| 1. |
- Brolin, Karin, 1974, et al.
(författare)
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Aiming for an average female virtual human body model for seat performance assessment in rear-end impacts
- 2015
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Ingår i: The 24th ESV Conference Proceedings.
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Konferensbidrag (refereegranskat)abstract
- The female part of the population suffers more Whiplash Associated Disorders (WAD) in car crashes than males. Several studies have illustrated the need to consider the female population when developing and assessing the WAD prevention performance of advanced restraint systems in rear-end collisions. Presently only one crash test dummy is available, the average sized male BioRID. Recently a virtual dummy model of an average female, EvaRID, was developed and used in rear impact simulations. The results stressed the need for models representing the female part of the population, as well. Virtual crash simulations have become essential in traffic safety and with models of both an average male and female, further steps in addressing improved assessment of WAD prevention can be taken. The present paper presents a starting point of research aiming to develop an open-source average female Finite Element (FE) model with an anatomically detailed cervical spine. This paper provides a review of the literature to identify gender specific neck biomechanics and anatomical differences, followed by a review of published FE models of the cervical spine. Data on vertebral body dimensions (height, width, depth, spinal canal diameter, facet joint angles) have been compiled from biomechanical literature. Significant gender differences exist for the vertebral body depth and width, the spinal curvature in the seated posture, and the spinal stiffness and range of motion. All have the potential to influence the outcome of an impact and should be accounted for in the development of WAD prevention. The review of FE models of the cervical spine presented 17 models based on male geometry but only one model scaled to represent a female. An overview of the models are given with respect to the solver, geometry source, number of elements, and implementation of the facet joints, ligaments, and muscles. It is recommended that an average female model is developed with focus on; 1) the shape of the female vertebral body, especially the depth and width that provides less support area than for males,2) defining the spinal curvature representative of seated female volunteers who generally display less lordosis than males, 3) the dimensions of the spinal ligaments, rather than the material properties, to capture the larger range of motion and less spinal stiffness of female subjects compared to males, and validation to female volunteers and PMHS tests for range of motion, while failure prediction seem less gender sensitive.
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| 2. |
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| 3. |
- Hasper, Thomas Berg, et al.
(författare)
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Water use by Swedish boreal forests in a changing climate
- 2016
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Ingår i: Functional Ecology. - : Wiley. - 0269-8463 .- 1365-2435. ; 30:5, s. 690-699
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Tidskriftsartikel (refereegranskat)abstract
- The rising levels of atmospheric carbon dioxide concentration ([CO2]) and temperature have the potential to substantially affect the terrestrial water and energy balance by altering the stomatal conductance and transpiration of trees. Many models assume decreases in stomatal conductance and plant water use under rising [CO2], which has been used as a plausible explanation for the positive global trend in river run-off over the past century. Plant water use is, however, also affected by changes in temperature, precipitation and land use, and there is yet no consensus about the contribution of different drivers to temporal trends of evapotranspiration (ET) and river run-off. In this study, we assessed water-use responses to climate change by using both long-term monitoring and experimental data in Swedish boreal forests. Historical trends and patterns in ET of large-scale boreal landscapes were determined using climate and run-off data from the past 50 years, while explicit tree water-use responses to elevated [CO2] and/or air temperature were examined in a whole-tree chamber experiment using mature Norway spruce (Picea abies (L.) Karst.) trees. The results demonstrated that ET estimated from water budgets at the catchment scale increased by 18% over the past 50 years while run-off did not significantly change. The increase in ET was related to increasing precipitation and a steady increase in forest standing biomass over time. The whole-tree chamber experiment showed that Norway spruce trees did not save water under elevated [CO2] and that experimentally elevated air temperature did not increase transpiration as decreased stomatal conductance cancelled the effect of higher vapour pressure deficit in warmed air. Our findings have important implications for projections of future water use of European boreal coniferous forests, indicating that changes in precipitation and standing biomass are more important than the effects of elevated [CO2] or temperature on transpiration rates.
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| 4. |
- Linder, Mats, 1983-, et al.
(författare)
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"Adapted Linear Interaction Energy" : A Structure-Based LIE Parametrization for Fast Prediction of Protein-Ligand Affinities
- 2013
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 9:2, s. 1230-1239
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Tidskriftsartikel (refereegranskat)abstract
- We present a structure-based parametrization of the Linear Interaction Energy (LIE) method and show that it allows for the prediction of absolute protein-ligand binding energies. We call the new model "Adapted" LIE (ALIE) because the a and beta coefficients are defined by system-dependent descriptors and do therefore not require any empirical gamma term. The best formulation attains a mean average deviation of 1.8 kcal/mol for a diverse test set and depends on only one fitted parameter. It is robust with respect to additional fitting and cross-validation. We compare this new approach with standard LIE by Aqvist and co-workers and the LIE + gamma SASA model (initially suggested by Jorgensen and co-workers) against in-house and external data sets and discuss their applicabilities.
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| 5. |
- Linder, Mats, 1983-, et al.
(författare)
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Computational design of a Diels-Alderase from a thermophilic esterase : the importance of dynamics
- 2012
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 26:9, s. 1079-1095
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Tidskriftsartikel (refereegranskat)abstract
- A novel computational Diels-Alderase design, based on a relatively rare form of carboxylesterase from Geobacillus stearothermophilus, is presented and theoretically evaluated. The structure was found by mining the PDB for a suitable oxyanion hole-containing structure, followed by a combinatorial approach to find suitable substrates and rational mutations. Four lead designs were selected and thoroughly modeled to obtain realistic estimates of substrate binding and prearrangement. Molecular dynamics simulations and DFT calculations were used to optimize and estimate binding affinity and activation energies. A large quantum chemical model was used to capture the salient interactions in the crucial transition state (TS). Our quantitative estimation of kinetic parameters was validated against four experimentally characterized Diels-Alderases with good results. The final designs in this work are predicted to have rate enhancements of a parts per thousand 10(3)-10(6) and high predicted proficiencies. This work emphasizes the importance of considering protein dynamics in the design approach, and provides a quantitative estimate of the how the TS stabilization observed in most de novo and redesigned enzymes is decreased compared to a minimal, 'ideal' model. The presented design is highly interesting for further optimization and applications since it is based on a thermophilic enzyme (T (opt) = 70 A degrees C).
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| 6. |
- Linder, Mats, 1983-
(författare)
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Computational enzyme design : Advances, hurdles and possible ways forward
- 2012
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 2:3
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Forskningsöversikt (refereegranskat)abstract
- This mini review addresses recent developments in computational enzyme design. Successful protocols as well as known issues and limitations are discussed from an energetic perspective. It will be argued that improved results can be obtained by including a dynamic treatment in the design protocol. Finally, a molecular dynamics-based approach for evaluating and refining computational designs is presented.
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| 7. |
- Linder, Mats, 1983-
(författare)
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Computational Studies and Design of Biomolecular Diels-Alder Catalysis
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Diels-Alder reaction is one of the most powerful synthetic tools in organic chemistry, and asymmetric Diels-Alder catalysis allows for rapid construction of chiral carbon scaffolds. For this reason, considerable effort has been invested in developing efficient and stereoselective organo- and biocatalysts. However, Diels-Alder is a virtually unknown reaction in Nature, and to engineer an enzyme into a Diels-Alderase is therefore a challenging task. Despite several successful designs of catalytic antibodies since the 1980’s, their catalytic activities have remained low, and no true artificial ’Diels-Alderase’ enzyme was reported before 2010.In this thesis, we employ state-of-the-art computational tools to study the mechanism of organocatalyzed Diels-Alder in detail, and to redesign existing enzymes into intermolecular Diels-Alder catalysts. Papers I–IV explore the mechanistic variations when employing increasingly activated reactants and the effect of catalysis. In particular, the relation between the traditionally presumed concerted mechanism and a stepwise pathway, forming one bond at a time, is probed. Papers V–X deal with enzyme design and the computational aspects of predicting catalytic activity. Four novel, computationally designed Diels-Alderase candidates are presented in Papers VI–IX. In Paper X, a new parameterization of the Linear Interaction Energy model for predicting protein-ligand affinities is presented.A general finding in this thesis is that it is difficult to attain large transition state stabilization effects solely by hydrogen bond catalysis. In addition, water (the preferred solvent of enzymes) is well-known for catalyzing Diels- Alder by itself. Therefore, an efficient Diels-Alderase must rely on large binding affinities for the two substrates and preferential binding conformations close to the transition state geometry. In Papers VI–VIII, we co-designed the enzyme active site and substrates in order to achieve the best possible complementarity and maximize binding affinity and pre-organization. Even so, catalysis is limited by the maximum possible stabilization offered by hydrogen bonds, and by the inherently large energy barrier associated with the [4+2] cycloaddition.The stepwise Diels-Alder pathway, proceeding via a zwitterionic intermediate, may offer a productive alternative for enzyme catalysis, since an enzyme active site may be more differentiated towards stabilizing the high-energy states than for the standard mechanism. In Papers I and III, it is demonstrated that a hydrogen bond donor catalyst provides more stabilization of transition states having pronounced charge-transfer character, which shifts the preference towards a stepwise mechanism.Another alternative, explored in Paper IX, is to use an α,β -unsaturated ketone as a ’pro-diene’, and let the enzyme generate the diene in situ by general acid/base catalysis. The results show that the potential reduction in the reaction barrier with such a mechanism is much larger than for conventional Diels-Alder. Moreover, an acid/base-mediated pathway is a better mimic of how natural enzymes function, since remarkably few catalyze their reactions solely by non-covalent interactions.
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| 8. |
- Linder, Mats, 1983-, et al.
(författare)
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Stepwise Diels-Alder : More than Just an Oddity? A Computational Mechanistic Study
- 2012
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:15, s. 6563-6573
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Tidskriftsartikel (refereegranskat)abstract
- We have employed hybrid DFT and SCS-MP2 calculations at the SMD-PCM–6-311++G(2d,2p)//6-31+G(d) level to investigate the relationship between three possible channels for forming a Diels–Alder adduct from a highly nucleophilic diene and moderately to highly electrophilic dienophiles. We discuss geometries optimized using the B3LYP and M06-2X functionals with the 6-31+(d) basis set. The transition states and intermediates are characterized on the basis of geometric and electronic properties, and we also address the possibility of predicting detectability of a zwitterionic intermediate based on its relative stability. Our results show that a conventional Diels–Alder transition state conformation yields intermediates in all four investigated cases, but that these are too short-lived to be detected experimentally for the less activated reactants. The stepwise trans pathway, beginning with a conjugate addition-like transition state, becomes increasingly competitive with more activated reactants and is indeed favored for the most electrophilic dienophiles. Addition of a trans diene leads to a dead-end as the trans intermediates have insurmountable rotation barriers that prohibit formation of the second bond, unless another, heterocyclic intermediate is formed. We also show that introduction of a hydrogen bond donating catalyst favors a stepwise pathway even for less activated dienophiles.
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| 9. |
- Östh, Jonas, 1983, et al.
(författare)
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A female head–neck model for rear impact simulations
- 2017
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 51, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- Several mathematical cervical models of the 50th percentile male have been developed and used for impact biomechanics research. However, for the 50th percentile female no similar modelling efforts have been made, despite females being subject to a higher risk of soft tissue neck injuries. This is a limitation for the development of automotive protective systems addressing Whiplash Associated Disorders (WADs), most commonly caused in rear impacts, as the risk for females sustaining WAD symptoms is double that of males.In this study, a finite element head and neck model of a 50th percentile female was validated in rear impacts. A previously validated ligamentous cervical spine model was complemented with a rigid body head, soft tissues and muscles. In both physiological flexion-extension motions and simulated rear impacts, the kinematic response at segment level was comparable to that of human subjects.Evaluation of ligament stress levels in simulations with varied initial cervical curvature revealed that if an individual assumes a more lordotic posture than the neutral, a higher risk of WAD might occur in rear impact. The female head and neck model, together with a kinematical whole body model which is under development, addresses a need for tools for assessment of automotive protection systems for the group which is at the highest risk to sustain WAD.
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| 10. |
- Östh, Jonas, 1983, et al.
(författare)
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A Female Ligamentous Cervical Spine Finite Element Model Validated for Physiological Loads
- 2016
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Ingår i: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 138:6
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Tidskriftsartikel (refereegranskat)abstract
- Mathematical cervical spine models allow for studying of impact loading that can cause whiplash associated disorders (WAD). However, existing models only cover the male anthropometry, despite the female population being at a higher risk of sustaining WAD in automotive rear-end impacts. The aim of this study is to develop and validate a ligamentous cervical spine intended for biomechanical research on the effect of automotive impacts. A female model has the potential to aid the design of better protection systems as well as improve understanding of injury mechanisms causing WAD. A finite element (FE) mesh was created from surface data of the cervical vertebrae of a 26-year old female (stature 167 cm, weight 59 kg). Soft tissues were generated from the skeletal geometry and anatomical literature descriptions. Ligaments were modeled with nonlinear elastic orthotropic membrane elements, intervertebral disks as composites of nonlinear elastic bulk elements, and orthotropic anulus fibrosus fiber layers, while cortical and trabecular bones were modeled as isotropic plastic-elastic. The model has geometrical features representative of the female cervical spine-the largest average difference compared with published anthropometric female data was the vertebral body depth being 3.4% shorter for the model. The majority the cervical segments compare well with respect to biomechanical data at physiological loads, with the best match for flexion-extension loads and less biofidelity for axial rotation. An average female FE ligamentous cervical spine model was developed and validated with respect to physiological loading. In flexion-extension simulations with the developed female model and an existing average male cervical spine model, a greater range of motion (ROM) was found in the female model.
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