions, five levels of speed-stress crossed with five levels of stimulus contrast. There were 25 parameters: 5 each for boundary separation, nondecision time, drift rates, and the probability of a fast guess. The mean and SD of the normal distribution for guesses were held constant across all conditions. There were also 3 across-trial variability parameters, also held constant across all conditions: the SD in drift rate, the range in nondecision time, and the range in starting point . This 25-parameter model had to fit correct and error RT distributions and accuracy, simultaneously, for all 25 conditions. To anticipate, the model fit the data well with selective influence, something that Rafiei and Rahnev claimed the model could not do. Drift rate changed only across stimulus contrast conditions and not speed-accuracy conditions, and boundary separation, nondecision time, and the probability of fast guesses changed only across speed-accuracy conditions and not stimulus contrast conditions.20. The quantile RTs and parameter values of the model were used to generate the predicted cumulative probabilities of a response by that quantile RT. Subtracting the cumulative probabilities for each successive quantile from the next higher quantile gives the expected proportion of responses between adjacent quantiles (πi). The observed proportion of responses between adjacent quantiles is pi = 0.1. The model was fit by minimizing the G-square multinomial maximum likelihood statistic G2 = 2 Σ N pi ln(pi/πi), where N is the number of observations for the condition. This statistic is equal to twice the difference between the maximum possible log likelihood and the log likelihood predicted by the model (because ln(p/π) = ln(p) − ln(π)).The model was fit using 9 quantile RTs, the 0.1, 0.2, 0.3,…, and 0.9 quantiles20, there were 10 degrees of freedom for each distribution because there are 10 bins outside and between the 0.1, 0.2, 0.3, …, 0.9 RT quantiles for both correct and error distributions. The total probabilities for each pair of correct and error RTs must add to 1, so the number of degrees of freedom for each condition, with correct and error RT distributions, is 19 (=20–1) giving 475 degrees of freedom to be explained by the 25 parameters of the model. There were two modifications for fitting the data. One was that we set the probability of fast guesses to zero if the proportion was less than 0.1. When the estimated proportion of fast guesses was so small, then for conditions with small error rates, there were sometimes mispredictions because these error conditions were not influential in determining the proportion of fast guesses. Setting the proportion to zero corrects this bias. The other modification was that the values of boundary separation and nondecision time were set equal for the two highest speed-stress conditions. This was done because for some of the subjects, the probability of fast guesses was very high (over 0.98) for the highest speed-stress condition which means that these parameters were identified poorly because of the small numbers of error responses (2%). The fits with parameters in Table With 9 quantile RTs to represent correct and error RT distributions for the 25 conditions21. The data are the x’s and the model predictions are the o’s. These plots provide information about how accuracy and the shapes of RT distributions change across the contrast conditions. The shapes can be seen by drawing equal-area rectangles between the quantile RTs, as shown in the top middle panel of Fig. We show the fits of the model to the data in several ways. First, Fig. There are two misses between predictions and data. The first is a miss between predictions and data for error RT quantiles in the medium speed-stress condition for the highest-accuracy stimulus contrast condition. The model misses these extreme errors likely because there are low numbers of these errors and so they receive little weight in the model fitting. The second miss is for the 0.1 quantile RTs for the highest speed-stress conditions. The empirical 0.1 quantile RTs are lower than the predictions in Fig. The second way we display fits of the model to data is shown in Fig. Figure Figure 22. This is because the G-square statistic is a function of the number of observations and small deviations between theory and data are magnified as the number of observations increases, leading to significant values.The G-square statistic that is minimized in fitting the model to data is asymptotically distributed as chi-square and so the values from fits to data can be compared with the critical value of chi-square. For 450 degrees of freedom (475–25), the critical value at the 0.95 level is 500.5. The mean value from the fits to the data is 654.4 which is larger than the critical value. However, examination of other diffusion model fits with this many data points per subject (close to 5000 observations per subject) has found that a value between one and two times the critical value represents quite good fits18 has a model for simple RT that was composed of a mixture of a rapid stimulus detection process and a slower level detection process. This detection model might be used here instead of the normal, but like the normal, it would miss the leading edge of the RT distributions when there are RTs too short to be due to detection of the stimulus onset . The mixture model gives good, quantitative matches with this pattern of data . Better measures are quartile skewness or Pearson’s skewness measures. Ratcliff found that the skewness measure did not correlate highly with quartile skewness or Pearson’s skewness measures (which correlated with each other) using Monte Carlo simulations. Fourth, there is a question as to how some of the quantities might be calculated. One could compute an overall SD over all the data for a subject or compute a SD for each subject in each experimental condition and average those.Although the patterns of results in Figs. Because the measures that Rafiei and Rahnev propose as benchmarks are quite variable for any individual with potentially large effects of outliers, we argue that this makes them less useful as quantitative benchmarks. Also, because the unusual patterns of results occur because of extensive fast guessing, we argue that this makes them less useful as qualitative benchmarks. But most importantly, the mixture model produces the qualitative U-shaped patterns of results that Rafiei and Rahnev argued showed failure of the diffusion model.1.No human subjects were involved or enrolled for this article. All data were from a previously published article1. The model assumes a simple normal distribution for fast guesses and a diffusion process for discriminative responses. It fit all aspects of the data for individual subjects including the bimodal RT distributions for some subjects, correct and error RT distributions, and accuracy as a function of both stimulus contrast and speed-accuracy conditions. This was done with considerable model constraint: There was the same guessing proportion for all stimulus contrast conditions for each speed-accuracy condition (as well as different boundary separation and nondecision times for each speed-accuracy condition), and there were different drift rates for each stimulus contrast condition but these were the same over all the speed-accuracy conditions. All in all, there were 475 degrees of freedom in the data explained by 25 model parameters.In the research here, we fit the mixture model to the data from Rafiei and Rahnev5. This means that we should expect a mixture model to account for their data and the analyses in this article show that it does, providing a good quantitative and qualitative account of their data.Rafiei and Rahnev claimed that the standard diffusion model could not account for their data, but their data are contaminated by responses so fast that they could not have come from decision processes that a diffusion model was designed to represent. The history of research with RT measures has made it extremely clear that mixture models are the most appropriate for data that include fast guesses23, but later they were found to affect both boundary separation and nondecision time24. If speed is stressed to a high degree and fast guessing is avoided, subjects may encode stimulus information to a lesser degree and drift rates may be lower25. In Rafiei and Rahnev’s experiment, the mixture model provided excellent fits with selective influence.Rafiei and Rahnev argued that the diffusion model fails to show selective influence, but in the fits presented here, selective influence was found. Stimulus contrast affected only drift rate and the speed-stress manipulation affected boundary separation, nondecision time, and the proportion of fast guesses but it did not affect drift rates. Early in development of the diffusion model, speed-accuracy manipulations were assumed to affect only boundary separationRafiei and Rahnev admitted that there might be other model-based approaches that could account for their data, but they did not evaluate them. Here we implemented a mixture model and found it provided a compact explanation of all the data. The conclusion is that the diffusion model can easily and accurately handle speed-accuracy stress with the addition of a fast-guess process, a process that has been part of research on RTs since the 1960’s.


Combinatorial chemistry invented nearly 40 years ago was welcomed with enthusiasm in the drug research community. The method offered access to a practically unlimited number of new compounds. The new compounds however are mixtures, and methods had to be developed for the identification of the bioactive components. This was one of the reasons why the method could not providethe expected cornucopia of new drugs. Among the different screening methods, two approaches seem to offer the best results. One of them is based on the intrinsic property of the combinatorial split and pool solid‐phase synthesis: One compound forms on each bead of the solid support. Different methods have been developed to encode the beads and identify the structure of compounds formed on them. The most important method applies DNA oligomers for encoding. As a second approach in screening, DNA‐encoded combinatorial libraries are synthesized omitting the solid support and the mixtures are screened in solution using affinity binding methods. Libraries containing billions and even trillions of components are synthesized and successfully tested, which led to the identification of a significant number of new leads. Combinatorial technology comprises the synthesis of a mixture containing a high number of compounds in one procedure and screening the mixture also in one procedure. The left part of the image shows a two‐step synthesis of a nine‐member library using three building blocks and three DNA codes in both steps. The central part shows screening the library by affinity‐based binding. The non‐binding molecules are washed away, and the code of the binding molecule is amplified then sequenced. The invention was described in a document notarized in 1982.“The essence of the proposal is that instead of one by one synthesis of peptides, peptide mixtures should be prepared containing several hundred or several thousand peptides in approximately 1 to 1 molar ratio, and these peptide mixtures should be submitted to screening tests. It will be shown that on this way much labor can be saved both in the synthetic work and in the screening experiments.”The copy of the full Hungarian document and the English version is a part of the Supplementary Materials. The basic idea of the invention is the use of compound mixtures in both synthesis and screening. The mixtures are so important that if a mixture is used in a synthesis, the procedure is inevitably combinatorial.Split of the solid support into equal portions;couple an amino acid to each portion;pooling and thoroughly mixing the portions.By replacing the single reactants used in conventional chemical syntheses with mixtures, millions and even billions of compounds can be easily synthesized. Both reactants can be replaced by mixtures. In the screening of mixtures, it is advantageous if the components of the library are present as close to equimolar quantities as possible. This was the reason for using only one mixture in the “split and pool” methodWhen a single reactant is coupled with a mixture of compounds, the number of newly formed compounds is equal to the number of components in the original mixture. As a consequence, the number of compounds increases exponentially with the number of coupling steps (cycles). This is the reason why combinatorial technology is so efficient. The best characterization of efficiency is the ratio of the number of the synthesized compounds to the number of couplings in the procedure. The ratio in conventional chemical synthesis is one or less, in the parallel synthesis, it is around a hundred, and in combinatorial synthesis, it is around millions.The exceptionally high efficiency leads to enormous savings in pharmaceutical research. According to Goodnow's estimation,In the beginning, peptide mixtures were synthesized. Since in the second operation of the cycles the coupling is done with only one amino acid, only one compound forms on each bead  libraries).The use of compound mixtures in the syntheses has a serious disadvantage: The structure of the produced compounds is unknown and finding a bioactive compound in a mixture of millions of peptides seemed to be similar to the task of finding a needle in a haystack. To overcome this difficulty, different deconvolution methods had been introduced.The first such method is described in the 1982 document and can be used for screening of libraries cleaved from the beads of the support. The method was independently described by Erb et al. and named it “recursive deconvolution.”Another combinatorial method published by Fodor et al. does not need deconvolution. The library is synthesized on the surface of solid plates, and the position of compounds on the plate defines their identity.2In the screening of OBOC libraries, the one‐bead‐one‐compound nature of the split‐and‐pool method is exploited. In one approach, the peptide libraries are incubated with a fluorescence dye‐labeled target protein, then the beads carrying the label are manually picked, and the peptides are sequenced by Edman degradationCha et al. automated the process from synthesis to screening. They applied Titan 357 bought from aapptec for automatic synthesis and used automatic MS (Mass Spectometry) and tandem mass spectrometry for data acquisition.The OBOC libraries have an advantage when compared to phage display librariesIn the other approach, the BBs and their coupling orders are encoded into the beads. Ohlmeyer et al. published a binary encoding methodBrenner and Lerner suggested the application of DNA oligomers for encoding in solid‐phase split and pool synthesis.In synthesizing organic OBOC libraries, organic solvents are commonly used, while in building the DNA oligomers, an aqueous medium is needed.Liu et al. introduced topologically segregated bifunctional beads, which are made by biphasic solvent strategy. The testing molecules are on the outer layer, while the coding tags occupy the interior of the beads and do not interfere with screening. The coding tags are peptides containing unnatural α‐amino acids.The OBOC libraries are easily synthesized, and good methods are available for screening. As a consequence, they are widely used in drug research. Dealing with individual beads in screening, however, slows the process and so it is less efficient than the use of DNA‐encoded soluble libraries discussed in Section 3.3Originally DNA‐encoding was proposed to encode the beads of OBOC libraries. In 2000, however, a significant innovation was described. Harbury and Halpin omitted the solid support in the synthesis of DNA‐encoded libraries and replaced it with the encoding DNA oligomers and ended up with soluble libraries.Another gain of the soluble DNA‐encoded libraries was the possibility to apply solution‐phase affinity‐based binding experiments in screening. It was also very important for the introduction of next‐generation DNA sequencing that made it possible to determine the identity and quantity of all binding molecules in a single process and at a low cost.A comparison of the most important operations performed in combinatorial technology and those of the DNA‐encoding procedures below clearly shows the novelty added by DNA‐encoding. The differences appear in bold.Dividing the solid support into portions;coupling a different BB to each portion;mixing the portions;repeating the 1–3 operations;screening the final mixture.Operations in combinatorial technologyDividing the solid support into portions;coupling a different BB to each portion;coupling an encoding DNA oligomer to each portion;mixing the portions;repeating the 1–4 operations;identifying the bioactive molecules by PCR (Polymerase chain reaction) amplification and sequencing.screening the final mixture and Operations in the DNA‐encoded combinatorial technology3.1A few years after the turn of the millennium, different types of DNA‐encoded soluble small molecule organic libraries were published.3.1.1DTSThe DNA strand has annealing regions for attachment of the second, third, and so forth BBs. The second library contains a BB attached by a cleavable bond to the DNA coding region. When the two libraries are mixed, the coding region of the second BBs anneals with the annealing region on the strand on the template library. After annealing, the second BB is in proximity to the first one and can make a covalent bond with it. After cleaving the bond between the BB and its coding region, DECL is formed.DTS allows the translation of libraries of DNA sequences into libraries of small molecules (peptide macrocycles) and offers the possibility to apply evolution‐based approaches. The DNA instruction sequences are mutated and reused during multiple rounds of translation, selection, and amplification to produce products with improved properties. O'Reilly et al. attempted to use organic BBs in DTS.3.1.2The synthesis based on sequence encoded routing is described by Halpin and HarburyIn the synthesis of a small molecule trimer organic library, for example, DNA oligomers are prepared for encoding the BBs. Then from these oligomers using the split‐and‐pool method, a template library (library of genes) is constructed that directs the synthesis of the DECL. In the template library, there is a unique DNA‐encoding sequence for identifying every component of the encoded organic library sowing the identity of the BBs and their coupling order Figure .Resin‐bound anticodons are also prepared, one for each BB‐code. The anticodons of the first coupling positions are mixed one by one with the template library, and after hybridizing with the proper member of the library, they are separated by filtration from the rest of the library and then coupled with the proper BB. After finishing with the coupling of the BBs of the first coupling position, the library members are eluted, mixed, and the procedure is followed with the second, third, and so forth position anticodons and BBs. After the final round of hybridization, separation, coupling, and elution, the encoded library can be submitted to affinity‐based binding, PCR amplification, and sequencing.The sequence encoded routing  can also be used as an evolution‐based approach and to improve the product by multiple rounds of mutation, translation, selection, and amplification,The sequence encoded routing and the DTS are elegant methods showing how natural evolution can be translated into a chemical system.3.1.3The use of yoctoliter‐size reactors for the synthesis of DECLs was described by Hansen et al.3.1.4Scheuermann and Neri.The structure of a member of a dual‐pharmacophore combinatorial library is shown in Figure By mixing the two sets of sub‐libraries, the single set of the double‐stranded dual pharmacophore library forms by hybridization. If each of the two sub‐libraries contains 1000 components, mixing them in a combinatorial way leads to a 1,000,000 component final double‐stranded library. Each component of the library contains two BBs and the code of the two BBs. If both BBs are bound to the target protein, a synergetic effect may occur. Hits can be identified by affinity‐based binding.3.1.5In pharmaceutical research, the most often used DECLs are the single pharmacophore libraries that are constructed according to the combinatorial technology with an added modification. In the coupling cycles of the synthesis, in addition to coupling with the BBs, the DNA‐encoding oligomer is also elongated with the code of the BBs. The structure of a component of the library is demonstrated in Figure ” filed in December 2006 by nearly 30 inventors. Mannocci et al.Such a library was first described in a patent application of the Danish Nuevolution A/S entitled “Enzymatic encoding methods for efficient synthesis of large librariesTaking into account the Lipinski rule, usually small organic molecules are synthesized. If three sets of BBs are used in the synthesis, each set containing 1000 BBs, a 1 billion member library forms.4Screening involves affinity‐based methods, PCR amplification, sequencing of the encoding DNA oligomers, and evaluating the results.In affinity‐based methods, the target proteins are immobilized on a solid support or can be used as solutions. It is very important that DNA‐encoding makes it possible to use both the library and the target protein in very low quantities. In a screening of the 4 billion member library of Deng et al. for example, the sum of the molar quantities of components in the affinity test was only 5 nmol. . The quantity of the target protein was also low at 10 μg.The members of the library are binding to the protein according to their affinity. The rest is washed away. The remaining part is submitted to PCR amplification and sequencing.Sequencing of the encoding oligonucleotides of the components of the mixture is done in a single fast process. The result is not only the identity of the binding compounds but the sequence counts also contain information about their relative quantity. The results can be visualized by plotting the compounds in 3D space.In the area of screening, an important new development was recently presented: screening of DECLs in living cellsAcinetobacter baumannii and Staphylococcus aureus and additional leads by screening 42 targets from Mycobacterium tuberculosis. Examples are found in Table The automatic parallel screening applied by Machutta and his more than 60 co‐authors5Combinatorial libraries as OBOC libraries and particularly in their DNA‐encoded form are extensively used in drug research. Pharmaceutical companies and academic research groups have already introduced combinatorial technology with DNA‐encoding in their drug discovery programs and are identifying more and more drug candidates. DNA‐encoding allows the full potential of combinatorial technology to be exploited to increase the number of new drugs. The costs of synthesis and screening are only small fractions of that of the conventional synthesis and HTS (High‐throughput screening)DNA‐encoding, however, has drawbacks, too. Many organic synthetic methods are excluded from the synthesis of DECL because the reaction conditions are incompatible with DNA. The newly reported DNA‐compatible reactions are expanding the usability of DNA‐encoding,Another problem is that the encoding DNA oligomer is shading one part of the surface of the encoded compound. MacConnell et al. developed an off DNA‐encoded library screening method to solve the problem.To eliminate the shading property of the DNA‐encoding oligomers, the best would be to use combinatorial libraries without any encoding and find a method that can read the structure of the screened compounds that have an affinity to the targets without having any attached label. Of course, this seems impossible today, but what today is impossible in the future may be routinely used. The synthesis of billions of compounds seemed also impossible before 1982. So there is room for innovation.The above‐mentioned two methods: screening in living cells and automatic parallel screening, promises a big leap in the speed and efficiency of pharmaceutical research, and it is expected to result in an increasing number of novel drugs to cure diseases in the near future. In addition, the automatic parallel screening helps to bring closer an old dream of the inventor of combinatorial technology: screening all combinatorial libraries against all available targets.This short overview shows that combinatorial technology after nearly 40 years of its invention is still an eminent player in the drug discovery area.The author declares no conflict of interest.Árpád Furka wrote this paper and prepared the figures.Not applicable.Supporting InformationClick here for additional data file.


Airship Aviation in Germany which consisted of four short films using found footage of zeppelin flights, of which the earliest images stem from around 1904 and the latest from 1937, the moment of the “Hindenburg disaster.” This article explores how Terveen sought to shape the political landscape of history teaching in the new Federal Republic of Germany by first setting up nation-wide visual archives to host historical film documents, and secondly by seeking to improve the political education of a new generation of young Germans with the aid of the moving image.Has the history of film digitization ever been incorporated in questions of evidence and knowledge production? The digitization of thousands of films from the former Institute for Scientific Film (IWF) that is currently underway gives an occasion to think about the provenance and reuses of filmic images as well as the ways in which they claim to produce scientific  evidence. In the years between 1956 and 1960, the German Social Democrat, historian and filmmaker Friedrich “Fritz” Terveen initiated a film series that used historical found film footage in order to educate university students about contemporary history. The first small series of films was entitled  Visual History of National Socialism by Gerhard Paul in the German daily newspaper Frankfurter Allgemeine Zeitung (FAZ), implying that perpetuating and re-editing visual material of former Nazi propaganda only leads to new problems with regard to the (re-)circulation and (re-)idolation of these images , which is housed at the German National Library of Science and Technology (TIB) in Hanover and is partially accessible online.2Not many studies have looked at historical film footage that was re-edited for scientific purposes and that was intended to produce knowledge within the discipline of history and the history of science and technology  at the Institute for Scientific Film  in Göttingen.Reichsanstalt für Film in Wissenschaft und Unterricht, hereafter RWU).Institut für Film und Bild in Wissenschaft und Unterricht, FWU) which distributed film for use in primary and secondary schools, IWF films were made available exclusively for research and teaching at universities  and was thus obtained after the Second World War by the Federal Film Archive. In particular, the film footage of the explosion and crash of the LZ 129 Hindenburg on May 6, 1937 in Lakehurst has entered the cultural memory of aviation history through its distribution via newsreels and later via documentation and excerpts in museums . Based on this film material, the following questions are to be discussed: how did historians of the war generation view historical film recordings of the recent past and how were questions of usability and reception of the films negotiated? What sort of understanding of historical evidence did historians like Fritz Terveen have, and what were their expectations of the films? It becomes apparent that there were divergent views within the IWF, which led to a renegotiation of the historical-critical content of the films by changing accompanying texts and metadata of the films.Despite the apparent ruptures with the Nazi era, continuities among personnel and institutional decision-making persisted. For example, Gotthard Wolf, who had been the director of the Technical Research Film Department at RWU, became the first director of the IWF Kühn : 53. Thems Frank . The serAirship Aviation in Germany was part of a larger film collection at the IWF, entitled Film Documents on Contemporary History (Filmdokumente zur Zeitgeschichte). This title is indebted to the institute’s concept of producing “documentation films” (Dokumentationsfilme). This term was deliberately chosen by Wolf, as opposed to the usual term “documentary films,” implying that these films documented processes of nature, history, social life or technical approaches in a style similar to the way in which a scientific observer in the field or in the laboratory does  at the IWF since its founding Forster : 351–352Film Documents on Contemporary History (Filmdokumente zur Zeitgeschichte) was part of the IWF’s large-scale project Encyclopaedia Cinematographica (EC). The basic idea of this encyclopedia of films was to capture in film all forms of life, movement and behavior in nature and even in technical processes.Filmdokumente in 1959. As for the historical film documents, initially, only “valuable” original recordings of events and personalities from the years 1895–1933 were published for use in research and university teaching  on the use of historical film documents from the Encyclopaedia Cinematographica from 1956 gives an idea of what it meant to fit historical found footage material into the rigid structure of the EC: “Each of the film units presented in the EC […] has been worked out as an individual source piece, for which a reference to the other historical sources and statements must be made or taken into account in order to clarify the facts contained therein.”Bewegungsdauerpräparat), which recorded movement in a broader sense and enabled analysis  which consisted of interviews with renowned artists, scientists and public figures , the accompanying script, which Terveen had created himself, was also of great importance for the audience’s perception of the film. It contains detailed background information on the origin of the material, the editing of the sequences and descriptions of the image content . In addition, the source material was heavily damaged due to in part to improper storage. As a result, the film had shrunken and had to be regenerated by a special process in order for it to be able to be copied at all. The image effect was severely impaired by the numerous cuts, aging, and copying of the material. Not least because of the poor image quality of the film material, the accompanying text played a decisive role in the reception of the film. Following the source evaluation, Terveen gives a detailed description of the images in his text, which he partly supplements with the origin of the footage as well as extensive technical details about the airship shown in each image Terveen a: 4. Fol Gunning , the texG 41 – lz 129 “Hindenburg” indicates that the film was not among the ones often borrowed from the IWF.The film and text together form a source-critical edition that was intended exclusively for distribution at universities. Each film box, like the one shown in Fig. film documents were among the most sought-after films—at least until 1960, the year when Terveen left the institute. Even though there were no overall statistics kept on the distribution and sales of historical films alone, there was a tendency for demand for these to increase over time. For example, a statistical report from 1959 shows that out of a total stock of 26 film documents, a total of 88 uses were made of them between 1955 and 1959, which corresponded to 70% of the use of the total stock. (Landesbildstellen), the FWU, and other universities and educational institutions. For Terveen, this was a clear signal to make the series accessible to groups outside the universities. The figures also show that the IWF slowly abandoned its goal of distributing films for exclusively research purposes.However, according to the statistics, the film documents get their visual evidence, or the sense of “truthfulness” to which Terveen referred? The early films about airship travel shared neither an aesthetic nor a narrative approach. The film Zeppelin Luftschiffe 1906–1910(g 24) consists of a montage of individual film snippets, laboriously held together by short intertitles. As Gregg Mitman and Kelley Wilder have argued, the power of (film) images lies in their indexicality, or the fact that they are integrated into a system of references, for instance by being archived and thus retrievable, referenceable and citable  entitled “Should We Show Hitler to the Youth?” Of course, these sources needed to be screened and explored by experts beforehand. The IWF had a very important role to play in this respect: in 1946 it was commissioned by the military government in Hamburg—still operating under the Research Department of the Institute for Film and Image—to clean up the film archives of all image locations in the British zone in accordance with the censorship lists that were issued by the British Allies.Film Documents, in the late 1950s Terveen sent out questionnaires to student working groups asking them to provide information on whether the film they had ordered was suitable as a working tool and how the films were to be assessed in connection with historical-political instruction. In addition, he asked whether the film used was examined in isolation or rather compared with other sources. Finally he also solicited criticism and suggestions for improvement. The responses to these questionnaires revealed that, generally speaking, students welcomed the films as a further aid in historical-political lessons. However, Terveen also received much criticism with respect to the presentation of the films themselves. Respondents often complained that the material seemed too incoherent and fragmentary to form a comprehensive impression of the events. Terveen replied that the film documents were often not self-contained films, but rather “remnants of tradition” that were not further processed because this would be an intervention into historical research  and finally the film ends with “the Lakehurst disaster” on May 6, 1937. The airship stands still in the air for a few seconds before a fire at the stern appears; finally, it sinks to the ground where it is consumed by flames —is given. It only appears in the film credits. The accompanying text by Rathjen, in turn, refers exclusively to the technical history of airship travel—explaining details of individual aircraft models and the journeys and the origins of the crash. Thus, the accompanying text does not supplement the film, nor does not classify it, but rather leaves the pictures and their impact to stand on their own. Rathjens’ text positions the film into the narrative of “great masterpieces” that was customary at the Deutsches Museum at the time, leaving the technical developments without social and political-historical contextualization . Interestingly enough, Terveen was not part of the editorial board, although the topics tackled in the book were compatible with the ideas he had developed for how to present images from the recent past . It would seem that television in the 1970s had found a more reflective solution to present problematic film material to students than the IWF had in the 1950s. Of course, the political atmosphere in West Germany had undergone significant changes between 1957 and 1974. A broad social and intellectual movement within the country had revealed Germany’s problematic treatment of the Nazi past and sensitized the public; audiences were prepared to treat these films responsibly by performing critical evaluations of images depicting terror, war and prosecution (for example Kraushaar About 15 years after Terveen had left the IWF to assume his position at the Airship Aviation in Germany was among the films that were chosen for digitization, along with the three other films from the series. As we look into the digitized film versions and the archival material that is connected to the genesis of the zeppelin films, it becomes clear that that the series had completely changed its context of usage in this new setting in the AV-Portal of the TIB, where all digitized IWF films are hosted today. Here, the fact that the zeppelin film series appeared in the history section of the IWF is completely omitted.Meanwhile in 2001, the IWF began its first digitization project, funded by the German government. The aim of the project was to improve the quality of “audiovisual knowledge” by increasing media competence as well as improving the supra-regional provision of the films (Beuers & Hanisch G 24 and G 41: while Terveen hosted these films within a series of contemporary history footage material, the zeppelin mini-series now appears in the context of the history of technology, which was not at all Terveen’s intention. This altered contextualization is partly due to the fact that the TIB is a technical institution and seeks to address academics with a background in the technical sciences. Nevertheless, presenting historical film documents like the series on airship aviation in Germany demands transparent decisions about both the content and context of the films so that they can be used by film historians, historians of science and academics from other fields alike. For the second time in the history of Airship Aviation in Germany, the films are found among films from other disciplines. Initially, within the context of the 1950s film encyclopedia, the zeppelin footage was found alongside biological films on movement and behavior, later it found a home on a platform made for technical films with annotations. However, this presentation is not fully adequate to contextualize the material: an optimal solution would embed the films in a curated platform that provides background information on each of the films, puts the images in dialogue with each other and offers further reading on each piece. Such databases already exist, for example at the Fortunoff ArchiveFilm Documents in the future.Thus, with the digitization and online publication of footage material new questions of reuses and reinterpretations arise. One is forced to consider what type of “audiovisual knowledge” is produced by a video platform like the AV-Portal. Is the content arranged in a user-friendly manner? Is the content curated so that a critical viewer might know where to seek out more information? The short answer to these questions is: no. This is in part due to the fact that the platform is not merely made for historical film documents but rather for all sorts of audiovisual content for academic use, of which the IWF Collection is only one part. Malte Hagener has convincingly argued that platforms such as Vimeo, YouTube and Dailymotion disadvantage content that lies beyond the mainstream, including historical video footage, because the algorithms are not optimized to privilege these films Hagener : 186–187