162 research outputs found
FACTOR XI ACTIVATION AND INHIBITION IN CATHETER-INDUCED CLOTTING
No full textIf you have comments or suggestions for improvements, please direct these to the corresponding author, Ruiqi Yin ([email protected]).Thrombosis, or blood clot formation in vessels, is responsible for 1 in 4 deaths in Canada and worldwide. Patients with acute coronary syndrome (ACS), atrial fibrillation (AF), or cancer often require central venous catheters (CVCs) for medical access, such as receiving chemotherapy, drugs, and nutrition. These catheters, like peripherally inserted central catheters (PICC) and implanted ports, are associated with an increased risk of thrombosis, as clots tend to form inside the catheters and block the vessels. Vascular blockages cause severe complications like deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, effective and safe anticoagulants are essential to manage and prevent catheter-induced clotting. Factor (F) XI in the contact pathway of coagulation has emerged as a promising target for anticoagulant therapy because FXI is key for blood clot formation but is not essential in normal blood clotting. Consequently, FXI inhibitors have become a safer alternative to currently available anticoagulants. FXI can be autoactivated by negatively charged surfaces like polyphosphate (polyP), released from activated platelets, or synthetic surfaces like catheters. Thus, FXI is a root cause of catheter- and polyP-induced clotting. Milvexian and abelacimab, both FXI inhibitors, are currently undergoing large phase 3 trials in patients with ACS, AF, or cancer. However, the effect of these FXI inhibitors on catheter-induced clotting has not been explored. We previously demonstrated that inhibiting FXI reduces catheter-induced clotting in rabbits. This thesis aims to investigate the role of catheters and polyP in FXI activation and to explore the anticoagulant effects of FXI inhibitors in catheter-induced thrombosis using our established plate-based assays. We found that catheters and polyP activate clotting at the level of FXI, bypassing FXII. Both milvexian and abelacimab attenuate catheter-induced clotting. These findings suggest that FXI inhibitors could be a potential therapeutic option for catheter- and polyP-induced thrombosis without increasing bleeding risk.ThesisDoctor of Philosophy (Medical Science
Regulation and function of interphase histone H1 phosphorylation in pluripotent cell differentiation
No full textHistone H1 phosphorylation is thought to be involved in multiple cellular processes including chromatin condensation and transcriptional regulation. Recent studies revealed changes in the expression and genomic distributions of H1 variants during cell differentiation which appear to contribute to phenotypic differences between cell types, but the functional significance of phosphorylation at specific sites in individual H1 variants and their dynamic regulation in this process has not been investigated. Here we show that the global levels of phosphorylation of H1.5-Ser18 (pS18-H1.5), H1.2/H1.5-Ser173 (pS173-H1.2/5) and H1.4-Ser187 (pS187-H1.4) are regulated differentially during pluripotent cell differentiation. Enrichment of pS187-H1.4, but not pS18-H1.5, near the transcription start sites (TSSs) of pluripotency factor genes is diminished after differentiation. Selective inhibition of CDK7 and CDK9, or siRNA depletion of CDK9 rapidly diminishes both the global levels and the enrichment of pS187-H1.4 at housekeeping genes. Moreover, inhibiting transcription with actinomycin D induces the accumulation of pS187-H1.4 at promoters and gene bodies. Notably, the levels of pS187-H1.4 enrichment after actinomycin D treatment or cell differentiation reflect the extent of CDK9 recruitment at the same loci. Remarkably, the global levels of H1.5-S18 and H1.2/H1.5-S173 phosphorylation are not affected by these transcription inhibitor treatments, and selective inhibition of CDK2 does not affect global phosphorylation of H1.4-S187 or H1.5-S18. Although Erk phosphorylates S187-H1.4 in vitro, our data with Erk inhibitor treatments and EGF stimulation suggest that Erk does not phosphorylate S187-H1.4 in vivo. Studies of cells expressing H1.4 mutants that mimic constitutive dephosphorylation and phosphorylation at one or two interphase sites reveal that interphase phosphorylation of H1.4 affects transcription in a gene-specific manner. Taken together, our data provide strong evidence that H1 variant phosphorylations are dynamically regulated in a site-specific and gene-specific fashion during pluripotent cell differentiation, and that the enrichment of pS187-H1.4 at genes is positively related to their transcription. H1.4-S187 is likely to be a direct target of CDK9 during interphase in vivo while other H1 variant phosphorylations appear to be mediated by distinct kinases.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2019-05-01The student, Ruiqi Liao, accepted the attached license on 2017-04-17 at 17:05.The student, Ruiqi Liao, submitted this Dissertation for approval on 2017-04-17 at 17:20.This Dissertation was approved for publication on 2017-04-18 at 12:54.DSpace SAF Submission Ingestion Package generated from Vireo submission #10822 on 2017-08-10 at 15:05:51Made available in DSpace on 2017-08-10T20:33:00Z (GMT). No. of bitstreams: 3
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Previous issue date: 2017-04-18Embargo set by: Colleen Fallaw for item 102773
Lift date: 2019-08-10T21:27:21Z
Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemU of I Only Restriction Lifted for Item 102773 on 2019-08-11T09:15:35Z
Apeldoorn leisure paradise
No full textThe graduation project attempts to discuss the possible approaches for transferring the Centraal Beheer into a leisure and recreation center.Centraal BeheerArchitecture, Urbanism and Building Science
An epigenetic switch involving a positive feedback loop linking inflammation to cancer effected by Myc and miRNA-17-92 microRNA cluster
No full text
Study on the method of improving the flashover voltage of 110kV suspension porcelain insulators based on neural network genetic algorithm
No full textMicro-nano bubbles assisted laccase for biocatalytic degradation of bisphenols
No full textBisphenols are important industrial materials for example for the production of plastics, but are also well known for their adverse health effects, in particular bisphenol A (BPA) is an endocrine disruptor. The widespread use of plastics has raised concerns. Therefore, the removal of bisphenols from wastewater has sparked the interest of the scientific community. This work introduces a novel hybrid technique of micro-nano bubbles assisted laccase (MNB-Lac) to degrade bisphenols in water. The feasibility of MNB-Lac using BPA as a model contaminant was evaluated by comparing with MNB, Lac, ultrasound (UL), UL-Lac, and UL-MNB-Lac. Comprehensive investigations were carried out to understand the specific influences of key process parameters including the initial pollutant concentration, temperature, air intake, pH, outlet pipe length, and Lac concentration on BPA degradation. The alkaline environment and extended length of outlet pipe could improve the degradation efficiency further. MNB-Lac exhibited 2.3–6.2 folds higher BPA degradation and less time than the other above process under the optimal parameters. The mechanism of MNB-Lac revealed that the generation of hydroxyl radical, high O2 solubility, and high mass transfer efficiency induced by MNB play important roles on enhancing the degradation catalyzed by Lac. MNB-Lac was successfully used for treating bisphenol B, bisphenol C, and the mixture of three bisphenols with high removal efficiency. Subsequently, these degradation products were analyzed by GC–MS. MNB-Lac potentially represents an innovative technology with considerable advantages in contaminant cleanup and time efficiency for treating phenolic contaminated water. Furthermore, the findings provide new insights into the enhancement of the performance of an oxidizing enzyme by introducing MNB technology.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.BT/Biocatalysi
Confidence envelopes for parametric model selection criteria and post-model selection inference
No full textIn choosing a candidate model in likelihood-based modeling via an information criterion, the practitioner is often faced with the difficult task of deciding just how far up the ranked list to look. Motivated by this pragmatic necessity, we construct an uncertainty band for a generalized (model selection) information criterion (GIC), defined as a criterion for which the limit in probability is identical to that of the normalized log-likelihood. This includes common special cases such as AIC & BIC. The method starts from the asymptotic normality of the GIC for the joint distribution of the candidate models in an independent and identically distributed (IID) data framework, and proceeds by deriving the (asymptotically) exact distribution of the minimum. This is a non-standard result from the theory of order statistics since although the original data are IID, the sample of GIC values are in fact dependent. The calculation of an upper quantile for its distribution then involves the computation of multivariate Gaussian integrals, which is amenable to efficient implementation via the R package "mvtnorm.'' The performance of the methodology is tested on simulated data by checking the coverage probability of nominal upper quantiles and compared to the three versions of bootstrap, parametric, non-parametric, and semi-parametric. All methods give coverages close to nominal for large samples except the non-parametric, but the bootstrap is two orders of magnitude slower. The methodology is subsequently extended to two other commonly used model structures: regression and time series. In the regression case, we derive the corresponding asymptotically exact distribution of the minimum GIC invoking Lindeberg-Feller type conditions for triangular arrays and are thus able to similarly calculate upper quantiles for its distribution via multivariate Gaussian integration. The bootstrap once again provides a default competing procedure, and we find that similar comparison performance metrics hold as for the IID case. The time series case is complicated by a far more intricate asymptotic regime for the joint distribution of the model GIC statistics. Under a Gaussian likelihood, the default in most packages, one needs to derive the limiting distribution of a normalized quadratic form for a realization from a stationary series. Under conditions on the process satisfied by ARMA models, a multivariate normal limit is once again achieved using the joint distribution of the normalized quadratic forms based on Toeplitz matrices as covariance matrices. The bootstrap can however be employed for its computation, whence we are once again in the multivariate Gaussian integration paradigm for upper quantile evaluation. Comparisons of this bootstrap-aided semi-exact method with the full-blown bootstrap once again reveal a similar performance, but faster computation speeds. Also, the derived asymptotic normal distribution for GIC values can be applied for real-world applications for all data structures. Using the uncertainty band for GIC values, we constructed a confidence envelope for the minimum GIC, we could see how far we needed to look at the ranked models when it comes to selecting the best model for the data. This method allowed us to spend less time in this process rather than considering all candidate models and see how confident we are in our AIC or BIC. One of the most difficult problems in contemporary statistical methodological research is to be able to account for the extra variability introduced by model selection uncertainty; the so-called post-model selection inference (PMSI). We explore ways in which the GIC uncertainty band can be inverted to make inferences on the parameters which can be used in a parametric setting. This is being attempted in the IID case by pivoting the CDF of the asymptotically exact distribution of the minimum GIC. For inference one parameter at a time, and a small number of candidate models, this works well, whence the attained PMSI confidence intervals are wider than the MLE-based Wald, as expected. For a large number of models, this approach is predictably quagmired by the lack of monotonically of the CDF as a function of the parameter and other numerical issues.Embargo status: Restricted until 09/2027. To request the author grant access, click on the PDF link to the left
Dialysis membrane enclosed laccase catalysis combines a controlled conversion rate and recyclability without enzyme immobilization
No full textLaccase is a versatile multicopper oxidase that holds great promise for many biotechnological applications. For such applications, it is essential to explore good biocatalytic systems for high activity and recyclability. The feasibility of membrane enclosed enzymatic catalysis (MEEC) for enzyme recycling with laccase was evaluated. The dialysis membrane enclosed laccase catalysis (DMELC) was tested for the conversion of the non-phenolic model substrate 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonate) (ABTS). Trametes versicolor laccase was found to be completely retained by the dialysis membrane during the process. The ABTS total conversion after DMELC reached the same values as the batch reaction of the enzyme in solution. The efficiency of DMELC conversion of ABTS under different process conditions including shaking speed, temperature, ABTS concentration and pH was investigated. The repetitive dialysis minimally affected the activity and the protein content of the enclosed laccase. DMELC retained 70.3 ± 0.8% of its initial conversion after 5 cycles. The usefulness of MEEC extends to other enzymes with the benefit of superior activity of an enzyme in solution and the recyclability which is normally only obtained with immobilized enzymes.[Figure not available: see fulltext.]BT/Biocatalysi
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