Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma

Translocations involving c-myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c-myc or L-myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These abnormalities include unusual and complex translocations and insertions that often juxtapose myc with an IgH or IgL locus. For two advanced primary MM tumors, some tumor cells contain a karyotypic abnormality of the c-myc locus, whereas other tumor cells do not, indicating that this karyotypic abnormality of c-myc occurs as a late event. All informative MM cell lines show monoallelic expression of c-myc. For Burkitt's lymphoma and mouse plasmacytoma tumors, balanced translocation that juxtaposes c-myc with one of the Ig loci is an early, invariant event that is mediated by B cell-specific DNA modification mechanisms. By contrast, for MM, dysregulation of c-myc apparently is caused principally by complex genomic rearrangements that occur during late stages of MM progression and do not involve B cell-specific DNA modification mechanisms.

The adipocyte specific transcription factor C/EBPalpha modulates human ob gene expression.

The ob gene product, leptin, apparently exclusively expressed in adipose tissue, is a signaling factor regulating body weight homeostasis and energy balance. ob gene expression is increased in obese rodents and regulated by feeding, insulin, and glucocorticoids, which supports the concept that ob gene expression is under hormonal control, which is expected for a key factor controlling body weight homeostasis and energy balance. In humans, ob mRNA expression is increased in gross obesity; however, the effects of the above factors on human ob expression are unknown. We describe the structure of the human ob gene and initial functional analysis of its promoter. The human ob gene's three exons cover approximately 15 kb of genomic DNA. The entire coding region is contained in exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp untranslated exon is located >10.5 kb upstream of the initiator ATG codon. Three kilobases of DNA upstream of the transcription start site has been cloned and characterized. Only 217 bp of 5' sequence are required for basal adipose tissue-specific expression of the ob gene as well as enhanced expression by C/EBPalpha. Mutation of the single C/EBPalpha site in this region abolished inducibility of the promoter by C/EBPalpha in cotransfection assays. The gene structure will facilitate our analysis of ob mutations in human obesity, whereas knowledge of sequence elements and factors regulating ob gene expression should be of major importance in the prevention and treatment of obesity.

E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins.

Ubiquitin-dependent proteolysis of the mitotic cyclins A and B is required for the completion of mitosis and entry into the next cell cycle. This process is catalyzed by the cyclosome, an approximately 22S particle that contains a cyclin-selective ubiquitin ligase activity, E3-C, that requires a cyclin-selective ubiquitin carrier protein (UBC) E2-C. Here we report the purification and cloning of E2-C from clam oocytes. The deduced amino acid sequence of E2-C indicates that it is a new UBC family member. Bacterially expressed recombinant E2-C is active in in vitro cyclin ubiquitination assays, where it exhibits the same substrate specificities seen with native E2-C. These results demonstrate that E2-C is not a homolog of UBC4 or UBC9, proteins previously suggested to be involved in cyclin ubiquitination, but is a new UBC family member with unique properties.

Viral dynamics in hepatitis B virus infection.

Treatment of chronic hepatitis B virus (HBV) infections with the reverse transcriptase inhibitor lamivudine leads to a rapid decline in plasma viremia and provides estimates for crucial kinetic constants of HBV replication. We find that in persistently infected patients, HBV particles are cleared from the plasma with a half-life of approximately 1.0 day, which implies a 50% daily turnover of the free virus population. Total viral release into the periphery is approximately 10(11) virus particles per day. Although we have no direct measurement of the infected cell mass, we can estimate the turnover rate of these cells in two ways: (i) by comparing the rate of viral production before and after therapy or (ii) from the decline of hepatitis B antigen during treatment. These two independent methods give equivalent results: we find a wide distribution of half-lives for virus-producing cells, ranging from 10 to 100 days in different patients, which may reflect differences in rates of lysis of infected cells by immune responses. Our analysis provides a quantitative understanding of HBV replication dynamics in vivo and has implications for the optimal timing of drug treatment and immunotherapy in chronic HBV infection. This study also represents a comparison for recent findings on the dynamics of human immunodeficiency virus (HIV) infection. The total daily production of plasma virus is, on average, higher in chronic HBV carriers than in HIV-infected patients, but the half-life of virus-producing cells is much shorter in HIV. Most strikingly, there is no indication of drug resistance in HBV-infected patients treated for up to 24 weeks.

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.

Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.

Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by approximately 50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of non-immune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.

Pluripotent hematopoietic stem cells contain high levels of mRNA for c-kit, GATA-2, p45 NF-E2, and c-myb and low levels or no mRNA for c-fms and the receptors for granulocyte colony-stimulating factor and interleukins 5 and 7.

Pluripotent hematopoietic stem cells (PHSCs) were highly enriched from mouse bone marrow by counterflow centrifugal elutriation, lineage subtraction, and fluorescence-activated cell sorting based on high c-kit receptor expression (c-kitBR). We used reverse transcriptase polymerase chain reaction to assay the c-kitBR subset and the subsets expressing low (c-kitDULL) and no (c-kitNEG) c-kit receptor for expression of mRNA encoding hematopoietic growth factor receptors and transcription factors. The c-kitBR cells had approximately 3.5-fold more c-kit mRNA than unfractionated bone marrow cells. The c-kitDULL cells had 47-58% of the c-kit mRNA found in c-kitBR cells and the c-kitNEG cells had 4-9% of the c-kit mRNA present in c-kitBR cells. By comparing mRNA levels in c-kitBR cells (enriched for PHSCs) with those of unfractionated bone marrow, we demonstrated that c-kitBR cells contained low or undetectable levels of mRNA for c-fms, granulocyte colony-stimulating factor receptor, interleukin 5 receptor (IL-5R), and IL-7R. These same cells had moderate levels of mRNA for erythropoietin receptor, IL-3R subunits IL-3R alpha (SUT-1), AIC-2A, and AIC-2B, IL-6R and its partner gp-130, and the transcription factor GATA-1 and high levels of mRNA for transcription factors GATA-2, p45 NF-E2, and c-myb. We conclude from these findings that PHSCs are programmed to interact with stem cell factor, IL-3, and IL-6 but not with granulocyte or macrophage colony-stimulating factor. These findings also indicate that GATA-2, p45 NF-E2, and c-myb activities may be involved in PHSC maintenance or proliferation.

Khulāṣah-ʼi aḥvāl-i Bānū Bagum mukhāṭab ba-Mumtāz Maḥall : manuscript, undated

Biography of Banū Begam, surnamed Mumtāz Maḥall, and known as Tāj Bībī, wife of Shāh Jahān, and of the buildings connected with her name.

AMS C-14 ages of coretops collected on RRS Charles Darwin cruise CD159, July 2004, N. Atlantic, for the NERC RAPID programme

Material and data were collected at 41 sites in the subpolar North Atlantic Ocean between Scotland and Newfoundland, during the RRS CharlesDarwin CD159 cruise in July 2004 (McCave, 2005). Sites were selected to reflect the major inputs of water that becomes the North Atlantic Deep Water (NADW); the Iceland-Scotland Overflow Water (ISOW), the Denmark Strait Overflow Water (DSOW) and the Labrador Sea Water (LSW). Areas cored were the south Iceland Rise, SE Greenland slope/rise and Eirik Drift, and the Labrador margin. A total of 29 box cores, 19 piston cores, 6 kasten cores, 9 short gravity cores and 20 CTD casts as well as 28 surface water samples were collected during the cruise. Here we present sediment core-top sample ages. The cores were sampled at 1 or 0.5 cm intervals and we used the top 1 or 2 cm, depending on availability of foraminifera in the samples. Sediment samples were disaggregated on an end-over-end wheel, wet sieved at >63 um, and dry sieved to 63-150 and >150 um. Accelerator Mass Spectrometer (AMS) radiocarbon dating was done for each core top based on between 900-1600 monospecific planktonic foraminifera (Globigerina bulloides or Neogloboquadrina pachyderma (sinistral)). All dates were of modern or late Holocene age except site RAPID-08-5B (9806 ± 38 uncorrected 14C years BP) and site RAPID-14-10B (11543 ± 40 uncorrected 14C years BP). The >150 um fraction was split until approximately 300 foraminifera remained and counted for number of lithic grains, benthic foraminifera, planktonic foraminifera and foraminifera fragments. In all but the shallowest sample (Greenland rise, 761m water depth) benthic foraminifera constituted less than 2% of the total >150 um fraction of the sample.

Ploutarchou Perikles = Plutarch's Life of Pericles /

Mode of access: Internet.

The Tyrolien lyre: a glee book, consisting of easy pieces arranged mostly for soprano, alto, tenor, and base [sic] voices, with and without piano-forte accompaniments; comprising a complete collection of solos, duetts, trios, quartetts, quintetts, choruses, &c. for the use of societies, schools, clubs, choirs, and the social circle,

Mode of access: Internet.

C. Suetoni Tranquilli quae supersunt omnia.

Mode of access: Internet.

Boron solubility in Fe-Cr-B cast irons

Boron solubility in the as-cast and solution treated martensite of Fe-Cr-B cast irons, containing approximately 1.35 wt.% of boron, 12 wt.% of chromium, as well as other alloying elements, has been investigated using conventional microanalysis. The significant microstructural variations after tempering at 750 degreesC for 0.5-4 h, compared with the original as-cast and solution treated microstructures, indicated that the matrix consisted of boron and carbon supersaturated solid solutions. The boron solubility detected by electron microprobe was between 0.185-0.515 wt.% for the as-cast martensite and 0.015-0.0589 wt.% for the solution treated martensite, much higher than the accepted value of 0.005 wt.% in pure iron. These remarkable increases are thought to be associated with some metallic alloying element addition, such as chromium, vanadium and molybdenum, which have atomic diameters larger than iron, and expand the iron lattice to sufficiently allow boron atoms to occupy the interstitial sites in iron lattice. (C) 2002 Elsevier Science B.V. All rights reserved.

(Appendix B) Benthic foraminifera in Indian Ocean surface sediments

Multivariate analysis was performed on percentages of 46 species of unstained deep-sea benthic foraminifera from 131 core-top to near-core-top samples (322-5013 m) from across the Indian Ocean. Faunal data are combined with GEOSECS geochemical data to investigate any relationship between benthic foraminifera (assemblages and species) and deep-sea properties. In general, benthic foraminifera show a good correlation to surface productivity, organic carbon flux to the sea floor, deep-sea oxygenation and, to a lesser extent, to bottom temperature, without correlation with the water depths. The foraminiferal census data combined with geochemical data has enabled the division of the Indian Ocean into two faunal provinces. Province A occupies the northwestern Indian Ocean (Arabian Sea region) where surface primary production has a major maximum during the summer monsoon season and a secondary maximum during winter monsoon season that leads to high organic flux to the seafloor, making the deep-sea one of the most oxygen-deficient regions in the world ocean, with a pronounced oxygen minimum zone (OMZ). This province is dominated by benthic foraminifera characteristic of low oxygen and high organic food flux including Uvigerina peregrina, Robulus nicobarensis, Bolivinita pseudopunctata, Bolivinita sp., Bulimina aculeata, Bulimina alazanensis, Ehrenbergina carinata and Cassidulina carinata. Province B covers southern, southeastern and eastern parts of the Indian Ocean and is dominated by Nuttallides umbonifera, Epistominella exigua, Globocassidulina subglobosa, Uvigerina proboscidea, Cibicides wuellerstorfi, Cassidulina laevigata, Pullenia bulloides, Pullenia osloensis, Pyrgo murrhina, Oridorsalis umbonatus, Gyroidinoides (= Gyroidina) soldanii and Gyroidinoides cf. gemma suggesting well-oxygenated, cold deep water with low (oligotrophic) and pulsed food supply.

Relative commutants of strongly self-absorbing C∗-algebras

Peer reviewed