Resolution of the clinical features of tyrosinemia following orthotopic liver transplantation for hepatoma

The clinical history before transplantation and subsequent clinical and biochemical course of 3 children and one adult with hereditary tyrosinemia treated by orthotopic hepatic transplantation is described. All four patients are now free of their previous dietary restrictions and appear to be cured of both their metabolic disease and their hepatic neoplasm. © 1986 Elsevier Science Publishers B.V. All rights reserved

On methods for assessment of the influence and impact of observations in convection-permitting numerical weather prediction

In numerical weather prediction (NWP), a large number of observations are used to create initial conditions for weather forecasting through a process known as data assimilation. An assessment of the value of these observations for NWP can guide us in the design of future observation networks, help us to identify problems with the assimilation system, and allow us to assess changes to the assimilation system. However, the assessment can be challenging in convection-permitting NWP. First, the strong nonlinearity in the forecast model limits the methods available for the assessment. Second, convection-permitting NWP typically uses a limited area model and provides short forecasts, giving problems with verification and our ability to gather sufficient statistics. Third, convection-permitting NWP often makes use of novel observations, which can be difficult to simulate in an observing system simulation experiment (OSSE). We compare methods that can be used to assess the value of observations in convection-permitting NWP and discuss operational considerations when using these methods. We focus on their applicability to ensemble forecasting systems, as these systems are becoming increasingly dominant for convection-permitting NWP. We also identify several future research directions: comparison of forecast validation using analyses and observations, the effect of ensemble size on assessing the value of observations, flow-dependent covariance localization, and generation and validation of the nature run in an OSSE.Comment: 35 page

CubeSat Constellation Cloud Winds(C3Winds) A New Wind Observing System to Study Mesoscale Cloud Dynamics and Processes

The CubeSat Constellation Cloud Winds (C3Winds) is a NASA Earth Venture Instrument (EV-I) concept with the primary objective to better understand mesoscale dynamics and their structures in severe weather systems. With potential catastrophic damage and loss of life, strong extratropical and tropical cyclones (ETCs and TCs) have profound three-dimensional impacts on the atmospheric dynamic and thermodynamic structures, producing complex cloud precipitation patterns, strong low-level winds, extensive tropopause folds, and intense stratosphere-troposphere exchange. Employing a compact, stereo IR-visible imaging technique from two formation-flying CubeSats, C3Winds seeks to measure and map high-resolution (2 km) cloud motion vectors (CMVs) and cloud geometric height (CGH) accurately by tracking cloud features within 5-15 min. Complementary to lidar wind observations from space, the high-resolution wind fields from C3Winds will allow detailed investigations on strong low-level wind formation in an occluded ETC development, structural variations of TC inner-core rotation, and impacts of tropopause folding events on tropospheric ozone and air quality. Together with scatterometer ocean surface winds, C3Winds will provide a more comprehensive depiction of atmosphere-boundary-layer dynamics and interactive processes. Built upon mature imaging technologies and long history of stereoscopic remote sensing, C3Winds provides an innovative, cost-effective solution to global wind observations with potential of increased diurnal sampling via CubeSat constellation

Crystal structures of oligonucleotides including the integrase processing site of the Moloney murine leukemia virus

In the first step of retroviral integration, integrase cleaves the linear viral DNA within its long terminal repeat (LTR) immediately 3′ to the CA dinucleotide step, resulting in a reactive 3′ OH on one strand and a 5′ two base overhang on the complementary strand. In order to investigate the structural properties of the 3′ end processing site within the Moloney murine leukemia virus (MMLV) LTR d(TCTTTCATT), a host-guest crystallographic method was employed to determine the structures of four self-complementary 16 bp oligonucleotides including LTR sequences (underlined), d(TTTCATTGCAATGAAA), d(CTTTCATTAATGAAAG), d(TCTTTCATATGAAAGA) and d(CACAATGATCATTGTG), the guests, complexed with the N-terminal fragment of MMLV reverse transcriptase, the host. The structures of the LTR-containing oligonucleotides were compared to those of non-LTR oligonucleotides crystallized in the same lattice. Properties unique to the CA dinucleotide step within the LTR sequence, independent of its position from the end of the duplex, include a positive roll angle and negative slide value. This propensity for the CA dinucleotide step within the MMLV LTR sequence to adopt only positive roll angles is likely influenced by the more rigid, invariable 3′ and 5′ flanking TT dinucleotide steps and may be important for specific recognition and/or cleavage by the MMLV integrase

An OSSE Investigating a Constellation of 4-5 Micrometer Infrared Sounders

NASA is investigating the utility of a strategically-constructed constellation of infrared sounders on board small satellites to be able to ultimately provide spaceborne measurements of wind. The method proposed by instrument teams is to fly multiple instruments in complementary orbits so that atmospheric motion vector measurements can be made. As part of the investigation of this measurement approach, the Global Modeling and Assimilation Office (GMAO) at NASA Goddard Space Flight Center performed a set of Observing System Simulation Experiments (OSSEs) to demonstrate the value of the wind measurements as well as the corresponding infrared radiance observations that will come from the constellation. This work was an extension of the GMAO OSSE infrastructure and is in the context of the MISTIC Winds concept. It is noted, though, that this provided insight to the overall measurement strategy. This talk addresses the simulation of the atmospheric motion vectors retrieved via the constellation, the simulation and validation of the radiance observations measured via the constellation, the specification of observations errors for both winds and radiances, and the extension of the data assimilation system to utilize these additional observations on top of a full global observation system. Finally, the results from a set of OSSE experiments is presented

Structures of (5′S)-8,5′-Cyclo-2′-deoxyguanosine Mismatched with dA or dT

pubs.acs.org/cr

Curative Effect of 18β-Glycyrrhetinic Acid in Experimental Visceral Leishmaniasis Depends on Phosphatase-Dependent Modulation of Cellular MAP Kinases

We earlier showed that 18β-glycyrrhetinic acid (GRA), a pentacyclic triterpenoid from licorice root, could completely cure visceral leishmaniasis in BALB/c mouse model. This was associated with induction of nitric oxide and proinflammatory cytokine production through the up regulation of NF-κB. In the present study we tried to decipher the underlying cellular mechanisms of the curative effect of GRA. Analysis of MAP kinase pathways revealed that GRA caused strong activation of p38 and to a lesser extent, ERK in bone marrow-derived macrophages (BMDM). Almost complete abrogation of GRA-induced cytokine production in presence of specific inhibitors of p38 and ERK1/2 confirmed the involvement of these MAP kinases in GRA-mediated responses. GRA induced mitogen- and stress-activated protein kinase (MSK1) activity in a time-dependent manner suggested that GRA-mediated NF-κB transactivation is mediated by p38, ERK and MSK1 pathway. As kinase/phosphatase balance plays an important role in modulating infection, the effect of GRA on MAPK directed phosphatases (MKP) was studied. GRA markedly reduced the expression and activities of three phosphatases, MKP1, MKP3 and protein phosphatase 2A (PP2A) along with a substantial reduction of p38 and ERK dephosphorylation in infected BMDM. Similarly in the in vivo situation, GRA treatment of L. donovani-infected BALB/c mice caused marked reduction of spleen parasite burden associated with concomitant decrease of individual phosphatase levels. However, activation of kinases also played an important role as the protective effect of GRA was significantly abrogated by pharmacological inhibition of p38 and ERK pathway. Curative effect of GRA may, therefore, be associated with restoration of proper cellular kinase/phosphatase balance, rather than modulation of either kinases or phosphatases

Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages

Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain preexposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in futur

Designer Lipid-Like Peptides: A Class of Detergents for Studying Functional Olfactory Receptors Using Commercial Cell-Free Systems

A crucial bottleneck in membrane protein studies, particularly G-protein coupled receptors, is the notorious difficulty of finding an optimal detergent that can solubilize them and maintain their stability and function. Here we report rapid production of 12 unique mammalian olfactory receptors using short designer lipid-like peptides as detergents. The peptides were able to solubilize and stabilize each receptor. Circular dichroism showed that the purified olfactory receptors had alpha-helical secondary structures. Microscale thermophoresis suggested that the receptors were functional and bound their odorants. Blot intensity measurements indicated that milligram quantities of each olfactory receptor could be produced with at least one peptide detergent. The peptide detergents' capability was comparable to that of the detergent Brij-35. The ability of 10 peptide detergents to functionally solubilize 12 olfactory receptors demonstrates their usefulness as a new class of detergents for olfactory receptors, and possibly other G-protein coupled receptors and membrane proteins.United States. Defense Advanced Research Projects Agency (DARPA-HR0011-09-C-0012)Massachusetts Institute of Technology. Undergraduate Research Opportunities Progra