Computerized texture analysis of atypical immature myeloid precursors in patients with myelodysplastic syndromes: an entity between blasts and promyelocytes

<p>Abstract</p> <p>Background</p> <p>Bone marrow (BM) blast count is an essential parameter for classification and prognosis of myelodysplastic syndromes (MDS). However, a high degree of cell atypias in bone marrow hemopoietic cells may be found in this group of clonal disorders, making it difficult to quantify precisely myeloblasts, and to distinguish them from promyelocytes and atypical immature myeloid precursors. Our aim was to investigate whether computerized image analysis of routine cytology would help to characterize these cells.</p> <p>Methods</p> <p>In May-Grünwald-Giemsa stained BM smears of 30 newly diagnosed MDS patients and 19 cases of normal BM, nuclei of blasts and promyelocytes were digitalized and interactively segmented. The morphological classification of the cells was done by consensus of two observers. Immature granulocytic precursors, which could not be clearly classified either as blasts or promyelocytes, were called "atypic myeloid precursors". Nuclear morphometry and texture features derived from the co-occurrence matrix and fractal dimension (FD) were calculated.</p> <p>Results</p> <p>In normal BM, when compared to myeloblasts, nuclei of promyelocytes showed significant increase in perimeter and local texture homogeneity and a decrease in form factor, chromatin gray levels, Haralick's entropy, inertia, energy, contrast, diagonal moment, cluster prominence, the fractal dimension according to Minkowski and its goodness-of-fit. Compared to normal myeloblast nuclei, the chromatin texture of MDS myeloblasts revealed higher local homogeneity and goodness-of-fit of the FD, but lower values of entropy, contrast, diagonal moment, and fractal dimension. The same differences were found between nuclei of normal promyelocytes and those of MDS. Nuclei of atypical myeloid precursors showed intermediate characteristics between those of blasts and promyelocytes according to the quantitative features (perimeter, form factor, gray level and its standard deviation), but were similar to promyelocytes according to the texture variables inertia, energy, contrast, diagonal moment, cluster prominence, and Minkowski's fractal dimension.</p> <p>Conclusion</p> <p>BM atypical immature myeloid precursors are difficult to be correctly classified in routine cytology. Although their cytoplasm is more similar to that of myeloblasts, computerized texture analysis indicates a nuclear chromatin remodeling more close to the promyelocyte, thus indicating an asynchronous intermediate maturation stage between blast and promyelocyte.</p

Platinum-group elements, S, Se and Cu in highly depleted abyssal peridotites from the Mid-Atlantic Ocean Ridge (ODP Hole 1274A): Influence of hydrothermal and magmatic processes

Highly depleted harzburgites and dunites were recovered from ODP Hole 1274A, near the intersection between the Mid-Atlantic Ocean Ridge and the 15°20′N Fracture Zone. In addition to high degrees of partial melting, these peridotites underwent multiple episodes of melt-rock reaction and intense serpentinization and seawater alteration close to the seafloor. Low concentrations of Se, Cu and platinum-group elements (PGE) in harzburgites drilled at around 35-85 m below seafloor are consistent with the consumption of mantle sulfides after high degrees (>15-20 %) of partial melting and redistribution of chalcophile and siderophile elements into PGE-rich residual microphases. Higher concentrations of Cu, Se, Ru, Rh and Pd in harzburgites from the uppermost and lowest cores testify to late reaction with a sulfide melt. Dunites were formed by percolation of silica- and sulfur-undersaturated melts into low-Se harzburgites. Platinum-group and chalcophile elements were not mobilized during dunite formation and mostly preserve the signature of precursor harzburgites, except for higher Ru and lower Pt contents caused by precipitation and removal of platinum-group minerals. During serpentinization at low temperature (<250 °C) and reducing conditions, mantle sulfides experienced desulfurization to S-poor sulfides (mainly heazlewoodite) and awaruite. Contrary to Se and Cu, sulfur does not record the magmatic evolution of peridotites but was mostly added in hydrothermal sulfides and sulfate from seawater. Platinum-group elements were unaffected by post-magmatic low-temperature processes, except Pt and Pd that may have been slightly remobilized during oxidative seawater alteration

Sulfide melts and long-term low seismic wavespeeds in lithospheric and asthenospheric mantle

Some studies of lithospheric and asthenospheric seismic structure, report mantle velocities as low as ∼4% below the reference models used. While these low wavespeeds may be attributed to thermal effects in tectonically young or actively volcanic regions, in older, tectonically stable regions low velocity anomalies apparently persist even past the decay time of any thermal perturbation, rendering such a mechanism implausible. Low volume melts can also reduce wavespeeds, but their buoyancy should drain them upward away from source regions, preventing significant accumulation if they are able to segregate. Sulfide, ubiquitous as inclusions in lithospheric mantle xenoliths, forms dense, non-segregating melts at temperatures and volatile fugacities characteristic of even old lithospheric mantle. We show that 1–5 volume percent sulfide melts can act to permanently create reductions up to 5.5% in seismic wavespeeds in areas of the lithosphere and the asthenosphere disturbed by prior melting events that carry and concentrate sulfide

Probing the Inner Jet of the Quasar PKS 1510-089 with Multi-waveband Monitoring during Strong Gamma-ray Activity

We present results from monitoring the multi-waveband flux, linear polarization, and parsec-scale structure of the quasar PKS 1510-089, concentrating on eight major gamma-ray flares that occurred during the interval 2009.0-2009.5. The gamma-ray peaks were essentially simultaneous with maxima at optical wavelengths, although the flux ratio of the two wavebands varied by an order of magnitude. The optical polarization vector rotated by 720 degrees during a 5-day period encompassing six of these flares. This culminated in a very bright, roughly 1 day, optical and gamma-ray flare as a bright knot of emission passed through the highest-intensity, stationary feature (the "core") seen in 43 GHz Very Long Baseline Array images. The knot continued to propagate down the jet at an apparent speed of 22c and emit strongly at gamma-ray energies as a months-long X-ray/radio outburst intensified. We interpret these events as the result of the knot following a spiral path through a mainly toroidal magnetic field pattern in the acceleration and collimation zone of the jet, after which it passes through a standing shock in the 43 GHz core and then continues downstream. In this picture, the rapid gamma-ray flares result from scattering of infrared seed photons from a relatively slow sheath of the jet as well as from optical synchrotron radiation in the faster spine. The 2006-2009.7 radio and X-ray flux variations are correlated at very high significance; we conclude that the X-rays are mainly from inverse Compton scattering of infrared seed photons by 20-40 MeV electrons.Comment: 10 pages of text + 5 figures, to be published in Astrophysical Journal Letters in 201

On the Location of the Gamma-ray Emission in the 2008 Outburst in the BL Lacertae Object AO 0235+164 through Observations across the Electromagnetic Spectrum

We present observations of a major outburst at centimeter, millimeter, optical, X-ray, and gamma-ray wavelengths of the BL Lacertae object AO 0235+164. We analyze the timing of multi-waveband variations in the flux and linear polarization, as well as changes in Very Long Baseline Array (VLBA) images at 7mm with 0.15 milliarcsecond resolution. The association of the events at different wavebands is confirmed at high statistical significance by probability arguments and Monte-Carlo simulations. A series of sharp peaks in optical linear polarization, as well as a pronounced maximum in the 7 mm polarization of a superluminal jet knot, indicate rapid fluctuations in the degree of ordering of the magnetic field. These results lead us to conclude that the outburst occurred in the jet both in the quasi-stationary "core" and in the superluminal knot, both parsecs downstream of the supermassive black hole. We interpret the outburst as a consequence of the propagation of a disturbance, elongated along the line of sight by light-travel time delays, that passes through a standing recollimation shock in the core and propagates down the jet to create the superluminal knot. The multi-wavelength light curves vary together on long time-scales (months/years), but the correspondence is poorer on shorter time-scales. This, as well as the variability of the polarization and the dual location of the outburst, agrees with the expectations of a multi-zone emission model in which turbulence plays a major role in modulating the synchrotron and inverse Compton fluxes.Comment: Accepted for Publication in the Astrophysical Journal Letters. 7 pages (including 5 figures). Minor corrections with regard to previous version, as proposed by the refere

Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA 2 B 2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis

Cytosolic Guanine Nucledotide Binding Deficient Form of Transglutaminase 2 (R580a) Potentiates Cell Death in Oxygen Glucose Deprivation

Transglutaminase 2 (TG2) is a hypoxia-responsive protein that is a calcium-activated transamidating enzyme, a GTPase and a scaffolding/linker protein. Upon activation TG2 undergoes a large conformational change, which likely affects not only its enzymatic activities but its non-catalytic functions as well. The focus of this study was on the role of transamidating activity, conformation and localization of TG2 in ischemic cell death. Cells expressing a GTP binding deficient form of TG2 (TG2-R580A) with high basal transamidation activity and a more extended conformation showed significantly increased cell death in response to oxygen-glucose deprivation; however, targeting TG2-R580A to the nucleus abrogated its detrimental role in oxygen-glucose deprivation. Treatment of cells expressing wild type TG2, TG2-C277S (a transamidating inactive mutant) and TG2-R580A with Cp4d, a reversible TG2 inhibitor, did not affect cell death in response to oxygen-glucose deprivation. These findings indicate that the pro-cell death effects of TG2 are dependent on its localization to the cytosol and independent of its transamidation activity. Further, the conformational state of TG2 is likely an important determinant in cell survival and the prominent function of TG2 in ischemic cell death is as a scaffold to modulate cellular processes