Facies architecture of Miocene subaqueous clinothems of the New Jersey passive margin: Results from IODP-ICDP Expedition 313

Understanding the history, causes, and impact of sea-level changes is a challenge for our societies that face accelerated global sea-level rise. In this context, improvement of our knowledge of sea-level changes and shoreline migration at geological time scales is critical. The preserved, laterally correlative sedimentary record of continental erosion on passive margins has been used to reconstruct past sea level. However, the detailed nature of a basic clinothem progradational pattern observed on many of these margins is still poorly known. This paper describes the sedimentary facies and interprets the depositional environments and the architecture of the clinothems of the New Jersey shelf (offshore northeastern USA) to depict the origin and controls of the distribution of the sediment on the margin. We analyze 612 cores totaling 1311 m in length collected at three sites 60 km offshore Atlantic City, New Jersey, during International Ocean Discovery Program–International Continental Scientific Drilling Program (IODP-ICDP) Expedition 313. The three sites sampled the lower to middle Miocene passive margin sediments of the New Jersey shelf clinothems. We also collected wireline logs at the three sites and tied the sedimentary architecture to the geometry observed on seismic profiles. The observed sediment distribution in the clinoform complex differs from that of current models based on seismic data, which predict a progressive increase in mud and decrease in sand contents in a seaward direction. In contrast, we observe that the clinoforms are largely composed of muds, with sands and coarser material concentrated at the rollover, the bottomset, and the toe of the slope. The shelf clinothem topsets are storm-influenced mud whereas the foreset slope is composed of a mud wedge largely dominated by density current deposits (e.g., low-density turbidites and debrites). The architecture of the clinothem complex includes a composite stack of ~30-m-thick clinothem units each made up of four systems tracts (Transgressive, Highstand, Forced-Regres­sive, and Lowstand Systems Tract) building individual transgressive-regres­sive sequences. The presence of mud-rich facies deposited during highstands on the topset of the clinoform, 40–60 km offshore from the sand-prone shoreface deposit (observed in the New Jersey onshore delta plain), and the lack of subaerial erosion (and continental depositional environments) point to a depositional model involving a subaerial delta (onshore) feeding a distant subaqueous delta. During forced regressions, shelf-edge deltas periodically overstep the stacks of flood-influenced, offshore-marine mud wedges of the New Jersey subaqueous delta, bringing sand to the rollover and building up the large-scale shelf-prism clinothems. The clinothem complex develops on a gently dipping platform with a ramp-like morphology (apparent dip of 0.75°–0.5°) below mean storm wave base, in 30–50 m of water depth, 40–60 km seaward of the coastal area. Its shape depends on the balance between accom­mo­da­tion and sedimentation rates. Subaqueous deltas show higher accumulation rates than their subaerial counterparts and prograde three times further and faster than their contemporaneous shoreline. The increase in the intensity of waves (height and recurrence intervals) favors the separation between subaqueous and subaerial deltas, and as a consequence, the formation of a flat topset geometry, a decrease in flood events and fluvial discharge, an overall progressive decrease in sediment grain size (from sequence m5.45, ca. 17.8–17.7 Ma, onwards), as well as an increase in sedimentation rates on the foresets of the clinoforms. All of these are recognized as preliminary signals that might characterize the entry into the Neogene icehouse world

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression

The PtdIns 3-Kinase/Akt Pathway Regulates Macrophage-Mediated ADCC against B Cell Lymphoma

Macrophages are important effectors in the clearance of antibody-coated tumor cells. However, the signaling pathways that regulate macrophage-induced ADCC are poorly defined. To understand the regulation of macrophage-mediated ADCC, we used human B cell lymphoma coated with Rituximab as the tumor target and murine macrophages primed with IFNγ as the effectors. Our data demonstrate that the PtdIns 3-kinase/Akt pathway is activated during macrophage-induced ADCC and that the inhibition of PtdIns 3-kinase results in the inhibition of macrophage-mediated cytotoxicity. Interestingly, downstream of PtdIns 3-kinase, expression of constitutively active Akt (Myr-Akt) in macrophages significantly enhanced their ability to mediate ADCC. Further analysis revealed that in this model, macrophage-mediated ADCC is dependent upon the release of nitric oxide (NO). However, the PtdIns 3-kinase/Akt pathway does not appear to regulate NO production. An examination of the role of the PtdIns 3-kinase/Akt pathway in regulating conjugate formation indicated that macrophages treated with an inhibitor of PtdIns 3-kinase fail to polarize the cytoskeleton at the synapse and show a significant reduction in the number of conjugates formed with tumor targets. Further, inhibition of PtdIns 3-kinase also reduced macrophage spreading on Rituximab-coated surfaces. On the other hand, Myr-Akt expressing macrophages displayed a significantly greater ability to form conjugates with tumor cells. Taken together, these findings illustrate that the PtdIns 3-kinase/Akt pathway plays a critical role in macrophage ADCC through its influence on conjugate formation between macrophages and antibody-coated tumor cells

Consumer involvement in consent document development: a multicenter cluster randomized trial to assess study participants' understanding.

BACKGROUND: Despite widespread agreement on the importance of informed consent in clinical research, uncertainty remains about the adequacy of current consent procedures and documentation. METHODS: The objective of the study was to compare an informed consent document developed by a consumer group of potential study participants to one developed by the study investigators. The study was a cluster randomized, controlled study embedded in a 'parent' randomized controlled trial of 1092 participants with Gulf War veterans' illnesses recruited in 1999-2000 at 20 US medical centers. Centers were randomized to the investigator-developed or participant-developed consent document. The primary outcome measure was an Informed Consent Questionnaire-4 (ICQ-4), a validated four-item scale measuring self-reported participant understanding scored from 0 to 1. Secondary outcomes included the Client Satisfaction Questionnaire-8 and measures of study refusal and adherence to the parent trial protocol. RESULTS: There were no significant differences between consent documents on the ICQ-4 score overall or at any of the time points. Mean (95% CI) treatment differences ranged from +0.020 (-0.015, 0.055) (better understanding) at entry to -0.021 (-0.054, 0.012) (worse understanding) at three-months for the participant versus the investigator document group. There were also no significant differences in satisfaction, adherence to the protocol, or in the proportion of patients who refused to participate in the trial. LIMITATIONS: The consumer group may not have been representative of the study participants and they did not suggest dramatic changes to the consent document. The outcome assessment questionnaire was not validated prior to the trial's initiation. CONCLUSIONS: Consumer modification of the consent document did not lead to either benefit or harm in understanding, satisfaction, or study refusal and adherence rates. This study did demonstrate, however, that embedding consent studies in a clinical trial is feasible and can address important questions about informed consent without disrupting the primary study