Acoustic properties of fine‐grained sediments from Emerald Basin: Toward an inversion for physical properties using the Biot–Stoll model

Acoustic data from two long cores, comprising marine clays and silts taken from Emerald Basin off Nova Scotia, are presented. High‐resolution measurements of compressional wavevelocity,attenuation, and power law exponent are made using ultrasonic frequencies between 100 to 1000 kHz. The observed values of the frequency dependence of attenuation suggest that a nonconstant Q mechanism is needed to explain these data, and Biot–Stoll theory is used to model the experimental results. An inversion scheme is used to constrain physical parameters in the Biot–Stoll dispersion relation. The inversion shows that there is a restricted range of permeability and grain size. By assigning reasonable values for grain size in the inversion, the Biot–Stoll model predicts unique values for the permeability and frame bulk modulus that agree well with estimates made by other means

Calculation of acoustic parameters by a filter-correlation method

This paper presents the filter correlation method, a technique for extracting consistent and accurate estimates of attenuation parameters from acoustic waveform data. The method minimizes problems associated with short time windows and multipath secondary arrivals. The method comprises two stages: a causal passband filter stage followed by a cross-correlation step. The results of the filter-correlation estimator are compared to those of the spectral difference approach for short time series with and without a secondary multipath arrival. Preliminary analyses of acoustic data collected on cored marine silts and clays show the attenuation properties of these materials cannot be described by a constant Q mechanism. The filter correlation method refines estimates of frequency-dependent velocity, revealing a small but systematic anisotropy between measurements made parallel and transverse to the sediments\u27 bedding plane. The observed velocity anisotropy can be modeled by assuming layered porosity variations in the cored sediments. No systematic anisotropy in attenuation was observed

High-resolution, whole-core magnetic susceptibility data from Leg 130, Ontong Java Plateau

High-resolution, whole-core magnetic susceptibility data, recorded at 3-cm intervals, were obtained for advanced hydraulic piston (APC) cores at Sites 805, 806, and 807 of Leg 130 on the Ontong Java Plateau. In this initial report, we present a preliminary evaluation of these data for their use in core correlations and paleoclimatic studies. The data allow detailed intrasite correlations between the offset APC cores and provide a means for intersite correlations of Pleistocene sediments. Variations in magnetic susceptibility values probably mirror variations in terrestrial influx and may act as proxy indicators of climate. Highly coherent cyclicity, representing Milankovitch orbital frequencies, is exhibited in some intervals and provides the potential to tune sedimentation rates. Postdepositional dissolution of magnetite by reduction diagenesis, which is also reflected in the magnetic susceptibility data, may be a limiting factor in these studies

Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes

Objective: Inhibitor of apoptosis proteins (IAPs), such as X-linked or cellular IAP 1/2 (XIAP, cIAP1/2), are important regulators of apoptosis. IAP antagonists are currently under clinical investigation as anticancer agents. Interestingly, IAPs participate in the inflammation-associated TNF receptor signaling complex and regulate NFκB signaling. This raises the question about the role of IAPs in inflammation. Here, we investigated the anti-inflammatory potential of IAP inhibitors and the role of IAPs in inflammatory processes of endothelial cells. Methods and Results: In mice, the small molecule IAP antagonist A-4.10099.1 (ABT) suppressed antigen-induced arthritis, leukocyte infiltration in concanavalin A-evoked liver injury, and leukocyte transmigration in the TNFα-activated cremaster muscle. In vitro, we observed an attenuation of leukocyte– endothelial cell interaction by downregulation of the intercellular adhesion molecule-1. ABT did not impair NFκB signaling but decreased the TNFα-induced activation of the TGF-β–activated kinase 1, p38, and c-Jun N-terminal kinase. These effects are based on the proteasomal degradation of cIAP1/2 accompanied by an altered ratio of the levels of membrane-localized TNF receptor-associated factors 2 and 5. Conclusion: Our results reveal IAP antagonism as a profound anti-inflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells

Atrial Natriuretic Peptide Protects against Histamine-Induced Endothelial Barrier Dysfunction in Vivo

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, β-catenin, and p120ctn morphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage

A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803.

PurposeTumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results.Patients and methodsTumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMR-D) and BRAF c.1799T > A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients.ResultsPatients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p =  .0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p =  .0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen.ConclusionThis large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy. The Oncologist 2017;22:107-114Implications for Practice: This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility

Flavopiridol Protects Against Inflammation by Attenuating Leukocyte-Endothelial Interaction via Inhibition of Cyclin-Dependent Kinase 9

Objective: The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death–inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte–endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms. Methods and Results: Flavopiridol suppressed concanavalin A–induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-α–induced leukocyte– endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-κB-dependent transcription. Flavopiridol did not affect inhibitor of κB (IκB) kinase, the degradation and phosphorylation of IκBα, nuclear translocation of p65, or nuclear factor-κB (NF-κB) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase Cθ (PKCθ), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol. Conclusion: Our study highlights flavopiridol as a promising antiinflammatory compound and inhibition of CDK9 as a novel approach for the treatment of inflammation-associated diseases

Sediment identification using free fall penetrometer acceleration-time histories

Abstract Knowledge of physical properties of near-surface sediments is an important requirement for many studies of the seafloor. Dynamic or Free Fall Penetrometers (FFP), instrumented with accelerometers, are widely used to assess the mechanical properties of the sediment by deriving penetration resistance from the deceleration response of the probe as it impacts and embeds the seabed. Other field investigations, a priori knowledge or a very basic description of the type of sediment (such as a description of the sediment as soft, medium or hard) derived from studying the deceleration response (accelerometer-time histories) are used for sediment identification prior to the application of an appropriate strength determination model. In many cases this information is site-specific and in others the penetration resistance is overestimated due to the dilatory effects observed in sediment with an undetected grain fraction. In this study variables affecting a dynamic penetrometer-sediment interaction system are identified. Using data from field investigations and literature we found a relationship among five variables: peak acceleration, embedment depth, total embedment time, velocity of impact and grain size. This is used to formulate a sediment identification model. The model accounts for variables that may vary widely within one deployment and it can be applied to other FFPs with different physical characteristics (such as a different mass or size). This may lead to the increased use of FFP as a deployment tool for rapid in situ characterization of the seafloor