Down Selection of Polymerized Bovine Hemoglobins for Use as Oxygen Releasing Therapeutics in a Guinea Pig Model

Editor's Highlight: The development of hemoglobin-based oxygen carriers (HBOCs) as a replacement for whole-blood transfusions has been impeded by their systemic toxicity. This paper presents data from a series of HBOCs, demonstrating one candidate that meets predetermined safety criteria. This approach may allow the development of an acceptable blood substitute for human us

Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification

Detoxification and clearance of extracellular hemoglobin (Hb) have been attributed to its removal by the CD163 scavenger receptor pathway. However, even low-level hydrogen peroxide (H(2)O(2)) exposure irreversibly modifies Hb and severely impairs Hb endocytosis by CD163. We show here that when Hb is bound to the high-affinity Hb scavenger protein haptoglobin (Hp), the complex protects Hb from structural modification by preventing alpha-globin cross-links and oxidations of amino acids in critical regions of the beta-globin chain (eg, Trp15, Cys93, and Cys112). As a result of this structural stabilization, H(2)O(2)-exposed Hb-Hp binds to CD163 with the same affinity as nonoxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163-expressing cells were found to be as efficient as with nonoxidized complex. Hp complex formation did not alter Hb's ability to consume added H(2)O(2) by redox cycling, suggesting that within the complex the oxidative radical burden is shifted to Hp. We provide structural and functional evidence that Hp protects Hb when oxidatively challenged with H(2)O(2) preserving CD163-mediated Hb clearance under oxidative stress conditions. In addition, our data provide in vivo evidence that unbound Hb is oxidatively modified within extravascular compartments consistent with our in vitro findings

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society

Алкогольные виртуальные реальности. Девиртуализация синдрома зависимости от алкоголя

Представлен новый взгляд на синдром зависимости от алкоголя с позиций виртуалистики как на параллельную виртуальную реальность. Подробно освещена рассматриваемая проблема, описан разработанный автором метод лечения алкоголизма ФорсажТМ и показана его высокая эффективность.A new idea about syndrome of alcohol addiction as a parallel virtual reality is presented. The problem is discussed in detail, the original method of treatment of alcoholism Forsazh(tm) is described, its high efficacy is shown

S-system theory applied to array-based GNSS ionospheric sensing

The GPS carrier-phase and code data have proven to be valuable sources of measuring the Earth’s ionospheric total electron content (TEC). With the development of new GNSSs with multi frequency data, many more ionosphere-sensing combinations of different precision can be formed as input of ionospheric modelling. We present the general way of interpreting such combinations through an application of S-system theory and address how their precision propagates into that of the unbiased TEC solution. Presenting the data relevant to TEC determination, we propose the usage of an array of GNSS antennas to improve the TEC precision and to expedite the rather long observational time-span required for high-precision TEC determination

Recent evolution of an ice‐cored moraine at the Gentianes Pass, Valais Alps, Switzerland

International audienceLateral moraines located in permafrost environments often preserve large amounts of both glacier and periglacial ice. To understand how ice‐cored moraines located in high alpine environments evolve in a context of both glacier retreat and permafrost degradation, we performed 11 terrestrial laser‐scanning measurement campaigns between 2007 and 2014 on a highly anthropogenic overprinted moraine prone to instability. Resulting comparison of the subsequent 3D models allowed to qualitatively and quantitatively analyze the morphological evolution of the moraine. The comparisons indicate a very high geomorphic activity of the moraine including large areas affected by downslope movements of blocks and 10 landslides with a volume between 24 ± 1 and 1,138 ± 47 m3. Data also indicated a very strong ice melt with a loss of ice thickness locally reaching 17.7 m at the foot of the moraine. These results, compared with resistivity and thermal measurements of the ground, suggest the combined role of ice loss at the foot of the moraine and the permafrost activity/warming in triggering these processes

Ionospheric modelling using GPS to calibrate the MWA. 1 : Comparison of first order ionospheric effects between GPS models and MWA observations

This document is the Accepted Manuscript version of the following article: B. S. Arora, et al, ‘Ionospheric Modelling using GPS to Calibrate the MWA. I: Comparison of First Order Ionospheric Effects between GPS Models and MWA Observations’, Publications of the Astronomical Society of Australia, Vol. 32, e029, August 2015. The final, published version is available online at doi: https://doi.org/10.1017/pasa.2015.29. COPYRIGHT: © Astronomical Society of Australia 2015.We compare first order (refractive) ionospheric effects seen by the Murchison Widefield Array (MWA) with the ionosphere as inferred from Global Positioning System (GPS) data. The first order ionosphere manifests itself as a bulk position shift of the observed sources across an MWA field of view. These effects can be computed from global ionosphere maps provided by GPS analysis centres, namely the Center for Orbit Determination in Europe (CODE), using data from globally distributed GPS receivers. However, for the more accurate local ionosphere estimates required for precision radio astronomy applications, data from local GPS networks needs to be incorporated into ionospheric modelling. For GPS observations, the ionospheric parameters are biased by GPS receiver instrument delays, among other effects, also known as receiver Differential Code Biases (DCBs). The receiver DCBs need to be estimated for any non-CODE GPS station used for ionosphere modelling, a requirement for establishing dense GPS networks in arbitrary locations in the vicinity of the MWA. In this work, single GPS station-based ionospheric modelling is performed at a time resolution of 10 minutes. Also the receiver DCBs are estimated for selected Geoscience Australia (GA) GPS receivers, located at Murchison Radio Observatory (MRO1), Yarragadee (YAR3), Mount Magnet (MTMA) and Wiluna (WILU). The ionospheric gradients estimated from GPS are compared with the ionospheric gradients inferred from radio source position shifts observed with the MWA. The ionospheric gradients at all the GPS stations show a correlation with the gradients observed with the MWA. The ionosphere estimates obtained using GPS measurements show promise in terms of providing calibration information for the MWA.Peer reviewe

Differential Expression of CD163 on Monocyte Subsets in Healthy and HIV-1 Infected Individuals

CD163, a haptoglobin-hemoglobin (Hp-Hb) scavenger receptor, expressed by monocytes and macrophages, is important in resolution of inflammation. Age-related non-AIDS co-morbidities in HIV-infected individuals, particularly dementia and cardiovascular disease, result in part from effects of HIV-1 infection on monocyte and macrophage biology. CD163 co-expression on CD14+CD16++ monocytes has been proposed as a useful biomarker for HIV-1 disease progression and the presence of HIV associated dementia. Here we investigated CD163 expression on monocyte subsets ex vivo, on cultured macrophages, and soluble in plasma, in the setting of HIV-1 infection. Whole blood immunophenotyping revealed CD163 expression on CD14++CD16- monocytes but not on CD14+CD16++ monocytes (P = 0.004), supported by CD163 mRNA levels. Incubation with M-CSF induced CD163 protein expression on CD14+CD16++ monocytes to the same extent as CD14++CD16− monocytes. CD163 expression on CD14++CD16+ monocytes from HIV-infected subjects was significantly higher than from uninfected individuals, with a trend towards increased expression on CD14++CD16− monocytes (P = 0.019 and 0.069 respectively), which is accounted for by HIV-1 therapy including protease inhibitors. Shedding of CD163 was shown to predominantly occur from the CD14++CD16− subset after Ficoll isolation and LPS stimulation. Soluble CD163 concentration in plasma from HIV-1 infected donors was similar to HIV-1 uninfected donors. Monocyte CD163 expression in HIV-1 infected patients showed a complicated relationship with classical measures of disease progression. Our findings clarify technical issues regarding CD163 expression on monocyte subsets and further elucidates its role in HIV-associated inflammation by demonstrating that CD163 is readily lost from CD14++CD16− monocytes and induced in pro-inflammatory CD14+CD16++ monocytes by M-CSF. Our data show that all monocyte subsets are potentially capable of differentiating into CD163-expressing anti-inflammatory macrophages given appropriate stimuli. Levels of CD163 expression on monocytes may be a potential biomarker reflecting efforts by the immune system to resolve immune activation and inflammation in HIV-infected individuals