UV hyper-resistance in Prochlorococcus MED4 results from a single base pair deletion just upstream of an operon encoding nudix hydrolase and photolyase.

Exposure to solar radiation can cause mortality in natural communities of pico-phytoplankton, both at the surface and to a depth of at least 30 m. DNA damage is a significant cause of death, mainly due to cyclobutane pyrimidine dimer formation, which can be lethal if not repaired. While developing a UV mutagenesis protocol for the marine cyanobacterium Prochlorococcus, we isolated a UV-hyper-resistant variant of high light-adapted strain MED4. The hyper-resistant strain was constitutively upregulated for expression of the mutT-phrB operon, encoding nudix hydrolase and photolyase, both of which are involved in repair of DNA damage that can be caused by UV light. Photolyase (PhrB) breaks pyrimidine dimers typically caused by UV exposure, using energy from visible light in the process known as photoreactivation. Nudix hydrolase (MutT) hydrolyses 8-oxo-dGTP, an aberrant form of GTP that results from oxidizing conditions, including UV radiation, thus impeding mispairing and mutagenesis by preventing incorporation of the aberrant form into DNA. These processes are error-free, in contrast to error-prone SOS dark repair systems that are widespread in bacteria. The UV-hyper-resistant strain contained only a single mutation: a 1 bp deletion in the intergenic region directly upstream of the mutT-phrB operon. Two subsequent enrichments for MED4 UV-hyper-resistant strains from MED4 wild-type cultures gave rise to strains containing this same 1 bp deletion, affirming its connection to the hyper-resistant phenotype. These results have implications for Prochlorococcus DNA repair mechanisms, genome stability and possibly lysogeny.

Genetic and environmental epidemiology of Alzheimer's disease in arabs residing in Israel.

We have found an unusually high prevalence of Alzheimer's disease (AD) in Wadi Ara, an inbred Arab community in northern Israel. Allele frequencies of 4.5% and 3.5% were found for the apolipoprotein E e4 allele among AD cases and nondemented controls, respectively, showing that other genetic or environmental influences must be responsible. Family studies revealed that more than one-third of the AD cases are members of one hamula (tribal group) within Wadi Ara. We hypothesize that the high risk of AD in this genetic isolate may be attributable to a founder effect enhanced by consanguinity. It is also possible that smoking or high fat diet are responsible. To map chromosomal loci contributing to AD susceptibility, we conducted a genome scan from specific hamulas and followed candidate regions found to be linked to disease. Markers from 18 chromosomal regions showed significant allelic association with AD. Smoking was very common in men but was not linked to the presence of AD in Wadi Ara, The unique characteristics of this community, together with the large amount of human genome data, should allow for the identification of AD genes in candidate regions.

Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part II. In vitro studies.

Inosine-5'-monophosphate-dehydrogenase (IMPDH) regulates the de novo synthesis of guanine ribonucleotides (GNT). IMPDH activity varies inversely with intracellular [GNT] and is linked to cellular proliferation. K562 leukemia cell growth was studied relative to IMPDH expression and activity following culture of the cells with Tiazofurin, an IMPDH inhibitor. Tiazofurin depressed IMPDH activity and [GTP] in K562 cells, and also increased IMPDH mRNA expression. Following exposure to Tiazofurin, K562 cell proliferation, entry into cycle, and sensitivity to cycle-active cytotoxic agents were increased. These findings indicate that the efficacy of standard chemotherapy in bcr-abl positive leukemias might be enhanced if combined sequentially with Tiazofurin.

Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part I. In vivo studies.

Six patients with bcr-abl positive AML or chronic myelogenous leukemia in blast crisis (CML-BC) were treated with the IMP-dehydrogenase (IMPDH) inhibitor, Tiazofurin, in a Phase-II trial. Tiazofurin was given by IV infusion (2200-2700 mg/m2 per day) for up to 10 days. Leukemia blasts rapidly disappeared from the circulation of patients during treatment, while mature myeloid cells in the marrow increased in number. Although these hematologic responses were transient, persisting less than 3-4 weeks, our findings confirm that Tiazofurin has anti-leukemia activity. This drug warrants further study in combination regimens with other chemotherapeutic agents for the treatment of bcr-abl positive AML and CML-BC.

Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community.

Several lines of evidence support for a role of angiotensin converting enzyme (ACE) in Alzheimer disease (AD). Most genetic studies have focused on an Alu insertion/deletion (I/D) polymorphism in the ACE gene (DCP1) and have yielded conflicting results. We evaluated the association between 15 single-nucleotide polymorphisms (SNPs) in DCP1, including the I/D variant, and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. Although there was no evidence for association between AD and I/D, we observed significant association with SNPs rs4343 (P = .00001) and rs4351 (P = .01). Haplotype analysis revealed remarkably significant evidence of association with the SNP combination rs4343 and rs4351 (global P = 7.5 x 10(-7)). Individuals possessing the haplotype "GA" (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0-343.2) compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant (lowest global P = 1.1 x 10(-12)), but the only consistently associated alleles were in rs4343 and rs4351. These results suggest that a variant in close proximity to rs4343 and rs4351 modulates susceptibility to AD in this community.

Lack of association between angiotensin-converting enzyme and dementia of the Alzheimer's type in an elderly Arab population in Wadi Ara, Israel.

The angiotensin-converting enzyme (ACE), a protease involved in blood pressure regulation, has been implicated as an important candidate gene for Alzheimer's disease (AD). This study investigated whether the ACE gene insertion-deletion (ID) polymorphism is associated with risk of developing dementia of Alzheimer's type (DAT) in an Arab-Israeli community, a unique genetic isolate where there is a high prevalence of DAT. In contrast to several other studies, we found no evidence of an association between this polymorphism and either DAT or age-related cognitive decline (ARCD).

Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community.

We have observed an unusually high prevalence of dementia of the Alzheimer type (DAT) in Wadi Ara, an inbred Arab community in northern Israel comprising approximately 850 persons over the age of 60 years. Family studies revealed that more than one-third of the DAT cases are members of one hamula (tribal group) within Wadi Ara. To map chromosomal loci contributing to DAT susceptibility, we conducted a 10 cM scan in a series of five cases and five controls selected from this hamula. Markers from 18 chromosomal regions showed significant allelic association with DAT (P<0.05). Locations on chromosomes 2, 9 and 10 remained significant after testing additional affected and non-demented individuals. Significant associations were also observed for markers on chromosome 12 which overlap with a locus implicated in previous genome scans. Analysis of allele frequency distributions for 12 markers spanning 20 cM on chromosome 9 narrowed the possible location of an DAT susceptibility gene to a 13 cM interval between D9S157 and D9S259 (most significant result: P = 2.3 x 10(-7)). Analysis of 14 markers spanning 24 cM on chromosome 12 narrowed the possible location to a 14 cM interval distal to the LRP1 locus (most significant result: P = 1.3 x 10(-6)). Evidence for linkage on chromosome 9 stemmed primarily from excess homozygosity of marker alleles in cases compared with controls, suggesting that the gene at this location behaves in either a recessive or additive fashion. The unique characteristics of this community together with the emergent human genome data should allow for the rapid identification of DAT genes in these candidate regions.