Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant

Mutations in superoxide dismutase 1 (SOD1; EC 1.15.1.1) are responsible for a proportion of familial amyotrophic lateral sclerosis (ALS) through acquisition of an as-yet-unidentified toxic property or properties. Two proposed possibilities are that toxicity may arise from imperfectly folded mutant SOD1 catalyzing the nitration of tyrosines [Beckman, J. S., Carson, M., Smith, C. D. & Koppenol, W. H. (1993) Nature (London) 364, 584] through use of peroxynitrite or from peroxidation arising from elevated production of hydroxyl radicals through use of hydrogen peroxide as a substrate [Wiedau-Pazos, M., Goto, J. J., Rabizadeh, S., Gralla, E. D., Roe, J. A., Valentine, J. S. & Bredesen, D. E. (1996) Science 271, 515–518]. To test these possibilities, levels of nitrotyrosine and markers for hydroxyl radical formation were measured in two lines of transgenic mice that develop progressive motor neuron disease from expressing human familial ALS-linked SOD1 mutation G37R. Relative to normal mice or mice expressing high levels of wild-type human SOD1, 3-nitrotyrosine levels were elevated by 2- to 3-fold in spinal cords coincident with the earliest pathological abnormalities and remained elevated in spinal cord throughout progression of disease. However, no increases in protein-bound nitrotyrosine were found during any stage of SOD1-mutant-mediated disease in mice or at end stage of sporadic or SOD1-mediated familial human ALS. When salicylate trapping of hydroxyl radicals and measurement of levels of malondialdehyde were used, there was no evidence throughout disease progression in mice for enhanced production of hydroxyl radicals or lipid peroxidation, respectively. The presence of elevated nitrotyrosine levels beginning at the earliest stages of cellular pathology and continuing throughout progression of disease demonstrates that tyrosine nitration is one in vivo aberrant property of this ALS-linked SOD1 mutant.

Induction of topoisomerase I cleavage complexes by 1-β-d-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells

1-β-d-Arabinofuranosylcytosine (Ara-C) is a nucleoside analog commonly used in the treatment of leukemias. Ara-C inhibits DNA polymerases and can be incorporated into DNA. Its mechanism of cytotoxicity is not fully understood. Using oligonucleotides and purified human topoisomerase I (top1), we found a 4- to 6-fold enhancement of top1 cleavage complexes when ara-C was incorporated at the +1 position (immediately 3′) relative to a unique top1 cleavage site. This enhancement was primarily due to a reversible inhibition of top1-mediated DNA religation. Because ara-C incorporation is known to alter base stacking and sugar puckering at the misincorporation site and at the neighboring base pairs, the observed inhibition of religation at the ara-C site suggests the importance of the alignment of the 5′-hydroxyl end for religation with the phosphate group of the top1 phosphotyrosine bond. This study also demonstrates that ara-C treatment and DNA incorporation trap top1 cleavage complexes in human leukemia cells. Finally, we report that camptothecin-resistant mouse P388/CPT45 cells with no detectable top1 are crossresistant to ara-C, which suggests that top1 poisoning is a potential mechanism for ara-C cytotoxicity.

Ukraine's cooperation with the IMF - unfulfilled hopes for deeper reforms. OSW Commentary No. 52, 2011-06-15

The Party of Regions took power in early 2010, after Ukraine had been plunged deep in economic crisis. Over the next year, with the external markets recovering, the country’s economic situation started to improve gradually. Ukraine’s economic stabilisation was also strengthened by its resumed cooperation with the International Monetary Fund, which provided for a loan worth $15.1 billion. The issuing of successive tranches of the loan was made dependent on the implementation of a comprehensive reform programme. The cooperation went quite smoothly at first; however, as the economic situation in Ukraine improved, the reformist zeal of the Ukrainian government started to fade, and obstacles began piling up. As a result, Ukraine was refused the third tranche, scheduled for this March, and for the moment the credit line remains frozen. Even though the IMF has numerous reservations about the Ukrainian government’s economic policy, the fundamental condition for resuming cooperation is reform of the pension system, which the parliament should adopt. The difficulties with fulfilling the obligations made to the IMF reflect the wider problem with implementing reforms in Ukraine, as the Party of Regions promised after taking power. Changes which do not affect the interests of influential lobbies are quite easy to carry out. Often, however, these changes are not conducive to the economy’s liberalisation; moreover, the influential lobbies are successful in blocking reforms that could harm their businesses. Another impediment to the changes is that some reforms are likely to bring about painful social consequences, and that can affect public support for the ruling group. Even though theoretically possible, it does not seem likely that Ukraine’s cooperation with the IMF will be terminated. But even if this cooperation is continued, deeper reforms in Ukraine are likely to be postponed until after the parliamentary elections in autumn 2012.

(Table 1) Radiocarbon ages of ODP Hole 146-893A

High-resolution planktonic foraminiferal census data from Santa Barbara Basin (Ocean Drilling Program hole 893A) demonstrate major assemblage switches between 25 and 60 ka that were associated with Dansgaard-Oeschger cycles. Stadials dominated by Neogloboquadrina pachyderma (sinistral), and Globigerinoides glutinata suggest a strong subpolar California Current influence, while interstadials marked by abundant N. pachyderma (dextral) and G. bulloides indicate a relative increase in subtropical countercurrent influence. Modern analog technique and transfer function (F-20RSC) temperature reconstructions support d18O evidence of large rapid (70 years or less) sea surface temperature shifts (3° to 5°C) between stadials and interstadials. Changes in the vertical temperature gradient and water column structure (thermocline depth) are recorded by planktonic faunal oscillations suggest bimodal stability in the organization of North Pacific surface ocean circulation. Santa Barbara Basin surface water demonstrates the rapid response of the California Current System to reorganization of North Pacific atmospheric circulation during rapid climate change.

Études et portraits.

v. 1 Portraits d'écrivains; et, Notes d'esthétique.--v. 2 Études anglaises.--v. 3 Sociologie et littérature.

Wilhelm Diltheys gesammelte Schriften.

Editions vary.

On some Optimal (n,t,1,2) and (n,t,1,3) Super Imposed Codes

Partially supported by the Technical University of Gabrovo under Grant C-801/2008

(Table 1) Composition of bottom sediments from the East Pacific

Adsorption of ion, nickel, cobalt, and manganese from ocean water by calcareous sediments, diatomaceous ooze, hydrogenous sediments, and red clay was studied under close to natural conditions using a tracer method. It was found that hydrogenous sediments selectively remove manganese from seawater. This may be associated with formation of chemical compounds between manganese and sediment material. It was also found that nickel, manganese, and iron exist in the ocean in several ionic and neutral forms. Cobalt typically present in only one ionic form Co(2+).

(Table 1) Relarive abundance of foraminiferal species in the surface layer of bottom sediments from the Atlantic Ocean

Quantitative ratios of tests of planktonic foraminiferal species in thanatocoenoses within the surface layer of bottom sediments from Iceland to the Equator are described. Subarctic, boreal, subtropical and tropical types of thanatocoenoses and their subtypes are distinguished. Each subtype corresponds to a 2-3°C interval of mean annual temperature of the upper layer of ocean water. Comparison of fossil thanatocoenoses from Quaternary sediment cores with recent thanatocoenoses offers new potentials for paleotemperature analysis.

(Table 1) Shell mass and chemistry of Globigerinoides sacculifer

Using bathymetric transects of surface sediments underlying similar sea surface temperatures but exposed to increasing dissolution, we examined the processes which affect the relationship between foraminiferal Mg/Ca and d18O. We found that Globigerinoides saccculifer calcifies over a relatively large range of water depth and that this is apparent in their Mg content. On the seafloor, foraminiferal Mg/Ca is substantially altered by dissolution with the degree of alteration increasing with water depth. Selective dissolution of the chamber calcite, formed in surface waters, shifts the shell's bulk Mg/Ca and d18O toward the chemistries of the secondary crust acquired in colder thermocline waters. The magnitude of this shift depends on both the range of temperatures over which the shell calcified and the degree to which it is subsequently dissolved. In spite of this shift the initial relationship between Mg/Ca and d18O, determined by their temperature dependence, is maintained. We conclude that paired measurements of d18O and Mg/Ca can be used for reconstructing d18Owater, though care must be taken to determine where in the water column the reconstruction applies.

(Table 1) Age determination of sediment core BC5, Golf of Lion

Hitherto unknown abundance peaks of left coiling (l.c.) Neogloboquadrina pachyderma from a Gulf of Lions piston core indicate that abrupt cold spells associated with Atlantic Heinrich events affected the Mediterranean. N. pachyderma (l.c.) is typical of (sub) polar waters in the open ocean. The southern edge of its glacial North Atlantic bioprovince reached south Portugal. Only trace abundances of N. pachyderma (l.c.) are known from Quaternary Mediterranean sediments, suggesting that no significant "invasions" occured via the Strait of Gibraltar. The Gulf of Lions abundance peaks therefore seem to reflect area-specific thriving of a normally rare but indigenous taxon in the western Mediterranean through local favorable habitat development. The general planktonic foraminiferal record suggests that the basic hydrographic regime in the Gulf of Lions, with wintertime deep convective overturn, was relatively stable over the past 60 kyr. Under these conditions, high abundances of N. pachyderma (l.c.) would essentially imply temperature reductions of the order of 5°-8° relative to the present.

Clinical Consequences Of Tityus Bahiensis And Tityus Serrulatus Scorpion Stings In The Region Of Campinas, Southeastern Brazil.

Scorpion stings account for most envenomations by venomous animals in Brazil. A retrospective study (1994-2011) of the clinical consequences of Tityus scorpion stings in 1327 patients treated at a university hospital in Campinas, southeastern Brazil, is reported. The clinical classification, based on outcome, was: dry sting (no envenoming), class I (only local manifestations), class II (systemic manifestations), class III (life-threatening manifestations, such as shock and/or cardiac failure requiring inotropic/vasopressor agents, and/or respiratory failure), and fatal. The median patient age was 27 years (interquartile interval = 15-42 years). Scorpions were brought for identification in 47.2% of cases (Tityus bahiensis 27.7%; Tityus serrulatus 19.5%). Sting severity was classified and each accounted for the following percentage of cases: dry stings - 3.4%, class I - 79.6%, class II - 15.1%, class III - 1.8% and fatal - 0.1%. Pain was the primary local manifestation (95.5%). Systemic manifestations such as vomiting, agitation, sweating, dyspnea, bradycardia, tachycardia, tachypnea, somnolence/lethargy, cutaneous paleness, hypothermia and hypotension were detected in class II or class III + fatal groups, but were significantly more frequent in the latter group. Class III and fatal cases occurred only in children <15 years old, with scorpions being identified in 13/25 cases (T. serrulatus, n = 12; T. bahiensis, n = 1). Laboratory blood abnormalities (hyperglycemia, hypokalemia, leukocytosis, elevations in serum total CK, CK-MB and troponin T, bicarbonate consumption and an increase in base deficit and blood lactate), electrocardiographic changes (ST segment) and echocardiographic alterations (ventricular ejected fraction <54%) were frequently detected in class III patients. Seventeen patients developed pulmonary edema, 16 had cardiac failure and seven had cardiogenic shock. These results indicate that most scorpion stings involved only local manifestations, mainly pain; the greatest severity was associated with stings by T. serrulatus and in children <15 years old.