Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.

The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BLC6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression.

Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases.

Long CTG triplet repeats which are associated with several human hereditary neuromuscular disease genes are stabilized in ColE1-derived plasmids in Escherichia coli containing mutations in the methyl-directed mismatch repair genes (mutS, mutL, or mutH). When plasmids containing (CTG)180 were grown for about 100 generations in mutS, mutL, or mutH strains, 60-85% of the plasmids contained a full-length repeat, whereas in the parent strain only about 20% of the plasmids contained the full-length repeat. The deletions occur only in the (CTG)180 insert, not in DNA flanking the repeat. While many products of the deletions are heterogeneous in length, preferential deletion products of about 140, 100, 60, and 20 repeats were observed. We propose that the E. coli mismatch repair proteins recognize three-base loops formed during replication and then generate long single-stranded gaps where stable hairpin structures may form which can be bypassed by DNA polymerase during the resynthesis of duplex DNA. Similar studies were conducted with plasmids containing CGG repeats; no stabilization of these triplets was found in the mismatch repair mutants. Since prokaryotic and human mismatch repair proteins are similar, and since several carcinoma cell lines which are defective in mismatch repair show instability of simple DNA microsatellites, these mechanistic investigations in a bacterial cell may provide insights into the molecular basis for some human genetic diseases.

Alignment of a 1.2-Mb chromosomal region from three strains of Rhodobacter capsulatus reveals a significantly mosaic structure.

High-resolution physical maps of the genomes of three Rhodobacter capsulatus strains, derived from ordered cosmid libraries, were aligned. The 1.2-Mb segment of the SB1003 genome studied here is adjacent to a 1-Mb region analyzed previously [Fonstein, M., Nikolskaya, T. & Haselkorn, H. (1995) J. Bacteriol. 177, 2368-2372]. Probes derived from the ordered cosmid set of R. capsulatus SB1003 were used to link cosmids from the St. Louis and 2.3.1 strain libraries. Cosmids selected this way did not merge into a single contig but formed several unlinked groups. EcoRV restriction maps of the ordered cosmids were then constructed using lambda terminase and fused to derive fragments of the chromosomal map. In order to link these fragments, their ends were transcribed to produce secondary probes for hybridization to gridded cosmid libraries of the same strains. This linking reduced the number of subcontigs to three for the St. Louis strain and one for the 2.3.1 strain. Hybridization of the same probes back to the ordered cosmid set of SB1003 positioned the subcontigs on the high-resolution physical map of SB1003. The final alignment of the restriction maps shows numerous large and small translocations in this 1.2-Mb chromosomal region of the three Rhodobacter strains. In addition, the chromosomes of the three strains, whose fine-structure maps can now be compared over 2.2 Mb, are seen to contain regions of 15-80 kb in which restriction sites are highly polymorphic, interspersed among regions in which the positions of restriction sites are highly conserved.

Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation.

Oncogenic potential of human mycoplasmas was studied using cultured mouse embryo cells, C3H/10T1/2 (C3H). Mycoplasma fermentans and Mycoplasma penetrans, mycoplasmas found in unusually high frequencies among patients with AIDS, were examined. Instead of acute transformation, a multistage process in promotion and progression of malignant cell transformation with long latency was noted; after 6 passages (1 wk per passage) of persistent infection with M. fermentans, C3H cells exhibited phenotypic changes with malignant characteristics that became progressively more prominent with further prolonged infection. Up to at least the 11th passage, all malignant changes were reversible if mycoplasmas were eradicated by antibiotic treatment. Further persistent infection with the mycoplasmas until 18 passages resulted in an irreversible form of transformation that included the ability to form tumors in animals and high soft agar cloning efficiency. Whereas chromosomal loss and translocational changes in C3H cells infected by either mycoplasma during the reversible stage were not prominent, the onset of the irreversible phase of transformation coincided with such karyotypic alteration. Genetic instability--i.e., prominent chromosomal alteration of permanently transformed cells--was most likely caused by mutation of a gene(s) responsible for fidelity of DNA replication or repair. Once induced, chromosomal alterations continued to accumulate both in cultured cells and in animals without the continued presence of the transforming microbes. Mycoplasma-mediated multistage oncogenesis exhibited here shares many characteristics found in the development of human cancer.

Nodulating strains of Rhizobium loti arise through chromosomal symbiotic gene transfer in the environment.

Rhizobia were isolated from nodules off a stand of Lotus corniculatus established with a single inoculant strain, ICMP3153, 7 years earlier in an area devoid of naturalized Rhizobium loti. The isolates showed diversity in growth rate, Spe I fingerprint of genomic DNA, and hybridization pattern to genomic DNA probes. The 19% of isolates that grew at the same rate as strain ICMP3153 were the only isolates that had the same fingerprint as strain ICMP3153. Sequencing of part of the 16S rRNA gene of several diverse isolates confirmed that they were not derived from the inoculant strain. Nevertheless, all non-ICMP3153 strains gave EcoRI and Spe I hybridization patterns identical to ICMP3153 when hybridized to nodulation gene cosmids. Hybridization of digests generated by the very rare cutting enzyme Swa I revealed that the symbiotic DNA region (at least 105 kb) was chromosomally integrated in the strains. The results suggest that the diverse strains arose by transfer of chromosomal symbiotic genes from ICMP3153 to nonsymbiotic rhizobia in the environment.

kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system.

Using the mouse delta-opioid receptor cDNA as a probe, we have isolated genomic clones encoding the human mu- and kappa-opioid receptor genes. Their organization appears similar to that of the human delta receptor gene, with exon-intron boundaries located after putative transmembrane domains 1 and 4. The kappa gene was mapped at position q11-12 in human chromosome 8. A full-length cDNA encoding the human kappa-opioid receptor has been isolated. The cloned receptor expressed in COS cells presents a typical kappa 1 pharmacological profile and is negatively coupled to adenylate cyclase. The expression of kappa-opioid receptor mRNA in human brain, as estimated by reverse transcription-polymerase chain reaction, is consistent with the involvement of kappa-opioid receptors in pain perception, neuroendocrine physiology, affective behavior, and cognition. In situ hybridization studies performed on human fetal spinal cord demonstrate the presence of the transcript specifically in lamina II of the dorsal horn. Some divergences in structural, pharmacological, and anatomical properties are noted between the cloned human and rodent receptors.

On the possibility of coherently stimulated recombination and cosmological structure generation: recombination instability.

Possible instabilities during cosmological recombination may produce an epoch of nonlinear density growth and fractal-like structural patterns out to the horizon scale at that epoch (approximately 200 Mpc today). With this motivation, we examine the consequences of the change in effective radiative recombination reaction rate coefficients produced by intense stimulated emission. The proton-electron recombination is considered as a natural laser, leading to the formation of spatially nonuniform distributions of neutral matter earlier than the recombination epoch.

Chromosomal insertion of foreign (adenovirus type 12, plasmid, or bacteriophage lambda) DNA is associated with enhanced methylation of cellular DNA segments.

Insertion of foreign DNA into an established mammalian genome can extensively alter the patterns of cellular DNA methylation. Adenovirus type 12 (Ad12)-transformed hamster cells, Ad12-induced hamster tumor cells, or hamster cells carrying integrated DNA of bacteriophage lambda were used as model systems. DNA methylation levels were examined by cleaving cellular DNA with Hpa II, Msp I, or Hha I, followed by Southern blot hybridization with 32P-labeled, randomly selected cellular DNA probes. For several, but not all, cellular DNA segments investigated, extensive increases in DNA methylation were found in comparison with the methylation patterns in BHK21 or primary Syrian hamster cells. In eight different Ad12-induced hamster tumors, moderate increases in DNA methylation were seen. Increased methylation of cellular genes was also documented in two hamster cell lines with integrated Ad12 DNA without the Ad12-transformed phenotype, in one cloned BHK21 cell line with integrated plasmid DNA, and in at least three cloned BHK21 cell lines with integrated lambda DNA. By fluorescent in situ hybridization, the cellular hybridization probes were located to different hamster chromosomes. The endogenous intracisternal A particle genomes showed a striking distribution on many hamster chromosomes, frequently on their short arms. When BHK21 hamster cells were abortively infected with Ad12, increases in cellular DNA methylation were not seen. Thus, Ad12 early gene products were not directly involved in increasing cellular DNA methylation. We attribute the alterations in cellular DNA methylation, at least in part, to the insertion of foreign DNA. Can alterations in the methylation profiles of hamster cellular DNA contribute to the generation of the oncogenic phenotype?

Characterization of the instability mechanisms affecting slopes on carbonatic Flysch: Alicante (SE Spain), case study

The studied Flysch sequence of Alicante occupies a widely populated area crossed by main communication routes. The slopes existing on this area usually suffer slope instabilities that cause substantial damage and a very high maintenance cost. In order to assess the type of instability mechanisms affecting these heterogeneous carbonatic slopes, in this paper a wide inventory of 194 Flysch rock slopes has been performed, reporting the existing lithologies, their competence and their relative arrangement and the geometrical relationship between bedding and the slope and the associated instability mechanism. All these data have been jointly used for performing an instability mechanisms characterization. For systematically characterizing the wide type of complex rock exposures existing in the study area, they are divided into basic units referred as lithological pattern columns to which the different observed instability mechanisms are associated. Inventoried instability mechanisms are diverse and sometimes are combined with each other. Rockfalls are a very common instability mechanism associated to the differential weathering and sapping of the marly lithologies which are present in a wide number of geometrical combinations. The other instability mechanisms closely depend on the combination of the geometrical and lithological parameters. Therefore, this work provides a new basic tool which can be easily used during preliminary project stages for knowing the instability mechanisms which can affect rock slopes excavated on carbonatic Flysch heterogeneous geological formations.

The Penetration of Financial Instability in Agricultural Credit and Leveraging. Factor Markets Working Paper No. 2, September 2011

This paper describes the aggregate rural capital markets of the EU and the main differences between the markets of its member countries. The results of our study suggest that the agricultural credit markets are still quite segmented and the segments are country- rather than currency- or region specific. Financial instability in Europe is also penetrating the agricultural sector and the variation of interest rates for agricultural credit is increasing across countries. Perhaps the most dramatic signal of growing financial instability is that the financial leverage (gearing rate) of European farms rose in 2008 by almost 4 percentage points, from 14 to 18%. The 4 percentage-point annual rise was twice the 2 percentage-point rise observed during the economic recession in the late 1980s and early 1990s. The distribution of the financial leverage of agriculture across countries does not, however, reflect the distribution of country-specific risk premiums in the manner that they are observed in government bond yields. Therefore, in those countries that have the weakest financial situation in the public sector and in which the bond markets are encumbered with high country-specific risk premiums, the agricultural sector is not directly exposed to a very large risk of increasing interest rates, since it is not so highly leveraged. For example in Greek and Spanish agriculture, the financial leverage (gearing) rate is only 0.6% and 2.2% respectively, while the highest gearing rates are found elsewhere (in Denmark), reaching 50%.

Kazakhstan: the regional success story; Tajikistan: a trial period; Uzbekistan: the major source of instability in Central Asia? OSW Study 15/2004

Kazakhstan: Kazakhstan can boast economic development like no other country in Central Asia. In contrast to other countries of the region, which have rich natural resources, Kazakhstan has managed to use its economic potential in a way that yields concrete benefits now and, at the same time, creates prospects for further sustainable economic growth. Tajikistan: Tajikistan in its present state has been built on the civil war experiences and provisions of the peace accords signed in 1997. These have had a great impact on the present form of the state, its political scene and power mechanisms. President Emomali Rakhmonov is the central figure in the state. The political system, which he has cocreated, is based on - unique in this region - political pluralism (the existence of the Islamic party), decentralisation (far-going independence of the regions and relatively limited potential of the central structures) and compromise as the basic way of resolving conflicts. Such a system has so far guaranteed stabilisation and normalisation of the country. Uzbekistan: With its geographic location, potential, ambitions and political priorities, Uzbekistan could play a leading role in Central Asia. The international community has perceived the country as the pillar of stability in the region. This perception was further reinforced after 11th September 2001 and was certainly among the factors that inspired the United States to start closer political and military cooperation with Tashkent. The administration in Washington had expected that closer contacts might galvanise political, economic and social change in Uzbekistan, thus reinforcing positive trends in other countries of the region as well. But the relations between Washington and Tashkent are in crisis (which the United States will certainly try to overcome), and we have seen rapprochement between Uzbekistan and Russia and China.

Strain-induced structural instability in FeRh

We perform density functional calculations to investigate the structure of the intermetallic alloy FeRh under epitaxial strain. Bulk FeRh exhibits a metamagnetic transition from a low-temperature antiferromagnetic (AFM) phase to a ferromagnetic phase at 350 K, and its strain dependence is of interest for tuning the transition temperature to the room-temperature operating conditions of typical memory devices. We find an unusually strong dependence of the structural energetics on the choice of exchange-correlation functional, with the usual local density approximation yielding the wrong ground-state structure, and generalized gradient (GGA) extensions being in better agreement with the bulk experimental structure. Using the GGA we show the existence of a metastable face-centered-cubic-like AFM structure that is reached from the ground-state body-centered-cubic-like AFM structure by following the epitaxial Bain path. We show that the behavior is well described using nonlinear elasticity theory, which captures the softening and eventual sign change of the orthorhombic shear modulus under compressive strain, consistent with this structural instability. Finally, we predict the existence of an additional unit-cell-doubling lattice instability, which should be observable at low temperature.

Gaussian elimination and numerical instability /

"UILU-ENG 77 1714."

Dimensional instability of Uranium.

Report year runs ends June 30.