Assessing the impact of comparative genomic sequence data on the functional annotation of the Drosophila genome.

Background: It is widely accepted that comparative sequence data can aid the functional annotation of genome sequences; however, the most informative species and features of genome evolution for comparison remain to be determined.

Results: We analyzed conservation in eight genomic regions (apterous, even-skipped, fushi tarazu, twist, and Rhodopsins 1, 2, 3 and 4) from four Drosophila species (D. erecta, D.

Finishing a whole-genome shotgun: release 3 of the Drosophila melanogaster euchromatic genome sequence.

Background: The Drosophila melanogaster genome was the first metazoan genome to have been sequenced by the whole-genome shotgun (WGS) method. Two issues relating to this achievement were widely debated in the genomics community: how correct is the sequence with respect to base-pair (bp) accuracy and frequency of assembly errors? And, how difficult is it to bring a WGS sequence to the accepted standard for finished sequence? We are now in a position to answer these questions.

Results: Our finishing process was designed to close gaps, improve sequence quality and validate the assembly.

Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(i)-poly(c), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons.

The recently developed hepatitis C virus (HCV) subgenomic replicon system was utilized to evaluate the efficacy of several known antiviral agents. Cell lines that persistently maintained a genotype 1b replicon were selected. The replicon resident in each cell line had acquired adaptive mutations in the NS5A region that increased colony-forming efficiency, and some replicons had acquired NS3 mutations that alone did not enhance colony-forming efficiency but were synergistic with NS5A mutations.

New benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives as selective antagonists of 5-HT4 receptors: binding profile and pharmacological characterization.

A series of benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives were prepared and evaluated to determine the necessary requirements for high affinity on the 5-HT(4) receptors and high selectivity versus other receptors. The compounds were synthesized by substituting the chlorine atom of benzonaphthyridines and azepinoquinolines with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR 113808 as the 5-HT(4) receptor radioligand.

Synthesis and biological evaluation of aristolactams.

A variety of aristolactam derivatives were synthesized and evaluated for cytotoxicity. Modulations were carried out on the phenanthrene nucleus and the lactam moiety as well. N-(N-dialkylaminoalkyl) derivatives exhibited interesting cytotoxic activity against the L1210 leukemia cell line.

Effects of respiratory rate, plateau pressure, and positive end-expiratory pressure on PaO2 oscillations after saline lavage.

One of the proposed mechanisms of ventilator-associated lung injury is cyclic recruitment of atelectasis. Collapse of dependent lung regions with every breath should lead to large oscillations in PaO2 as shunt varies throughout the respiratory cycle. We placed a fluorescence-quenching PO2 probe in the brachiocephalic artery of six anesthetized rabbits after saline lavage.

Novel collagen glomerulopathy in a homotrimeric type I collagen mouse (oim).

Background: Oim/oim mice [osteogenesis imperfecta model; homozygous null for the proalpha2(I) collagen gene] synthesize exclusively the homotrimeric type I collagen isotype, alpha1(I)3, and are unable to synthesize the normal heterotrimeric type I collagen isotype, alpha1(I)2alpha2(I). Previous studies of the oim/oim mouse have focused on the musculoskeletal system, with no systematic evaluation of other organ systems.

Methods: Multiple tissues from oim/oim, oim/+ (heterozygous) and +/+ (wild-type) mice were examined for gross and histological abnormalities.

Dimers from dechlorinated rebeccamycin: synthesis, interaction with DNA, and antiproliferative activities.

In the course of structure-activity relationships on rebeccamycin analogues, two dimers of dechlorinated rebeccamycin were synthesised with the aim to improve the interaction with DNA and in vitro antiproliferative activities. The synthesis of two dimeric compounds obtained by joining two molecules of dechlorinated rebeccamycin via the imide nitrogen is described. Melting temperature and DNase I footprinting studies were performed to investigate their interaction with DNA.

Mechanical ventilation with permissive hypercapnia increases intrapulmonary shunt in septic and nonseptic patients with acute respiratory distress syndrome.

Objective: To compare the effects of conventional mechanical ventilation with low-volume, pressure-limited ventilation (LVPLV) and permissive hypercapnia on ventilation-perfusion (V/Q) distributions in patients with acute respiratory distress syndrome. We hypothesized that the advantageous cardiopulmonary effects of LVPLV would be greater in patients with sepsis than in those without sepsis.

Patients And Interventions: Twenty-two patients with acute respiratory distress syndrome were studied (group 1: 12 patients with hyperdynamic sepsis; group 2: 10 nonseptic patients).

Syntheses and antiproliferative activities of new rebeccamycin derivatives with the sugar unit linked to both indole nitrogens.

The synthesis of new rebeccamycin derivatives, in which the carbohydrate moiety is attached to both indole nitrogens, is described. The newly synthesized compounds were tested for their abilities to block the cell cycle of murine leukemia L1210 cells and their in vitro antiproliferative activities against four tumor cell lines (murine L1210 leukemia and human HT29 colon carcinoma, A549 non-small-cell lung carcinoma, K-562 leukemia). Their biological activities are compared with those of the parent compound rebeccamycin.

A green prescription study: does written exercise prescribed by a physician result in increased physical activity among older adults?

Objective: To determine if a written exercise prescription increases physical activity when added to verbal advice.

Methods: Forty-nine community-dwelling older adults supplied their geriatricians with baseline data on their exercise levels using a questionnaire. Participants were randomly placed in a verbal advice only group or a verbal advice plus written prescription, "green" prescription, group.

Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome.

A major challenge in interpreting genome sequences is understanding how the genome encodes the information that specifies when and where a gene will be expressed. The first step in this process is the identification of regions of the genome that contain regulatory information. In higher eukaryotes, this cis-regulatory information is organized into modular units [cis-regulatory modules (CRMs)] of a few hundred base pairs.

Synthesis and biological activities of indolocarbazoles bearing amino acid residues.

Three indolocarbazole compounds bearing a tripeptide or a lysine group attached to one of the indole nitrogens via a propylamino chain and two rebeccamycin derivatives bearing a lysine residue on the sugar moiety were synthesised with the aim of improving the binding to DNA and the antiproliferative activities. Four tumour cell lines, from murine L1210 leukemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells and their antimicrobial properties against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also investigated.

Synthesis and cytotoxic activity of tetracenomycin D and of saintopin analogues.

Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemann's ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di-O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained.

Induction of cyclin E and inhibition of DNA synthesis by the novel acronycine derivative S23906-1 precede the irreversible arrest of tumor cells in S phase leading to apoptosis.

S23906-1 is a diester derivative of 1,2-dihydrobenzo[b]acronycine with an unknown mechanism of action. This cytotoxic compound was 20-fold more potent than acronycine in inhibiting the proliferation of six tumor cell lines. Using a clonogenic assay of cell survival, the HT29 human colon carcinoma cell line was 100-fold more sensitive to S23906-1 than acronycine.

(22)Ne(alpha,n)(25)Mg: the key neutron source in massive stars.

The excitation function of the reaction (22)Ne(alpha,n)(25)Mg, the key neutron source in the astrophysical s process in massive stars, has been determined from threshold at E(alpha) = 570 up to 1450 keV with an experimental sensitivity of 10(-11) b. For all resonances in this energy range new resonance parameters have been measured. For a possible resonance at about 635 keV a new upper limit omega gamma < 60 neV for the strength was obtained.

A novel series of 2,6,7-substituted 2,3-dihydro-1,4-benzodioxin and 2,6,7-substituted 1,4-benzodioxin derivatives as lipid peroxidation inhibitors. Structure-activity relationships for high inhibition of human low-density lipoprotein peroxidation.

A series of 6- or 7-substituted 2-carboxamido- or 2-(aminomethyl)-1,4-benzodioxin and -2,3-dihydro-1,4-benzodioxin derivatives were synthesized and evaluated to determine the necessary structural requirements for a high inhibition of human low-density lipoprotein copper-induced peroxidation. The most active compounds (21, 25, 28, 36, and 37) were found between 5 and >45 times more active than probucol itself. Due to both their potency and their structural features, compounds 25 and 36 were selected with others for complementary in vitro and in vivo investigations.

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine.

Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1,10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22.

Cytotoxic activities of novel hexahydroindolizino[8,7-b]indole derivatives prepared by 1,3-dipolar cycloaddition reactions of 3,4-dihydro-beta-carboline ylides.

A series of 1-cyano and 2-cyanohexahydroindolizino[8,7-b]indole derivatives was prepared by 1,3-dipolar cycloaddition of acrylonitrile with ylides derived from 3,4-dihydro-beta-carboline and its 6-methoxy, 6-benzyloxy, 9-methyl and 9-benzyl analogues. The products, together with their reduced 1- or 2-aminomethyl derivatives, were evaluated for cytotoxic activity in L1210 cancer cells. Compounds derived from 6-benzyloxy or 9-benzyl-3,4-dihydro-beta-carboline were found to be the most active, with IC(50)'s in the 2-50 microM range.

Marked antitumor activity of a new potent acronycine derivative in orthotopic models of human solid tumors.

S 23906-1 is a novel acronycine derivative selected on the basis of its potency in vitro. We investigated the antitumor activity of S 23906-1 against several murine transplantable tumors (C38 colon carcinoma, P388 leukemia, B16 melanoma, and Lewis lung carcinoma) and in orthotopic models of human lung (NCI-H460 and A549), ovarian (IGROV1 and NIH:OVCAR-3), and colorectal cancers (HCT116 and HT-29). Against established C38 colon carcinoma, S 23906-1 administered twice i.

5-substituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives: synthesis and interaction with serotoninergic receptors.

A new series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives (1 and 2) bearing various substituents on the 5-position was successfully prepared via palladium-mediated cross-coupling reactions. Some of the new compounds showed high affinity for 5-HT1A and 5-HT7 receptors. The best affinity for the 5-HT1A and 5-HT7 receptors was obtained for 2b (Ki = 0.

Recent advances in continuous glucose monitoring.

Continuous glucose monitoring, providing more detailed information on glucose excursions than single spot measurements, should help to improve the therapy in diabetic patients and is also required for feedback-controlled insulin delivery. At the Institute for Diabetes-Technology in Ulm, founded by EF Pfeiffer, a portable glucose sensor for continuous tissue glucose monitoring has been developed. The combination of microdialysis and enzymatic amperometric glucose measurement implemented in this device marked a break-through in achieving reliable and precise continuous tissue glucose monitoring.

Synthesis and cytotoxic activity of benzopyranoxanthone analogues of benz.

Condensation of 3-hydroxy-2-naphthalenecarboxylic acid with phloroglucinol afforded 1,3-dihydroxy-12H-benzo[b]xanthen-12-one. Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to a series of benzo[b]pyrano[2,3-i]xanthen-6-ones and benzo[b]pyrano[3,2-h]xanthen-7-ones related to psorospermine and benzo[b]acronycine. In contrast with what is observed in the pyridoacridone and benzopyridoacridone series, the linear benzo[b]-pyrano[2,3-i]xanthen-6-one derivatives were more potent than their angular benzo[b]pyrano[3,2-h]xanthen-7-one isomers.

The role of type I collagen in aortic wall strength with a homotrimeric.

Purpose: Elastin and collagen (types I and III) are the primary load-bearing elements in aortic tissue. Deficiencies and derangements in elastin and type III collagen have been associated with the development of aneurysmal disease. However, the role of type I collagen is less well defined.

Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA).