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| 2. |
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| 3. |
- Maurichi, A, et al.
(författare)
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Reply to E. Hindié
- 2020
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 38:27, s. 3238-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Casolino, M., et al.
(författare)
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Cosmic ray measurements with Pamela experiment
- 2009
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Konferensbidrag (refereegranskat)abstract
- PAMELA is a satellite borne experiment designed to study with great accuracy cosmic rays of galactic, solar, and trapped nature hi a wide energy range (protons: 80 MeV-700 GeV, electrons 50 MeV-400 GeV). Main objective is the study of the antimatter component: antiprotons (80 MeV-190 GeV), positrons (50 MeV-270 GeV) and search for antinuclei with a precision of the order of 10(-8)). The experiment, housed on board the Russian Resurs-DK1 satellite, was launched on June, 15(th) 2006 in a 350 X 600 km orbit with an inclination of 70 degrees. In this work we describe the scientific objectives awl the performance of PAMELA in its first two years of operation. Data oil protons of trapped, secondary and galactic nature - as well as measurements of the December 13(th) 2006 Solar Particle Event - are also provided.
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| 5. |
- Bailey-Wilson, Joan E, et al.
(författare)
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Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
- 2012
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Ingår i: BMC Medical Genetics. - London : BioMed Central. - 1471-2350. ; 13, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
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| 6. |
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| 7. |
- Gladush, G. G., et al.
(författare)
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Studying the mechanisms of steel sheet perforation by the radiation of a continuous-wave fiber laser
- 2016
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Ingår i: Bulletin of the Russian Academy of Sciences: Physics. - 1062-8738 .- 1934-9432. ; 80:4, s. 393-396
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Tidskriftsartikel (refereegranskat)abstract
- Aspects of steel sheet perforation are studied experimentally. Calculations show that the mechanisms of thin sheet perforation change as the focal spot size is increased at a constant laser power. If the spot is small, the melt is removed and the film is disrupted by steel boiling in the spot center. With larger spots, the melt is removed by the force of gravity. The hole diameter grows along with the focal spot size and sheet thickness and is reduced upon an increase in laser power.
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| 8. |
- Lu, Lingyi, et al.
(författare)
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Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:4, s. 410-426
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD?=?1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD cores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS. These results will be useful in prioritizing future susceptibility gene discovery efforts in thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Sclafani, F., et al.
(författare)
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Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer : results of the EXPERT-C trial
- 2015
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 26:9, s. 1936-1941
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Tidskriftsartikel (refereegranskat)abstract
- Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.
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| 13. |
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| 14. |
- Stevanovic, D., et al.
(författare)
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Measurement invariance of the Childhood Autism Rating Scale (CARS) across six countries
- 2021
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Ingår i: Autism Research. - : Wiley. - 1939-3792 .- 1939-3806. ; 14:12, s. 2544-2554
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Tidskriftsartikel (refereegranskat)abstract
- The Childhood Autism Rating Scale (CARS) is a simple and inexpensive tool for Autism spectrum disorder (ASD) assessments, with evidenced psychometric data from different countries. However, it is still unclear whether ASD symptoms are measured the same way across different societies and world regions with this tool, since data on its cross-cultural validity are lacking. This study evaluated the cross-cultural measurement invariance of the CARS among children with ASD from six countries, for whom data were aggregated from previous studies in India (n = 101), Jamaica (n = 139), Mexico (n = 72), Spain (n = 99), Turkey (n = 150), and the United States of America (n = 186). We analyzed the approximate measurement invariance based on Bayesian structural equation modeling. The model did not fit the data and its measurement invariance did not hold, with all items found non-invariant across the countries. Items related to social communication and interaction (i.e., relating to people, imitation, emotional response, and verbal and nonverbal communication) displayed lower levels of cross-country non-invariance compared to items about stereotyped behaviors/sensory sensitivity (i.e., body and object use, adaptation to change, or taste, smell, and touch response). This study found that the CARS may not provide cross-culturally valid ASD assessments. Thus, cross-cultural comparisons with the CARS should consider first which items operate differently across samples of interest, since its cross-cultural measurement non-invariance could be a source of cross-cultural variability in ASD presentations. Additional studies are needed before drawing valid recommendations in relation to the cultural sensitivity of particular items.
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| 15. |
- Asquith, Nathan L., et al.
(författare)
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Fibrin protofibril packing and clot stability are enhanced by extended knob-hole interactions and catch-slip bonds
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:13, s. 4015-4027
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Tidskriftsartikel (refereegranskat)abstract
- Fibrin polymerization involves thrombin-mediated exposure of knobs on one monomer that bind to holes available on another, leading to the formation of fibers. In silico evidence has suggested that the classical A:a knob-hole interaction is enhanced by surrounding residues not directly involved in the binding pocket of hole a, via noncovalent interactions with knob A. We assessed the importance of extended knob-hole interactions by performing biochemical, biophysical, and in silico modeling studies on recombinant human fibrinogen variants with mutations at residues responsible for the extended interactions. Three single fibrinogen variants, yD297N, yE323Q, and yK356Q, and a triple variant yDEK (yD297N/yE323Q/yK356Q) were produced in a CHO (Chinese Hamster Ovary) cell expression system. Longitudinal protofibril growth probed by atomic force microscopy was disrupted for yD297N and enhanced for the yK356Q mutation. Initial polymerization rates were reduced for all variants in turbidimetric studies. Laser scanning confocal microscopy showed that yDEK and yE323Q produced denser clots, whereas yD297N and yK356Q were similar to wild type. Scanning electron microscopy and light scattering studies showed that fiber thickness and protofibril packing of the fibers were reduced for all variants. Clot viscoelastic analysis showed that only yDEK was more readily deformable. In silico modeling suggested that most variants displayed only slip-bond dissociation kinetics compared with biphasic catch-slip kinetics characteristics of wild type. These data provide new evidence for the role of extended interactions in supporting the classical knob-hole bonds involving catch-slip behavior in fibrin formation, clot structure, and clot mechanics.
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| 16. |
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| 17. |
- Hobbs, David, et al.
(författare)
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All-sky visible and near infrared space astrometry
- 2021
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Ingår i: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 51:3, s. 783-843
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Tidskriftsartikel (refereegranskat)abstract
- The era of all-sky space astrometry began with the Hipparcos mission in 1989 and provided the first very accurate catalogue of apparent magnitudes, positions, parallaxes and proper motions of 120 000 bright stars at the milliarcsec (or milliarcsec per year) accuracy level. Hipparcos has now been superseded by the results of the Gaia mission. The second Gaia data release contained astrometric data for almost 1.7 billion sources with tens of microarcsec (or microarcsec per year) accuracy in a vast volume of the Milky Way and future data releases will further improve on this. Gaia has just completed its nominal 5-year mission (July 2019), but is expected to continue in operations for an extended period of an additional 5 years through to mid 2024. Its final catalogue to be released ∼ 2027, will provide astrometry for ∼ 2 billion sources, with astrometric precisions reaching 10 microarcsec. Why is accurate astrometry so important? The answer is that it provides fundamental data which underpin much of modern observational astronomy as will be detailed in this White Paper. All-sky visible and Near-InfraRed (NIR) astrometry with a wavelength cutoff in the K-band is not just focused on a single or small number of key science cases. Instead, it is extremely broad, answering key science questions in nearly every branch of astronomy while also providing a dense and accurate visible-NIR reference frame needed for future astronomy facilities.
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| 18. |
- Jansen, Karin A., et al.
(författare)
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Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling
- 2020
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 16:35, s. 8272-8283
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Tidskriftsartikel (refereegranskat)abstract
- Fibrin is the major extracellular component of blood clots and a proteinaceous hydrogel used as a versatile biomaterial. Fibrin forms branched networks built of laterally associated double-stranded protofibrils. This multiscale hierarchical structure is crucial for the extraordinary mechanical resilience of blood clots, yet the structural basis of clot mechanical properties remains largely unclear due, in part, to the unresolved molecular packing of fibrin fibers. Here the packing structure of fibrin fibers is quantitatively assessed by combining Small Angle X-ray Scattering (SAXS) measurements of fibrin reconstituted under a wide range of conditions with computational molecular modeling of fibrin protofibrils. The number, positions, and intensities of the Bragg peaks observed in the SAXS experiments were reproduced computationally based on the all-atom molecular structure of reconstructed fibrin protofibrils. Specifically, the model correctly predicts the intensities of the reflections of the 22.5 nm axial repeat, corresponding to the half-staggered longitudinal arrangement of fibrin molecules. In addition, the SAXS measurements showed that protofibrils within fibrin fibers have a partially ordered lateral arrangement with a characteristic transverse repeat distance of 13 nm, irrespective of the fiber thickness. These findings provide fundamental insights into the molecular structure of fibrin clots that underlies their biological and physical properties.
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| 19. |
- Stevanovic, Dejan, et al.
(författare)
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Cross-cultural similarities and differences in reporting autistic symptoms in toddlers: A study synthesizing M-CHAT(-R) data from ten countries
- 2022
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Ingår i: Research in Autism Spectrum Disorders. - : Elsevier BV. - 1750-9467. ; 95
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study aimed to evaluate the endorsement rates of M-CHAT(-R) items by parents/ caregivers of toddlers with autism spectrum disorder (ASD) synthesizing data from ten countries: Albania, Chile, Georgia, Macedonia, Malaysia, Mexico, Serbia, Turkey, United Kingdom, and the United States of America.Method: Data were aggregated for toddlers aged 14-36 months who participated in previous studies or completed clinical screening. An item with < 30% of endorsements was classified as low endorsement, an item falling within the range of 30-60% as moderate endorsement, and an item with > 60% as high endorsement.Results: All items had a low endorsement rate in at least one country and moderate to high in others. Of 20 items, 14 had a moderate to high endorsement rate in seven to nine countries. Of particular relevance are items with moderate to high endorsement rates in all countries excluding Malaysia, such as points to get help, points to show, brings things to show, follows a point, follows your gaze, and understands what is said. On the other hand, makes eye contact, responds to name, hearing concerns, and reciprocal smile were interpreted differently across the countries.Conclusions: This study showed differences in parent/caregiver responding to M-CHAT(-R) items across ten countries, which may indicate cross-country variations in the recognition and evaluation of autistic symptoms in toddlers. Items related to joint attention, social engagement, and language comprehension were reported in a similar manner across countries and could be interpreted as universal autistic symptoms in toddlers.
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| 20. |
- Gold, Gregory, et al.
(författare)
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Backreaction of Schwinger pair creation in massive QED(2)
- 2021
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Ingår i: Journal of High Energy Physics (JHEP). - : Springer Nature. - 1126-6708 .- 1029-8479. ; :10
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Tidskriftsartikel (refereegranskat)abstract
- Particle-antiparticle pairs can be produced by background electric fields via the Schwinger mechanism provided they are unconfined. If, as in QED in (3+1)-d these particles are massive, the particle production rate is exponentially suppressed below a threshold field strength. Above this threshold, the energy for pair creation must come from the electric field itself which ought to eventually relax to the threshold strength. Calculating this relaxation in a self-consistent manner, however, is difficult. Chu and Vachaspati addressed this problem in the context of capacitor discharge in massless QED(2) [1] by utilizing bosonization in two-dimensions. When the bare fermions are massless, the dual bosonized theory is free and capacitor discharge can be analyzed exactly [1], however, special care is required in its interpretation given that the theory exhibits confinement. In this paper we reinterpret the findings of [1], where the capacitors Schwinger-discharge via electrically neutral dipolar meson-production, and generalize this to the case where the fermions have bare masses. Crucially, we note that when the initial charge of the capacitor is large compared to the charge of the fermions, Q >> e, the classical equation of motion for the bosonized model accurately characterizes the dynamics of discharge. For massless QED(2), we find that the discharge is suppressed below a critical plate separation that is commensurate with the length scale associated with the meson dipole moment. For massive QED(2), we find in addition, a mass threshold familiar from (3+1)-d, and show the electric field relaxes to a final steady state with a magnitude proportional to the initial charge. We discuss the wider implications of our findings and identify challenges in extending this treatment to higher dimensions.
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| 21. |
- Golovitchev, Valeri, 1945, et al.
(författare)
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Development of dual fuel combustion models for direct injected heavy duty diesel engines
- 2013
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Ingår i: Diesel Fuels: Characteristics, Performances and Environmental Impacts. - 9781626188662 ; , s. 85-118
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- A new model incorporating two combustion modes was developed to simulate dualfuel(DF) combustion engines with different fuel compositions (natural gas/diesel oil andmethanol/dimethyl ether (DME)). The model involved two coupled combustion modes: a"conventional" partially premixed reactor diesel mode and a flame propagation mode.For the flame propagation combustion mode, an expression for the reaction rate wasdeduced based on the equation for the flame speed. Laminar flame speeds for theaspirated fuels were calculated using the PREMIX code within the Chemkin-2 packageby using the chemical mechanisms for the fuel compositions and species moleculartransport properties and were subsequently fitted to polynomial expressions. Theturbulent flame speed was assumed to depend on the laminar speed and characteristics offlow turbulence.CFD partial and full cycle engine simulations were performed for two heavy dutydiesel engines, a Volvo D12C and an IF (Isotta Fraschini), using the 3D CFD KIVA3Vand KIVA4 codes supplemented by similar spray models and semi-detailed combustionand emission formation mechanisms for both fuel compositions. The natural gas fuel wasselected as a four-component mixture of methane (>90%), ethane, propane and n-butane,while diesel oil vapor was represented as a blend of n-heptane and toluene. The solutionalgorithm accounted for the two coupled combustion modes by employing aninterpolation procedure. The predicted DF engine in-cylinder parameters (pressure,energy release rate, NOx and H2O/CO2 concentrations) and combustion efficiencies forhe different DF compositions were compared with conventional diesel data for bothengines.
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| 22. |
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| 23. |
- Imren, A., et al.
(författare)
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The Full Cycle HD diesel Engine Simulation using KIVA-4 Code
- 2010
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Ingår i: SAE Technical Papers. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 0148-7191 .- 2688-3627. ; , s. 20-
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Konferensbidrag (refereegranskat)abstract
- With the advent of the KIVA-4 code which employs an unstructured mesh to represent the engine geometry, the gap in flexibility between commercial and research modeling software becomes more narrow. In this study, we tried to perform a full cycle simulation of a 4-stroke HD diesel engine represented by a highly boosted research IF (Isotta Fraschini) engine using the KIVA-4 code. The engine mesh including the combustion chamber, intake and exhaust valves and helical manifolds was constructed using optional O-Grids catching a complex geometry of the engine parts with the help of the ANSYS ICEM CFD software. The KIVA-4 mesh input was obtained by a homemade mesh converter which can read STAR-CD and CFX outputs. The simulations were performed on a full 360 deg mesh consisting of 300,000 unstructured hexahedral cells at BDC. The physical properties of the liquid fuel were taken corresponding to those of real diesel #2 oil. The spray atomization and droplet dynamics models were described by the KH-RT hybrid model which is a modified replica of the ERC model; the droplet collisions were modeled by the droplet-trajectory-based method with a reduced grid dependency. The original KIVA-4 droplet evaporation model was replaced by the KIVA-3V model. Chemical kinetics (71 species, 323 reactions) was based on the mechanism for diesel oil surrogate represented by a blend of n-heptane (70%) and toluene (30%) coupled with the EDC (eddy dissipation concept) model to simulate turbulent combustion. The emission (soot and NO\dx) formations were described in terms of sub-models based on the evolution of soot precursors, A2R5, and the extended Zel'dovich mechanism, respectively. All stages of the engine cycle were successfully calculated. Due to a small amount of experimental data available for the research IF engine, predictions were successfully compared with experimental data on the in-cylinder pressure and RoHR (rate of heat release) histories only. Comparisons of the predictions produced on the full and sector meshes were also made.
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| 24. |
- Kliuchnikov, Evgenii, et al.
(författare)
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CellDynaMo-stochastic reaction-diffusion-dynamics model : Application to search-and-capture process of mitotic spindle assembly
- 2022
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:6
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a Stochastic Reaction-Diffusion-Dynamics Model (SRDDM) for simulations of cellular mechanochemical processes with high spatial and temporal resolution. The SRDDM is mapped into the CellDynaMo package, which couples the spatially inhomogeneous reaction-diffusion master equation to account for biochemical reactions and molecular transport within the Langevin Dynamics (LD) framework to describe dynamic mechanical processes. This computational infrastructure allows the simulation of hours of molecular machine dynamics in reasonable wall-clock time. We apply SRDDM to test performance of the Search-and-Capture of mitotic spindle assembly by simulating, in three spatial dimensions, dynamic instability of elastic microtubules anchored in two centrosomes, movement and deformations of geometrically realistic centromeres with flexible kinetochores and chromosome arms. Furthermore, the SRDDM describes the mechanics and kinetics of Ndc80 linkers mediating transient attachments of microtubules to the chromosomal kinetochores. The rates of these attachments and detachments depend upon phosphorylation states of the Ndc80 linkers, which are regulated in the model by explicitly accounting for the reactions of Aurora A and B kinase enzymes undergoing restricted diffusion. We find that there is an optimal rate of microtubule-kinetochore detachments which maximizes the accuracy of the chromosome connections, that adding chromosome arms to kinetochores improve the accuracy by slowing down chromosome movements, that Aurora A and kinetochore deformations have a small positive effect on the attachment accuracy, and that thermal fluctuations of the microtubules increase the rates of kinetochore capture and also improve the accuracy of spindle assembly. Author summary The CellDynaMo package models, in 3D, any cellular subsystem where sufficient detail of the macromolecular players and the kinetics of relevant reactions are available. The package is based on the Stochastic Reaction-Diffusion-Dynamics model that combines the stochastic description of chemical kinetics, Brownian diffusion-based description of molecular transport, and Langevin dynamics-based representation of mechanical processes most pertinent to the system. We apply the model to test the Search-and-Capture mechanism of mitotic spindle assembly. We find that there is an optimal rate of microtubule-kinetochore detachments which maximizes the accuracy of chromosome connections, that chromosome arms improve the attachment accuracy by slowing down chromosome movements, that Aurora A kinase and kinetochore deformations have small positive effects on the accuracy, and that thermal fluctuations of the microtubules increase the rates of kinetochore capture and also improve the accuracy.
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| 25. |
- Kliuchnikov, Evgenii, et al.
(författare)
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Microtubule assembly and disassembly dynamics model : Exploring dynamic instability and identifying features of Microtubules' Growth, Catastrophe, Shortening, and Rescue
- 2022
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 20, s. 953-974
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Tidskriftsartikel (refereegranskat)abstract
- Microtubules (MTs), a cellular structure element, exhibit dynamic instability and can switch stochastically from growth to shortening; but the factors that trigger these processes at the molecular level are not understood. We developed a 3D Microtubule Assembly and Disassembly DYnamics (MADDY) model, based upon a bead-per-monomer representation of the alpha beta-tubulin dimers forming an MT lattice, stabilized by the lateral and longitudinal interactions between tubulin subunits. The model was parameterized against the experimental rates of MT growth and shortening, and pushing forces on the Dam1 protein complex due to protofilaments splaying out. Using the MADDY model, we carried out GPU-accelerated Langevin simulations to access dynamic instability behavior. By applying Machine Learning techniques, we identified the MT characteristics that distinguish simultaneously all four kinetic states: growth, catastrophe, shortening, and rescue. At the cellular 25 mu M tubulin concentration, the most important quantities are the MT length L, average longitudinal curvature kappa(long), MT tip width w, total energy of longitudinal interactions in MT lattice U-long, and the energies of longitudinal and lateral interactions required to complete MT to full cylinder U-long(add) and U-lat(add) . At high 250 mu M tubulin concentration, the most important characteristics are L, kappa(long), number of hydrolyzed alpha beta-tubulin dimers n(hyd) and number of lateral interactions per helical pitch n(lat) in MT lattice, energy of lateral interactions in MT lattice U-lat, and energy of longitudinal interactions in MT tip u(long). These results allow greater insights into what brings about kinetic state stability and the transitions between states involved in MT dynamic instability behavior.
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