The linear (Winkler) foundation is a simple model widely used for decades to account for the surface response of elastic bodies. It models the response as purely local, linear, and perpendicular to ...the surface. We extend this model to the case where the foundation is made of a structured material such as a polymer network, which has characteristic scales of length and time. We use the two-fluid model of viscoelastic structured materials to treat a film of finite thickness, supported on a rigid solid and subjected to a concentrated normal force at its free surface. We obtain the foundation modulus (Winkler constant) as a function of the film's thickness, intrinsic correlation length, and viscoelastic moduli, for three choices of boundary conditions. The results can be used to readily extend earlier applications of the Winkler model to more complex, microstructured substrates. They also provide a way to extract the intrinsic properties of such complex materials from mechanical surface measurements.
We examined two groups of combat veterans, one with Posttraumatic Stress Disorder (PTSD) (n=27) and another without PTSD (n=16), using an emotional Stroop task (EST) with word lists matched across a ...series of lexical variables (e.g., length, frequency, neighbourhood size, etc.). Participants with PTSD exhibited a strong EST effect (longer colour-naming latencies for combat-relevant words as compared to neutral words). Veterans without PTSD produced no such effect, t <.918, p >.37. Participants with PTSD then completed eight sessions of attention training (Attention Control Training or Attention Bias Modification Training) with a dot-probe task utilizing threatening and neutral faces. After training, participants - especially those undergoing Attention Control Training - no longer produced longer colour-naming latencies for combat-related words as compared to other words, indicating normalized attention allocation processes after treatment.
Background Measure of ventricular dyssynchrony by gated single photon emission computed tomography phase analysis aids in the assessment of left ventricular function in subjects undergoing myocardial ...perfusion imaging.
(2013) YopP-Expressing Variant of Y. pestis Activates a Potent Innate Immune Response Affording Cross-Protection against Yersiniosis and Tularemia. (2014) Correction: YopP-Expressing Variant of Y. ...pestis Activates a Potent Innate Immune Response Affording Cross-Protection against Yersiniosis and Tularemia.
Hemophilia B is a blood clotting disorder caused by deficient activity of coagulation factor IX (FIX). Multiple recombinant FIX proteins are currently approved to treat hemophilia B and several gene ...therapy products are currently being developed. Codon optimization is a frequently used technique in the pharmaceutical industry to improve recombinant protein expression by recoding a coding sequence using multiple synonymous codon substitutions. The underlying assumption of this gene recoding is that synonymous substitutions do not alter protein characteristics since the primary sequence of the protein remains unchanged. However, a critical body of evidence shows that synonymous variants can affect cotranslational folding and protein function. Gene recoding could potentially alter the structure, function and in-vivo immunogenicity of recoded therapeutic proteins. Here, we evaluated multiple recoded variants of F9 designed to further explore the effects of codon usage bias on protein properties. The detailed evaluation of these constructs showed altered conformations and assessment of translation kinetics by ribosome profiling revealed differences in local translation kinetics. Assessment of wild-type and recoded constructs using a Major Histocompatibility Complex (MHC) Associated Peptide Proteomics (MAPPs) assay showed distinct presentation of FIX derived peptides bound to MHC Class II (MHC-II) molecules suggesting that despite identical amino acid sequence, recoded proteins could exhibit different immunogenicity risk. Posttranslational modification analysis indicated that overexpression from gene recoding results in suboptimal posttranslational processing. Overall, our results highlight potential functional and immunogenicity concerns associated with gene recoded F9 products. These findings have general applicability and implications for other gene recoded recombinant proteins.
Abstract 3877
Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the Western world with nearly 15,000 new cases diagnosed every year in the USA. The characterization of CLL has ...resulted in the identification of important disease biomarkers: these include the recurrent genomic deletions del17p and del11q, genomic complexity, TP53 mutations, the expression level of ZAP70 and the mutational status of IgVH. While genomic and transcriptional profiling of CLL identified clinically and biologically relevant markers, there is still significant uncertainty about the pathobiology and the origin of CLL. It is increasingly clear that epigenetic deregulation plays an important role in the biology of all lymphomas/leukemias including CLL.
We hypothesized that DNA methylation profiling would allow us to identify new, biologically significant CLL subtypes and yield greater insight into the biology of this disease. We therefore examined the DNA methylation of over 240 patients with CLL using the HELP assay and hybridization to high density custom microarray that reports on the methylation status of more than 250,000 CpGs corresponding to 20,401 genes. Gene expression profiling and SNP array-based copy number assessments and targeted gene resequencing were available on most of these cases. We performed unsupervised analysis on the most variable probesets (standard deviation > 1.3) using K-means consensus clustering.
The experimental approach reproducibly identified three robust CLL subtypes based on epigenetic profiles. To identify the genes that define these three subtypes we next performed unequal variance t-test of the CLL subtypes comparing them to Peripheral Blood CD19+ B cells as a normal control, and identified that clusters are defined by differential methylation of 3719, 6145 and 3349 genes (selected probes displayed changes in methylation of at least 30% and FDR corrected p-value < 0.05), The three clusters featured respectively i) aberrant methylation of MYC and WNT target genes, ii) aberrant methylation of NOTCH1 targets and iii) aberrant methylation of bcl6 and inflammatory cytokines. There was inverse correlation between gene expression and cytosine methylation, suggesting that DNA methylation had an impact on the transcriptional programming of these CLL cases. Strikingly the CLL MYC/WNT cluster displayed poorer prognosis as opposed to the CLL BCL6 cluster (HR=0.14 95% CI: 0.07–0.30). The CLL NOTCH1 cluster had an intermediate prognosis. It was also notable that all CLL patients exhibited deregulation of the B-cell receptor pathway as compared to normal CD19+ B-cells, consistent with the notion that this pathway plays a critical role in CLL pathogenesis. Finally, we divided the cohort into training and testing cohorts and used a machine learning BDVAL algorithm to identify DNA methylation outcome classifiers. This procedure identified a 40-probeset classifier that accurately predicted outcome (Area Under the ROC Curve of 0.77; performance was assessed with 10 fold cross-validation in a training set with 76 patients; validation on an independent set of 105 samples).
This large epigenetic profiling study in CLL identifies aberrant epigenetic regulation as a core part of the pathobiology of CLL and identifies novel CLL clusters with distinct effects on survival. MYC-WNT pathway inhibitors are warranted for use in clinical trials for patients belonging to this aggressive epigenetically defined subtype.
No relevant conflicts of interest to declare.
PDF
