Technical Note: Is radiation important for the high amplitude variability of the MOC in the North Atlantic?

International audienceRadiation is of fundamental importance to climate modeling and it is customary to assume that it is also important for the variability of North Atlantic Deep Water (NADW) formation and the meridional overturning cell (MOC). Numerous articles follow this scenario and incorporate radiation into the calculation. Using relatively old heat-flux maps based on measurements taken in the nineteen sixties, Sandal and Nof (2007) recently suggested that, even though the radiation terms are of the same order as the other heat-flux terms, they are not important for the variability of the NADW and the MOC. They proposed that only sensible and latent heat fluxes are important for the long-term variability of the convection, i.e., for processes such as Heinrich events, which supposedly correspond to turning convection on-and-off in the Atlantic. Here, we place this suggestion on a firmer ground by presenting new and accurate up-to-date heat flux maps that also suggest that the radiation is of no major consequence to the NADW variability. Also, we attribute the relative importance of sensible and latent heat fluxes and the contrasting negligible role of radiation to the fact that the latent and sensible heat fluxes are primarily proportional to the difference between the sea surface and the air temperature whereas the radiation is primarily proportional to the sea surface temperature, i.e., radiation is approximately independent of the atmospheric temperature. Due the small heat capacity ratio of air/water (1/4), the difference between the ocean temperature and the air temperature varies dramatically between the state of active and inactive MOC, whereas the ocean temperature by itself varies very modestly between a state of active and inactive convection

Tat RNA silencing suppressor activity contributes to perturbation of lymphocyte miRNA by HIV-1

<p>Abstract</p> <p>Background</p> <p>MicroRNA (miRNA)-mediated RNA silencing is integral to virtually every cellular process including cell cycle progression and response to virus infection. The interplay between RNA silencing and HIV-1 is multifaceted, and accumulating evidence posits a strike-counterstrike interface that alters the cellular environment to favor virus replication. For instance, miRNA-mediated RNA silencing of HIV-1 translation is antagonized by HIV-1 Tat RNA silencing suppressor activity. The activity of HIV-1 accessory proteins Vpr/Vif delays cell cycle progression, which is a process prominently modulated by miRNA. The expression profile of cellular miRNA is altered by HIV-1 infection in both cultured cells and clinical samples. The open question stands of what, if any, is the contribution of Tat RNA silencing suppressor activity or Vpr/Vif activity to the perturbation of cellular miRNA by HIV-1.</p> <p>Results</p> <p>Herein, we compared the perturbation of miRNA expression profiles of lymphocytes infected with HIV-1^NL4-3or derivative strains that are deficient in Tat RNA silencing suppressor activity (Tat K51A substitution) or ablated of the vpr/vif open reading frames. Microarrays recapitulated the perturbation of the cellular miRNA profile by HIV-1 infection. The miRNA expression trends overlapped ~50% with published microarray results on clinical samples from HIV-1 infected patients. Moreover, the number of miRNA perturbed by HIV-1 was largely similar despite ablation of Tat RSS activity and Vpr/Vif; however, the Tat RSS mutation lessened HIV-1 downregulation of twenty-two miRNAs.</p> <p>Conclusions</p> <p>Our study identified miRNA expression changes attributable to Tat RSS activity in HIV-1^NL4-3. The results accomplish a necessary step in the process to understand the interface of HIV-1 with host RNA silencing activity. The overlap in miRNA expression trends observed between HIV-1 infected CEMx174 lymphocytes and primary cells supports the utility of cultured lymphocytes as a tractable model to investigate interplay between HIV-1 and host RNA silencing. The subset of miRNA determined to be perturbed by Tat RSS in HIV-1 infection provides a focal point to define the gene networks that shape the cellular environment for HIV-1 replication.</p

Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.This work was supported, in part, by NIH grants CA122694 (to K. Ghoshal), DK088076 (to K. Ghoshal), CA086978 (to K. Ghoshal and S.T. Jacob), Pelotonia Idea Grant (to J. Yu and K. Ghoshal), CA120185 (to J.T. Mendell), CA134292 (to J.T. Mendell), and the Cancer Prevention and Research Institute of Texas (to J.T. Men- dell). Bo Wang is supported by a Pelotonia graduate fellowship

Initial experience with off-pump left ventricular assist device implantation in single center: retrospective analysis

<p>Abstract</p> <p>Background</p> <p>We hypothesize that implantation of left ventricular assist device through off-pump technique is feasible and has a comparable result to implantation on cardiopulmonary bypass and could improve one-year survival.</p> <p>Methods</p> <p>This retrospective, observational, single-center study was conducted on 29 consecutive patients at our institution who underwent off-pump left ventricular assist device implantation by a single surgeon.</p> <p>Results</p> <p>Twenty-seven procedures were performed successfully using the off-pump technique. The survival rate was 92% at 30 days, 76% at 90 days, and 67% at one year. We compared the one-year survival of different implantation periods, and divided our study into three time intervals (2004-2005, 2006, and 2007). There was a trend in reduction in number of deaths over one year that demonstrated a decrease in death rate from 50% to 17%, as well as improvement in our experience over time. However, this trend is not statistically significant (p = 0.08) due to limited sample size.</p> <p>Conclusions</p> <p>Based upon our findings, off-pump left ventricular assist device implantation is a feasible surgical technique, and combining this technique with improved device technology in the future may provide even greater improvement in patient outcomes.</p

Stabilin receptors clear LPS and control systemic inflammation

Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1

RNA helicase A modulates translation of HIV-1 and infectivity of progeny virions

Retroviruses rely on host RNA-binding proteins to modulate various steps in their replication. Previously several animal retroviruses were determined to mediate Dhx9/RNA helicase A (RHA) interaction with a 5′ terminal post-transcriptional control element (PCE) for efficient translation. Herein PCE reporter assays determined HTLV-1 and HIV-1 RU5 confer orientation-dependent PCE activity. The effect of Dhx9/RHA down-regulation and rescue with siRNA-resistant RHA on expression of HIV-1NL4–3 provirus determined that RHA is necessary for efficient HIV-1 RNA translation and requires ATPase-dependent helicase function. Quantitative analysis determined HIV-1 RNA steady-state and cytoplasmic accumulation were not reduced; rather the translational activity of viral RNA was reduced. Western blotting determined that RHA-deficient virions assemble with Lys-tRNA synthetase, exhibit processed reverse transcriptase and contain similar level of viral RNA, but they are poorly infectious on primary lymphocytes and HeLa cells. The results demonstrate RHA is an important host factor within the virus-producer cell and within the viral particle. The identification of RHA-dependent PCE activity in cellular junD RNA and in six of seven genera of Retroviridae suggests conservation of this translational control mechanism among vertebrates, and convergent evolution of Retroviridae to utilize this host mechanism

A semi-nonparametric mixture model for selecting functionally consistent proteins

Background High-throughput technologies have led to a new era of proteomics. Although protein microarray experiments are becoming more common place there are a variety of experimental and statistical issues that have yet to be addressed, and that will carry over to new high-throughput technologies unless they are investigated. One of the largest of these challenges is the selection of functionally consistent proteins. Results We present a novel semi-nonparametric mixture model for classifying proteins as consistent or inconsistent while controlling the false discovery rate and the false non-discovery rate. The performance of the proposed approach is compared to current methods via simulation under a variety of experimental conditions. Conclusions We provide a statistical method for selecting functionally consistent proteins in the context of protein microarray experiments, but the proposed semi-nonparametric mixture model method can certainly be generalized to solve other mixture data problems. The main advantage of this approach is that it provides the posterior probability of consistency for each protein

Impact of aprotinin and renal function on mortality: a retrospective single center analysis

<p>Abstract</p> <p>Background</p> <p>An estimated up to 7% of high-risk cardiac surgery patients return to the operating room for bleeding. Aprotinin was used extensively as an antifibrinolytic agent in cardiac surgery patients for over 15 years and it showed efficacy in reducing bleeding. Aprotinin was removed from the market by the U.S. Food and Drug Administration after a large prospective, randomized clinical trial documented an increased mortality risk associated with the drug. Further debate arose when a meta-analysis of 211 randomized controlled trials showed no risk of renal failure or death associated with aprotinin. However, only patients with normal kidney function have been studied.</p> <p>Methods</p> <p>In this study, we look at a single center clinical trial using patients with varying degrees of baseline kidney function to answer the question: Does aprotinin increase odds of death given varying levels of preoperative kidney dysfunction?</p> <p>Results</p> <p>Based on our model, aprotinin use was associated with a 3.8-fold increase in odds of death one year later compared to no aprotinin use with p-value = 0.0018, regardless of level of preoperative kidney dysfunction after adjusting for other perioperative variables.</p> <p>Conclusions</p> <p>Lessons learned from our experience using aprotinin in the perioperative setting as an antifibrinolytic during open cardiac surgery should guide us in testing future antifibrinolytic drugs for not only efficacy of preventing bleeding, but for overall safety to the whole organism using long-term clinical outcome studies, including those with varying degree of baseline kidney function.</p

Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation

: Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to&nbsp;RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases