Techniques used to identify the Brazilian variant of HIV-1 subtype B

The purpose of the present study was to compare the sensitivity and specificity of V3 enzyme immunoassay (solid phase EIA and EIA inhibition) and restriction fragment length polymorphism (RFLP) with the DNA sequencing "gold standard" to identify the Brazilian HIV-1 variants of subtype B and B"-GWGR. Peripheral blood mononuclear cells were collected from 61 HIV-1-infected individuals attending a clinic in São Paulo. Proviral DNA was amplified and sequentially cleaved with the Fok I restriction enzyme. Plasma samples were submitted to a V3-loop biotinylated synthetic peptide EIA. Direct partial DNA sequencing of the env gene was performed on all samples. Based on EIA results, the sensitivity for detecting B-GPGR was 70%, compared to 64% for the Brazilian variant B"-GWGR while, the specificity of B-GPGR detection was 85%, compared to 88% for GWGR. The assessment of RFLP revealed 68% sensitivity and 94% specificity for the B-GPGR strain compared to 84 and 90% for the B"-GWGR variant. Moreover, direct DNA sequencing was able to detect different base sequences corresponding to amino acid sequences at the tip of the V3 loop in 22 patients. These results show a similar performance of V3 serology and RLFP in identifying the Brazilian variant GWGR. However, V3 peptide serology may give indeterminate results. Therefore, we suggest that V3 serology be used instead of DNA sequencing where resources are limited. Samples giving indeterminate results by V3 peptide serology should be analyzed by direct DNA sequencing to distinguish between B-GPGR and the Brazilian variant B"-GWGR

Global ocean modeling and state estimation in support of climate research

During the last decade it has become obvious that the ocean circulation shows vigorous variability on a wide range of time and space scales and that the concept of a "sluggish" and slowly varying circulation is rather elusive. Increasing emphasis has to be put, therefore, on observing the rapidly changing ocean state on time scales ranging from weeks to decades and beyond, and on understanding the ocean's response to changing atmospheric forcing conditions. As outlined in various strategy and implementation documents (e.g., the implementation plans of WOCE, AMS, CLIVAR, and GODAE) a combination of the global ocean data sets with a state-of-the-art numerical circulation model is required to interpret the various diverse data sets and to produce the best possible estimates of the time-varying ocean circulation. The mechanism of ocean state estimates is a powerful tool for such a "synthesis" of observations, obtained on very complex space-time pattern, into one dynamically consistent picture of the global time-evolving ocean circulation. This process has much in common with ongoing analysis and reanalysis activities in the atmospheric community. But because the ocean is, and will remain for the foreseeable future, substantially under-sampled, the burden put on the modeling and estimations components is substantially larger than in the atmosphere. Moreover, the smaller dynamical eddy scales which need to be properly parameterized or resolved in ocean model simulations, put stringent requirements on computational resources for ongoing and participated climate research

Sea Level and the role of coastal trapped waves in mediating the influence of the open ocean on the coast

The fact that ocean currents must flow parallel to the coast leads to the dynamics of coastal sea level being quite different from the dynamics in the open ocean. The coastal influence of open-ocean dynamics (dynamics associated with forcing which occurs in deep water, beyond the continental slope) therefore involves a hand-over between the predominantly geostrophic dynamics of the interior ocean and the ageostrophic dynamics which must occur at the coast. An understanding of how this hand-over occurs can be obtained by considering the combined role of coastal trapped waves and bottom friction. We here review understanding of coastal trapped waves, which propagate cyclonically around ocean basins along the continental shelf and slope, at speeds which are fast compared to those of baroclinic planetary waves and currents in the open ocean (excluding the large-scale barotropic mode). We show that this results in coastal sea-level signals on western boundaries which, compared to the nearby open-ocean signals, are spatially smoothed, reduced in amplitude, and displaced along the coast in the direction of propagation of coastal trapped waves. The open-ocean influence on eastern boundaries is limited to signals propagating polewards from the equatorial waveguide (although a large-scale diffusive influence may also play a role). This body of work is based on linearised equations, but we also discuss the nonlinear case. We suggest that a proper consideration of nonlinear terms may be very important on western boundaries, as the competition between advection by western boundary currents and a counter-propagating influence of coastal trapped waves has the potential to lead to sharp gradients in coastal sea level where the two effects come into balance

An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C-terminal to histidine 157, a position where an AD-associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig-like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full-length TREM2 and lowers TREM2-dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2

Successful treatment of pediatric IgG4 related systemic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune pancreatitis literature

Autoimmune pancreatitis is frequently associated with elevated serum and tissue IgG4 levels in the adult population, but there are few reports of pediatric autoimmune pancreatitis, and even fewer reports of IgG4 related systemic disease in a pediatric population. The standard of care treatment in adults is systemic corticosteroids with resolution of symptoms in most cases; however, multiple courses of corticosteroids are occasionally required and some patients require long term corticosteroids. In these instances, steroid sparing disease modify treatments are in demand. We describe a 13-year-old girl with IgG4 related systemic disease who presented with chronic recurrent autoimmune pancreatitis resulting in surgical intervention for obstructive hyperbilirubinemia and chronic corticosteroid treatment. In addition, she developed fibrosing medianstinitis as part of her IgG4 related systemic disease. She was eventually successfully treated with mycophenolate mofetil allowing for discontinuation of corticosteroids. This is the first reported use of mycophenolate mofetil for IgG4 related pancreatitis. Although autoimmune pancreatitis as part of IgG4 related systemic disease is rarely reported in pediatrics, autoimmune pancreatitis is also characterized as idiopathic fibrosing pancreatitis. All pediatric autoimmune pancreatitis cases reported in the world medical literature were identified via a PUBMED search and are reviewed herein. Twelve reports of pediatric autoimmune pancreatitis were identified, most of which were treated with corticosteroids or surgical approaches. Most case reports failed to report IgG4 levels, so it remains unclear how commonly IgG4 related autoimmune pancreatitis occurs during childhood. Increased evaluation of IgG4 levels in patients with autoimmune pancreatitis may shed further light on the association of IgG4 with pancreatitis and the underlying pathophysiology

Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment

Prostate cancer will develop chemoresistance following a period of chemotherapy. This is due, in part, to the acquisition of antiapoptotic properties by the cancer cells and, therefore, development of novel strategies for treatment is of critical need. Here, we attempt to clarify the role of the antiapoptotic molecule galectin-3 in prostate cancer cells using siRNA and antagonist approaches. The data showed that Gal-3 inhibition by siRNA or its antagonist GCS-100/modified citrus pectin (MCP) increased cisplatin-induced apoptosis of PC3 cells. Recent studies have indicated that cisplatin-induced apoptosis may be mediated by calpain, a calcium-dependent protease, as its activation leads to cleavage of androgen receptor into an androgen-independent isoform in prostate cancer cells. Thus, we examined whether calpain activation is associated with the Gal-3 function of regulating apoptosis. Here, we report that Gal-3 inhibition by siRNA or GCS-100/MCP enhances calpain activation, whereas Gal-3 overexpression inhibits it. Inhibition of calpain using its inhibitor and/or siRNA attenuated the proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate cancer is suggested whereby a combination of a non-toxic anti-Gal-3 drug together with a toxic chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers

Thermohaline structure in the California Current System : observations and modeling of spice variance

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C02008, doi:10.1029/2011JC007589.Upper ocean thermohaline structure in the California Current System is investigated using sustained observations from autonomous underwater gliders and a numerical state estimate. Both observations and the state estimate show layers distinguished by the temperature and salinity variability along isopycnals (i.e., spice variance). Mesoscale and submesoscale spice variance is largest in the remnant mixed layer, decreases to a minimum below the pycnocline near 26.3 kg m−3, and then increases again near 26.6 kg m−3. Layers of high (low) meso- and submesoscale spice variance are found on isopycnals where large-scale spice gradients are large (small), consistent with stirring of large-scale gradients to produce smaller scale thermohaline structure. Passive tracer adjoint calculations in the state estimate are used to investigate possible mechanisms for the formation of the layers of spice variance. Layers of high spice variance are found to have distinct origins and to be associated with named water masses; high spice variance water in the remnant mixed layer has northerly origin and is identified as Pacific Subarctic water, while the water in the deeper high spice variance layer has southerly origin and is identified as Equatorial Pacific water. The layer of low spice variance near 26.3 kg m−3 lies between the named water masses and does not have a clear origin. Both effective horizontal diffusivity, κh, and effective diapycnal diffusivity, κv, are elevated relative to the diffusion coefficients set in the numerical simulation, but changes in κh and κv with depth are not sufficient to explain the observed layering of thermohaline structure.We gratefully acknowledge funding from the Gordon and Betty Moore Foundation, the Coastal Ocean Currents Monitoring Project (COCMP), and NOAA. R. E. Todd was partially supported by the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution, with funding provided by the Cooperative Institute for the North Atlantic Region.2012-08-0

Galectins as immunoregulators during infectious processes: from microbial invasion to the resolution of the disease

Recent evidence has implicated galectins, a family of evolutionarily conserved carbohydrate-binding proteins, as regulators of immune cell homeostasis and host-pathogen interactions. Galectins operate at different levels of innate and adaptive immune responses, by modulating cell survival and cell activation or by influencing the Th1/Th2 cytokine balance. Furthermore, galectins may contribute to host-pathogen recognition and may serve as receptors for specific interactions of pathogens with their insect vectors. Here we will explore the influence of galectins in immunological processes relevant to microbial infection and will summarize exciting recent work related to the specific interactions between galectins and their glycoconjugate ligands as critical determinants of pathogen recognition. Understanding the role of galectin-sugar interactions during the course of microbial infections might contribute to defining novel targets for disease prevention and immune intervention.Fil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Steric sea level variability (1993-2010) in an ensemble of ocean reanalyses and objective analyses

Quantifying the effect of the seawater density changes on sea level variability is of crucial importance for climate change studies, as the sea level cumulative rise can be regarded as both an important climate change indicator and a possible danger for human activities in coastal areas. In this work, as part of the Ocean Reanalysis Intercomparison Project, the global and regional steric sea level changes are estimated and compared from an ensemble of 16 ocean reanalyses and 4 objective analyses. These estimates are initially compared with a satellite-derived (altimetry minus gravimetry) dataset for a short period (2003–2010). The ensemble mean exhibits a significant high correlation at both global and regional scale, and the ensemble of ocean reanalyses outperforms that of objective analyses, in particular in the Southern Ocean. The reanalysis ensemble mean thus represents a valuable tool for further analyses, although large uncertainties remain for the inter-annual trends. Within the extended intercomparison period that spans the altimetry era (1993–2010), we find that the ensemble of reanalyses and objective analyses are in good agreement, and both detect a trend of the global steric sea level of 1.0 and 1.1 ± 0.05 mm/year, respectively. However, the spread among the products of the halosteric component trend exceeds the mean trend itself, questioning the reliability of its estimate. This is related to the scarcity of salinity observations before the Argo era. Furthermore, the impact of deep ocean layers is non-negligible on the steric sea level variability (22 and 12 % for the layers below 700 and 1500 m of depth, respectively), although the small deep ocean trends are not significant with respect to the products spread