Role of shear and extensional rheology

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2001.Includes bibliographical references (p. 207-214).Understanding the flow of polymeric fluids is important for optimizing commercial processes such as injection molding and fiber spinning. The combination of streamwise curvature and elastic normal stresses can lead to the onset of elastic flow instabilities, severely rate-limiting such processes. This thesis focuses on the stability of two complex non-Newtonian flows of dilute polystyrene solutions: the viscometric flow between a rotating cone-and-plate and the flow through an axisymmetric contraction-expansion. Torsional shear flows of elastic fluids with closed streamlines can accumulate heat from viscous dissipation resulting in spatial nonuniformities in the temperature profile and viscometric properties. In this thesis, a detailed study of the effect of viscous heating on the steady shearing of elastic fluids between a rotating cone-and-plate is performed. The relative importance of viscous heating and elasticity can be quantified by a new dimensionless thermoelastic number. This parameter is a fluid material property which is a function of polymer molecular weight, geometry and temperature. As the thermoelastic number is increased, strong temperature gradients reduce the elasticity of the test fluid and delay the onset of the instability, eventually stabilizing the flow completely. The flow of elastic fluids into an axisymmetric abrupt contraction-expansion is a complex flow containing regions of both shear and extension that tests the limits of current viscoelastic constitutive models.(cont.) A large extra pressure drop above that measured for a similar Newtonian fluid is documented and found to correlate to the stress-conformation hysteresis observed in transient uniaxial extension measurements. Laser Doppler velocimetry, particle image velocimetry and flow induced birefringence are used to investigate the global kinematics upstream of contraction-expansions of various contraction ratios and degrees of re-entrant corner curvature. For a contraction ratio of beta=2 a steady elastic lip vortex is observed whereas for 4<beta<8, no lip vortex is observed and instead a corner vortex is seen. At large Deborah numbers a time-dependent elastic flow instability is observed. Measurements of the transient extensional rheology show that the differing vortex growth pathways in viscoelastic fluids can be systematically understood in terms of a dimensionless ratio of the normal stress differences in shear and in extension.by Jonathan P. Rothstein.Ph.D

Effects of particle stiffness on the extensional rheology of model rod-like nanoparticle suspensions

The linear and nonlinear rheological behavior of two rod-like particle suspensions as a function of concentration is studied using small amplitude oscillatory shear, steady shear and capillary breakup extensional rheometry. The rod-like suspensions are composed of fd virus and its mutant fdY21M, which are perfectly monodisperse, with a length on the order of 900 nm. The particles are semiflexible yet differ in their persistence length. The effect of stiffness on the rheological behavior in both, shear and extensional flow, is investigated experimentally. The linear viscoelastic shear data is compared in detail with theoretical predictions for worm-like chains. The extensional properties are compared to Batchelor\u27s theory, generalized for the shear thinning nature of the suspensions. Theoretical predictions agree well with the measured complex moduli at low concentrations as well as the nonlinear shear and elongational viscosities at high flow rates. The results in this work provide guidelines for enhancing the elongational viscosity based on purely frictional effects in the absence of strong normal forces which are characteristic for high molecular weight polymers

Surface Nano-structured Coating for Improved Performance of Axial Piston Pumps

The work starts from the consideration that most of the power losses in a hydraulic pump is due to frictional losses made by the relative motion between moving parts. This fact is particularly true at low operating velocities, when the hydraulic lift effect must be able to maintain a minimum clearance in meatus to limit the volumetric losses. The potential of structured coatings at nanoscale, with super-hydrophobic and oleophobic characteristics, has never been exploited before in an industrial application. The work studies the potential application of nano-coating on piston slippers surface in a real industrial case. The aim is to develop a new industrial solution to increase the energetic efficiency of hydraulic pump used in earthmoving machines. The proposed solution is investigated using a dedicated test bench, designed to reproduce real working conditions of the pump. The results showa reduction of friction coefficient while changing working pressure and rotation velocity

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.Fidelity Biosciences (Firm)Fidelity Biosciences (Firm) (Research Inititative)ALS Therapy AllianceNational Institutes of Health (U.S.) (NIH 1RC1NS06839)National Institutes of Health (U.S.) (NIH U01NS05225-03)National Institutes of Health (U.S.) (NIH R01NS050557-05)National Institutes of Health (U.S.) (NIH 1RC2NS070342-01)Pierre L. de Bourgknecht ALS Research FoundationNational Science Foundation (U.S.) (NS614192

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.Other Research Uni

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The Nurses’ Health Studies would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital ‘Womens Health Theme’ and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y.L. was supported by the NHMRC Early Career Fellowship. G.C.T. is supported by the National Health and Medical Research Council. S.M. was supported by an ARC Future Fellowship

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe