Part III. Analysis of data gaps pertaining to enterotoxigenic Escherichia coli infections in low and medium human development index countries, 1984-2005.

Enterotoxigenic Escherichia coli (ETEC) is a common cause of profuse watery diarrhoea in the developing world, often leading to severe dehydration or death. We found only 15 population-based studies in low and medium human development index (HDI) countries from 1984 to 2005 that evaluate disease incidence. Reported incidence ranged from 39 to 4460 infections/1000 persons per year.

Cyclin E overexpression impairs progression through mitosis by inhibiting APC(Cdh1).

Overexpression of cyclin E, an activator of cyclin-dependent kinase 2, has been linked to human cancer. In cell culture models, the forced expression of cyclin E leads to aneuploidy and polyploidy, which is consistent with a direct role of cyclin E overexpression in tumorigenesis. In this study, we show that the overexpression of cyclin E has a direct effect on progression through the latter stages of mitotic prometaphase before the complete alignment of chromosomes at the metaphase plate.

A hand-off mechanism for primosome assembly in replication restart.

Collapsed DNA replication forks must be reactivated through origin-independent reloading of the replication machinery (replisome) to ensure complete duplication of cellular genomes. In E. coli, the PriA-dependent pathway is the major replication restart mechanism and requires primosome proteins PriA, PriB, and DnaT for replisome reloading.

A central role for SSB in Escherichia coli RecQ DNA helicase function.

RecQ DNA helicases are critical components of DNA replication, recombination, and repair machinery in all eukaryotes and bacteria. Eukaryotic RecQ helicases are known to associate with numerous genome maintenance proteins that modulate their cellular functions, but there is little information regarding protein complexes involving the prototypical bacterial RecQ proteins. Here we use an affinity purification scheme to identify three heterologous proteins that associate with Escherichia coli RecQ: SSB (single-stranded DNA-binding protein), exonuclease I, and RecJ exonuclease.

Magic spots cast a spell on DNA primase.

The bacterial signaling molecules ppGpp and pppGpp regulate transcription initiation in response to starvation by altering RNA polymerase activity. In this issue, Wang et al. (2007) show that (p)ppGpp also inhibits DNA replication elongation by interfering with DNA primase activity.

An instrument for observational assessment of nausea in young children.

The purpose of this study was to evaluate the Keller Index of Nausea (KIN), a new instrument for observational assessment of nausea in children 1 through 5 years of age. The KIN and the University of Wisconsin Children's Hospital Pain Scale were used to assess children brought to a general pediatric outpatient clinic for a variety of health problems. There were statistically significant positive point biserial correlations between the KIN scores and three criteria: (a) a medical diagnosis consistent with the presence of nausea, (b) a chief complaint per parent consistent with the presence of nausea, and (c) the parent's statement that the child is experiencing nausea.

Sit down, relax and unwind: structural insights into RecQ helicase mechanisms.

Helicases are specialized molecular motors that separate duplex nucleic acids into single strands. The RecQ family of helicases functions at the interface of DNA replication, recombination and repair in bacterial and eukaryotic cells. They are key, multifunctional enzymes that have been linked to three human diseases: Bloom's, Werner's and Rothmund-Thomson's syndromes.

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland.

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually.

Structure of the Sir3 protein bromo adjacent homology (BAH) domain from S. cerevisiae at 1.95 A resolution.

Sir3p is a silent-information-regulator (SIR) protein required for the assembly of a transcriptionally "silent" chromatin structure at telomeres and the cryptic HM mating-type loci in Saccharomyces cerevisiae. Sir3p contains a putative "bromo adjacent homology" (BAH) domain at its N terminus that shares strong sequence similarity with the BAH domain of a subunit of the origin recognition complex (ORC), Orc1p. The Orc1p-BAH domain forms a well-defined complex with the ORC interaction region (OIR) of another Sir protein, Sir1p, which targets formation of silent chromatin to the HM-loci.

Three HRDC domains differentially modulate Deinococcus radiodurans RecQ DNA helicase biochemical activity.

RecQ helicases are key genome maintenance enzymes that function in DNA replication, recombination, and repair. In contrast to nearly every other identified RecQ family member, the RecQ helicase from the radioresistant bacterium Deinococcus radiodurans encodes three "Helicase and RNase D C-terminal" (HRDC) domains at its C terminus. HRDC domains have been implicated in structure-specific nucleic acid binding with roles in targeting RecQ proteins to particular DNA structures; however, only RecQ proteins with single HRDC domains have been examined to date.

Coupling DNA-binding and ATP hydrolysis in Escherichia coli RecQ: role of a highly conserved aromatic-rich sequence.

RecQ enzymes are broadly conserved Superfamily-2 (SF-2) DNA helicases that play critical roles in DNA metabolism. RecQ proteins use the energy of ATP hydrolysis to drive DNA unwinding; however, the mechanisms by which RecQ links ATPase activity to DNA-binding/unwinding are unknown. In many Superfamily-1 (SF-1) DNA helicases, helicase sequence motif III links these activities by binding both single-stranded (ss) DNA and ATP.

PriB stimulates PriA helicase via an interaction with single-stranded DNA.

The frequency with which replication forks break down in all organisms requires that specific mechanisms ensure completion of genome duplication. In Escherichia coli a major pathway for reloading of the replicative apparatus at sites of fork breakdown is dependent on PriA helicase. PriA acts in conjunction with PriB and DnaT to effect loading of the replicative helicase DnaB back onto the lagging strand template, either at stalled fork structures or at recombination intermediates.

Structure of the calcium-rich signature domain of human thrombospondin-2.

Thrombospondins (THBSs) are secreted glycoproteins that have key roles in interactions between cells and the extracellular matrix. Here, we describe the 2.6-A-resolution crystal structure of the glycosylated signature domain of human THBS2, which includes three epidermal growth factor-like modules, 13 aspartate-rich repeats and a lectin-like module.

Conferring substrate specificity to DNA helicases: role of the RecQ HRDC domain.

RecQ DNA helicases are multidomain enzymes that play pivotal roles in genome maintenance pathways. While the ATPase and helicase activities of these enzymes can be attributed to the conserved catalytic core domain, the role of the Helicase-and-RNase-D-C-terminal (HRDC) domain in RecQ function has yet to be elucidated. Here, we report the crystal structure of the E.

The HRDC domain of BLM is required for the dissolution of double Holliday junctions.

Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase IIIalpha (TOPO IIIalpha) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution.

Structural basis of the Sir1-origin recognition complex interaction in transcriptional silencing.

The Sir1 protein plays a key role in establishing a silent chromatin structure at the cryptic mating-type loci HMR and HML in Saccharomyces cerevisiae by interacting with the bromo-adjacent homology (BAH) domain of the Orc1p subunit of the origin recognition complex (ORC). Here, we present the high-resolution crystal structures of the ORC interaction region (OIR) of Sir1p and that of the complex formed between the OIR and BAH domains. Amino acids within the OIR previously shown to be required for a Sir1p/ORC interaction are presented on a conserved, convex surface that forms a complementary interface with a concave region of the Orc1 BAH domain that is critical for transcriptional silencing.

Crystal structure of PriB, a component of the Escherichia coli replication restart primosome.

Maintenance of genome stability following DNA damage requires origin-independent reinitiation of DNA replication at repaired replication forks. In E. coli, PriA, PriB, PriC, and DnaT play critical roles in recognizing repaired replication forks and reloading the replisome onto the template to reinitiate DNA replication.

Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor.

Foot and hand massage as an intervention for postoperative pain.

Physiological responses to pain create harmful effects that prolong the body's recovery after surgery. Patients routinely report mild to moderate pain even though pain medications have been administered. Complementary strategies based on sound research findings are needed to supplement postoperative pain relief using pharmacologic management.

In vitro and in vivo prevention of HIV protease inhibitor-induced insulin resistance by a novel small molecule insulin receptor activator.

Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance.

Structure and function of RecQ DNA helicases.

RecQ family helicases play important roles in coordinating genome maintenance pathways in living cells. In the absence of functional RecQ proteins, cells exhibit a variety of phenotypes, including increased mitotic recombination, elevated chromosome missegregation, hypersensitivity to DNA-damaging agents, and defects in meiosis. Mutations in three of the five human RecQ family members give rise to genetic disorders associated with a predisposition to cancer and premature aging, highlighting the importance of RecQ proteins and their cellular activities for human health.

Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies.

Purpose: To determine the dose-limiting toxicities, maximum tolerated dose, and pharmacokinetics of TLK286, a novel cancer prodrug, administered weekly.

Patients And Methods: Patients with advanced malignancies were treated with TLK286 administered weekly by i.v.