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Medical School: University Of Pittsburgh School Of Medicine - 1996
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The spin and orbital contributions to the total magnetic moments of free Fe, Co, and Ni clusters. - The Journal of chemical physics
We present size dependent spin and orbital magnetic moments of cobalt (Con (+), 8 â‰¤ n â‰¤ 22), iron (Fen (+), 7 â‰¤ n â‰¤ 17), and nickel cluster (Nin (+), 7 â‰¤ n â‰¤ 17) cations as obtained by X-ray magnetic circular dichroism (XMCD) spectroscopy of isolated clusters in the gas phase. The spin and orbital magnetic moments range between the corresponding atomic and bulk values in all three cases. We compare our findings to previous XMCD data, Stern-Gerlach data, and computational results. We discuss the application of scaling laws to the size dependent evolution of the spin and orbital magnetic moments per atom in the clusters. We find a spin scaling law "per cluster diameter," âˆ¼n(-1/3), that interpolates between known atomic and bulk values. In remarkable contrast, the orbital moments do likewise only if the atomic asymptote is exempt. A concept of "primary" and "secondary" (induced) orbital moments is invoked for interpretation.
Orbit and spin resolved magnetic properties of size selected [ConRh](+) and [ConAu](+) nanoalloy clusters. - Physical chemistry chemical physics : PCCP
Bi-metallic nanoalloys of mixed 3d-4d or 3d-5d elements are promising candidates for technological applications. The large magnetic moment of the 3d materials in combination with a high spin-orbit coupling of the 4d or 5d materials give rise to a material with a large magnetic moment and a strong magnetic anisotropy, making them ideally suitable in for example magnetic storage devices. Especially for clusters, which already have a higher magnetic moment compared to the bulk, these alloys can profit from the cooperative role of alloying and size reduction in order to obtain magnetically stable materials with a large magnetic moment. Here, the influence of doping of small cobalt clusters on the spin and orbital magnetic moment has been studied for the cations [Co8-14Au](+) and [Co10-14Rh](+). Compared to the undoped pure cobalt [CoN](+) clusters we find a significant increase in the spin moment for specific CoN-1Au(+) clusters and a very strong increase in the orbital moment for some CoN-1Rh(+) clusters, with more than doubling for Co12Rh(+). This result shows that substitutional doping of a 3d metal with even just one atom of a 4d or 5d metal can lead to dramatic changes in both spin and orbital moment, opening up the route to novel applications.
Less Is More: Low-dose Prothrombin Complex Concentrate Effective in Acute Care Surgery Patients. - The American surgeon
Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (Â± 10%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18-94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) nontrauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking prehospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion.
Kinetic analysis of PCNA clamp binding and release in the clamp loading reaction catalyzed by Saccharomyces cerevisiae replication factor C. - Biochimica et biophysica acta
DNA polymerases require a sliding clamp to achieve processive DNA synthesis. The toroidal clamps are loaded onto DNA by clamp loaders, members of the AAA+family of ATPases. These enzymes utilize the energy of ATP binding and hydrolysis to perform a variety of cellular functions. In this study, a clamp loader-clamp binding assay was developed to measure the rates of ATP-dependent clamp binding and ATP-hydrolysis-dependent clamp release for the Saccharomyces cerevisiae clamp loader (RFC) and clamp (PCNA). Pre-steady-state kinetics of PCNA binding showed that although ATP binding to RFC increases affinity for PCNA, ATP binding rates and ATP-dependent conformational changes in RFC are fast relative to PCNA binding rates. Interestingly, RFC binds PCNA faster than the Escherichia coli Î³ complex clamp loader binds the Î²-clamp. In the process of loading clamps on DNA, RFC maintains contact with PCNA while PCNA closes, as the observed rate of PCNA closing is faster than the rate of PCNA release, precluding the possibility of an open clamp dissociating from DNA. Rates of clamp closing and release are not dependent on the rate of the DNA binding step and are also slower than reported rates of ATP hydrolysis, showing that these rates reflect unique intramolecular reaction steps in the clamp loading pathway.Copyright Â© 2014 Elsevier B.V. All rights reserved.
Methotrexate-gelonin conjugate - an inhibitor of MCF-7 cells expressing the dihydrofolate receptor. - Biological chemistry
An immunotoxin composed of gelonin, a basic ribosome-inactivating protein, type I of 30 kDa, isolated from the seeds of the Indian plant Gelonium multiflorum and methotrexate (MTX) has been studied as a potential tool of gelonin delivery into the cytoplasm of MTX-responsive cells. On the average, about five molecules of methotrexate were chemically coupled to gelonin via an N-hydroxysuccinimide ester of the drug. The MTX-gelonin conjugate was able to reduce the viability of MCF-7 cells in a dose-dependent manner with ID50 of 10 nm, whereas gelonin or MTX alone showed none or very little effects. Besides its ribosome-inactivating activity, which is about ten-fold lower in an in vitro translation assay (IC50 of 50.5 ng/ml as compared to 4.6 ng/ml), the conjugate also significantly induced direct and oxidative DNA damage as shown by the alkaline comet assay. Hence, MTX-gelonin conjugates are promising candidates for the treatment of MTX-responsive cancers.
Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector function but does not prevent deletional tolerance. - Journal of leukocyte biology
CD8(+) T cells must detect foreign antigens and differentiate into effector cells to eliminate infections. But, when self-antigen is recognized instead, mechanisms of peripheral tolerance prevent acquisition of effector function to avoid autoimmunity. These distinct responses are influenced by inflammatory and regulatory clues from the tissue environment, but the mechanism(s) by which naive T cells interpret these signals to generate the appropriate immune response are unclear. The identification of the molecules operative in these cell-fate decisions is crucial for developing new treatment options for patients with cancer or autoimmunity, where manipulation of T cell activity is desired to alter the course of disease. With the use of an in vivo murine model to examine CD8(+) T cell responses to healthy self-tissue, we correlated self-tolerance with a failure to induce the T-box transcription factors T-bet and Eomes. However, inflammation associated with acute microbial infection induced T-bet and Eomes expression and promoted effector differentiation of self-reactive T cells under conditions that normally favor tolerance. In the context of a Listeria infection, these functional responses relied on elevated T-bet expression, independent of Eomes. Alternatively, infection with LCMV induced higher Eomes expression, which was sufficient in the absence of T-bet to promote effector cytokine production. Our results place T-box transcription factors at a molecular crossroads between CD8(+) T cell anergy and effector function upon recognition of peripheral self-antigen, and suggest that inflammation during T cell priming directs these distinct cellular responses.Â© 2014 Society for Leukocyte Biology.
Reproductive physiology in eastern snapping turtles (Chelydra serpentina) exposed to runoff from a concentrated animal feeding operation. - Journal of wildlife diseases
The eastern snapping turtle (Chelydra serpentina) is widely distributed throughout the eastern and central US and is a useful model organism to study land-use impacts on water quality. We compared the reproductive condition of turtles from a pond impacted by runoff from land applied with animal manure from a concentrated animal feeding operation (CAFO) relative to animals from a control pond. Turtles from the CAFO site were heavier and had higher plasma concentrations of vitellogenin (VTG, mean Â± SE; females; 859 Â± 115 vs. 401 Â± 127 ng/mL from controls) and testosterone (T, males; 39 Â± 7.0 vs. 3.8 Â± 6.9 ng/mL from controls). No VTG was detected in males. Body mass was positively correlated with VTG and T. Our results suggest that nutrient pollution of the CAFO pond indirectly resulted in higher plasma VTG in females and T in males because of an increase in body mass. The population-level consequences of these effects are not clear, but could result in females producing larger clutches.
Topographic diversity of fungal and bacterial communities in human skin. - Nature
Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete's foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota. Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders. However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease. Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria. Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes. Here we sequenced and analysed fungal communities of 14â€‰skin sites in 10â€‰healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites--plantar heel, toenail and toe web--showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis.
Protease-activated receptor 1 inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts. - Journal of cardiovascular pharmacology and therapeutics
Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemic cardiomyopathy. Transforming growth factor-Î² (TGF-Î²) is a potent stimulus for fibrosis, and the extracellular signal-regulated kinases(ERK) 1/2 pathway also contributes to the fibrotic response. The thrombin receptor, protease-activated receptor 1 (PAR1), has been shown to play an important role in the excessive fibrosis in different tissues. The aim of this study was to investigate the influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effects of PAR1 inhibition on thrombin-induced TGF-Î² and (ERK) 1/2 activities in cardiac fibroblasts.We used a rat model of myocardial ischemia-reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated to ascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling.The PAR1 inhibitor attenuated LV dilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with a nonsignificant decrease in scar size (%LV) from 23 Â± % in the control group (n = 10) to 16% Â± 5.5% in the treated group (n = 9; P = .052). In the short term, the PAR1 inhibitor did not rescue infarct size or LV systolic function after 3 days. The PAR1 inhibition abolished thrombin-mediated ERK1/2 phosphorylation, TGF-Î² and type I procollagen production, matrix metalloproteinase-2/9 activation, myofibroblasts transformation in vitro, and abrogated the remodeling of 3D tissues induced by chronic thrombin treatment.These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodeling through late-stage antifibrotic events.
CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor. - Immunological investigations
During chronic viral infections, responses by virus-specific CD8(+) T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8(+) T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8(+) T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8(+) T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus-specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction.
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