Characterization of G1 checkpoint control in the yeast Saccharomyces cerevisiae following exposure to DNA-damaging agents.

The delay of S-phase following treatment of yeast cells with DNA-damaging agents is an actively regulated response that requires functional RAD9 and RAD24 genes. An analysis of cell cycle arrest indicates the existence of (at least) two checkpoints for damaged DNA prior to S-phase; one at START (a G1 checkpoint characterized by pheromone sensitivity of arrested cells) and one between the CDC4- and CDC7-mediated steps (termed the G1/S checkpoint). When a dna1-1 mutant (that affects early events of replicon initiation) also carries a rad9 deletion mutation, it manifests a failure to arrest in G1/S following incubation at the restrictive temperature. This failure to execute regulated G1/S arrest is correlated with enhanced thermosensitivity of colony-forming ability. In an attempt to characterize the signal for RAD9 gene-dependent G1 and G1/S cell cycle arrest, we examined the influence of the continued presence of unexcised photoproducts. In mutants defective in nucleotide excision repair, cessation of S-phase was observed at much lower doses of UV radiation compared to excision-proficient cells. However, this response was not RAD9-dependent. We suggest that an intermediate of nucleotide excision repair, such as DNA strand breaks or single-stranded DNA tracts, is required to activate RAD9-dependent G1 and G1/S checkpoint controls.

Comparison of the unwanted optical images produced by 6 mm and 7 mm intraocular lenses.

Unwanted optical images are noticed by a surprisingly large number of patients following cataract extraction with implantation of posterior chamber intraocular lenses (IOLs). These images are caused by the positioning holes, lens edge, or laser ridge. We studied 550 eyes in which one of seven different IOLs was inserted. The IOLs varied in optic diameter, the presence or absence of positioning holes or a laser ridge, the use of partial depth holes or placement of positioning holes in tabs outside the optical zone. We determined that unwanted optical images could practically be eliminated by using a 7 mm optic without positioning holes. This study also demonstrated that partial depth holes offer no advantage over full thickness holes for reducing unwanted optical images and that positioning holes, even on a 7 mm optic, produce a significant number of complaints.

Operationalizing a bedside pen entry notebook clinical database system in consultation-liaison psychiatry.

No current system of computerized data entry of clinical information in consultation-liaison (C-L) psychiatry has been well received or has demonstrated that it saves the consultant's time. The inability to achieve accurate, complete, systematic collection of discrete variables and data entry in the harried C-L setting is a major impediment to the advancement of the subspecialty and health services research. The hand-held Notebook computer with Windows PEN ENTRY MICROCARES capabilities has permitted one-time direct entry of data at the time of collection at the patient's bedside. Variable choice and selection enhances the completeness and accuracy of data collection. For example, ICD-9, Axis III diagnoses may be selected from a "look-up" which at the same time automatically assigns the appropriate code and diagnostic-related groups, (DRG) number. A patient narrative can be typed at the nurse's station, a chart note printed for the medical record, and the MICRO-CARES literature database perused with the printing of selected citations, abstracts, and in some cases experts' commentaries for the consultee. The consultant's documentation time is halved using the NOTEBOOK WINDOWS PEN ENTRY MICRO-CARES software, with the advantage of more accurate and complete data description than with the traditional handwritten consultation records. Consultees preferred typewritten in contrast to handwritten notes. The cost of the hardware (about $2000) is less than that of an optical scanner, and it permits report generation and archival searches at the nurses' station without returning to the C-L office for scanning. Radio frequency or ethernet download from the Notebook permits direct data transfer to th C-L office archive computer.

Jewish emigration from Israel.

PIP: Issues raised by the emigration of Jews from Israel are discussed. The primary focus is on the debate within Israel concerning what measures could be taken to reduce emigration levels or to induce emigrants to return to Israel.^ieng

RAD9-dependent G1 arrest defines a second checkpoint for damaged DNA in the cell cycle of Saccharomyces cerevisiae.

Exposure of the yeast Saccharomyces cerevisiae to ultraviolet (UV) light, the UV-mimetic chemical 4-nitroquinoline-1-oxide (4NQO), or gamma radiation after release from G1 arrest induced by alpha factor results in delayed resumption of the cell cycle. As is the case with G2 arrest following ionizing radiation damage [Weinert, T. A. & Hartwell, L. H. (1988) Science 241, 317-322], the normal execution of DNA damage-induced G1 arrest depends on a functional yeast RAD9 gene. We suggest that the RAD9 gene product may interact with cellular components common to the G1/S and G2/M transition points in the cell cycle of this yeast. These observations define a checkpoint in the eukaryotic cell cycle that may facilitate the repair of lesions that are otherwise processed to lethal and/or mutagenic damage during DNA replication. This checkpoint apparently operates after the mating pheromone-induced G1 arrest point but prior to replicative DNA synthesis, S phase-associated maximal induction of histone H2A mRNA, and bud emergence.

Evidence that the Rad1 and Rad10 proteins of Saccharomyces cerevisiae participate as a complex in nucleotide excision repair of UV radiation damage.

A newly characterized rad1 missense mutation (rad1-20) in the yeast Saccharomyces cerevisiae maps to a region of the Rad1 polypeptide known to be required for Rad1-Rad10 complex formation. The UV sensitivity of the rad1-20 mutant can be partially and specifically corrected by overexpression of wild-type Rad10 protein. These results suggest that complex formation between the Rad1 and Rad10 proteins is required for nucleotide excision repair.

Heme arginate therapy for beta thalassemia: in vitro versus in vivo effects.

Hemin has a profound effect on erythroid cell maturation and promotes fetal hemoglobin synthesis in vitro. In beta-thalassemia, increasing fetal hemoglobin levels can ameliorate the anemia. We administered heme arginate, a novel stable form of hemin, to 4 patients with thalassemia intermedia and studied the in vitro versus in vivo effects. In erythroid cultures, there was a marked rise in total hemoglobin and hemoglobin F. In vivo, 3 of 4 patients had a rise in hemoglobin levels (from 0.4 to 1.1 g%), which was statistically significant in 1 patient. There were no serious adverse effects. Heme arginate may be useful in the treatment of thalassemia intermedia.

Impaired neutrophil chemotaxis in patients with thalassaemia major.

Random and directed migration, O2- production, degranulation and adhesion were studied in neutrophils obtained from patients with homozygous beta-thalassaemia and iron overload, in the presence or absence of thalassaemic serum. The only significant defect found was an impairment in directed chemotaxis, further depressed after addition of thalassaemic serum. The chemotactic defect was encountered in all the patients that have suffered from pyogenic infections except one, and was not correlated with the severity of the iron overload. It is suggested that the described neutrophil migration impairment may contribute to the tendency towards infection in certain patients with homozygous beta-thalassaemia.

Cloning and characterization of a human cDNA (INPPL1) sharing homology with inositol polyphosphate phosphatases.

We have cloned a novel human cDNA, INPPL1 (GenBank Accession No. L36818), which maps to 11q23. The corresponding mRNA is 4657 nt in length and is widely expressed in both fetal and adult tissues. An open reading frame of 3441 nt encodes a putative polypeptide that shares several domains with inositol triphosphate phosphatases. Several polymorphisms have been mapped to the 3'-untranslated region, yet the putative coding region showed no polymorphisms in nine independent cDNA samples.