The genus Cryptotendipes Beck et Beck in Florida, with the description of a new species (Diptera: Chironomidae: Chironominae).

Species of the genus Cryptotendipes Beck et Beck in Florida are reviewed. Previous Florida records of C. casuarius (Townes) are shown to be misidentifications of C.

Comprehensive inventory of true flies (Diptera) at a tropical site.

Estimations of tropical insect diversity generally suffer from lack of known groups or faunas against which extrapolations can be made, and have seriously underestimated the diversity of some taxa. Here we report the intensive inventory of a four-hectare tropical cloud forest in Costa Rica for one year, which yielded 4332 species of Diptera, providing the first verifiable basis for diversity of a major group of insects at a single site in the tropics. In total 73 families were present, all of which were studied to the species level, providing potentially complete coverage of all families of the order likely to be present at the site.

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

Background: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine.

Remarkable fly (Diptera) diversity in a patch of Costa Rican cloud forest: Why inventory is a vital science.

Study of all flies (Diptera) collected for one year from a four-hectare (150 x 266 meter) patch of cloud forest at 1,600 meters above sea level at Zurquí de Moravia, San José Province, Costa Rica (hereafter referred to as Zurquí), revealed an astounding 4,332 species. This amounts to more than half the number of named species of flies for all of Central America. Specimens were collected with two Malaise traps running continuously and with a wide array of supplementary collecting methods for three days of each month.

A new species of (Diptera: Chironomidae) from Florida.

A new species of Dicrotendipes is described in all life stages from Florida. Adults of this new species are nearly identical to D. modestus (Say); pupae are similar to D.

Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window.

p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window.

Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously.

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development.

A rapid method of species identification of wild chironomids (Diptera: Chironomidae) via electrophoresis of hemoglobin proteins in sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE).

Studying aquatic benthic macroinvertebrates (BMIs) in the field requires accurate taxonomic identification, which can be difficult and time consuming. Conventionally, head capsule morphology has been used to identify wild larvae of Chironomidae. However, due to the number of species and possible damage and/or deformity of their head capsules, another supporting approach for identification is needed.

Combination drug scheduling defines a "window of opportunity" for chemopotentiation of gemcitabine by an orally bioavailable, selective ChK1 inhibitor, GNE-900.

Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe.

Chironomus calligraphus (Diptera: Chironomidae), a new pest species in Georgia.

Chironomid midges are ubiquitous and ecologically important aquatic insects. However, some species can become pests when they occur in extremely high numbers, particularly those that colonize man-made habitats. Chironomus calligraphus is a Neotropical, pan-American species that has recently been found in the Nearctic region.

Pyrimidoaminotropanes as potent, selective, and efficacious small molecule kinase inhibitors of the mammalian target of rapamycin (mTOR).

We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals.

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity.

Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway.

Potent, selective, and orally bioavailable inhibitors of mammalian target of rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine.

A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i) < 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases.

Assessing macroinvertebrate biodiversity in freshwater ecosystems: advances and challenges in DNA-based approaches.

Assessing the biodiversity of macroinvertebrate fauna in freshwater ecosystems is an essential component of both basic ecological inquiry and applied ecological assessments. Aspects of taxonomic diversity and composition in freshwater communities are widely used to quantify water quality and measure the efficacy of remediation and restoration efforts. The accuracy and precision of biodiversity assessments based on standard morphological identifications are often limited by taxonomic resolution and sample size.

Recognition of breast cancer cells by CD8+ cytotoxic T-cell clones specific for NY-BR-1.

Immunotherapy for breast cancer using cytotoxic T cells (CTL) is hindered by the lack of well-characterized breast cancer antigens that are expressed in most breast tumor cells and recognized by CD8+ CTL. A recently described breast tissue differentiation antigen, NY-BR-1, is expressed in >80% breast tumors and elicits a humoral response in a subset of breast cancer patients. To identify potential NY-BR-1 epitopes that are recognized by CTL, CD8+ T cells were stimulated in vitro with autologous dendritic cells pulsed with NY-BR-1 peptides that were predicted to bind to HLA-A2.

A Leishmania major response locus identified by interval-specific congenic mapping of a T helper type 2 cell bias-controlling quantitative trait locus.

The propensity of naive CD4 T cells to become T helper (Th) type 2 cells correlates with susceptibility to infection by the protozoal parasite Leishmania major. Using genetic linkage analysis, we earlier identified Dice1 as a Th2 cell bias-controlling quantitative trait locus on chromosome 16. Using interval-specific congenic mapping, we now resolve Dice1 into two independent genetic loci, Dice1.

From the ECM to the cytoskeleton and back: how integrins orchestrate T cell action.

T lymphocytes constitute a highly dynamic tissue type. During the course of their lives, they travel through a variety of physiological environments and experience a multitude of interactions with extracellular matrix components and other cells. In order to do this, they must receive many environmental cues, and translate these signals into the appropriate biological actions.

Regulation of beta 1 integrin-mediated adhesion by T cell receptor signaling involves ZAP-70 but differs from signaling events that regulate transcriptional activity.

Stimulation of the CD3/TCR results within minutes in an increase in T cell adhesion mediated by beta(1) integrins. The biochemical pathways that control CD3-mediated increases in beta(1) integrin-mediated adhesion remain poorly characterized. In this study, the role of the tyrosine kinase ZAP-70 in the regulation of beta(1) integrin activity by the CD3/TCR was investigated.

The distribution of dermal tumorigens in coal liquids: relationship of tumorigenicity and microbial mutagenicity.

Polycyclic aromatic hydrocarbons and/or their pyrolle derivatives were found to be the primary contributors to the skin tumorigenicity of the neutral fractions of two coal oils. Mutagenicity of the neutral fraction in Salmonella test strains was found to be due primarily to polycyclic aromatics containing polar substituents. Thus, the chemical classes responsible for skin tumorigenicity differ from those responsible for mutagenicity.

Effects of genotype and age on mixed-function oxidase activities in adult Drosophila melanogaster.

The mixed-function oxidases that metabolize dimethylnitrosamine, aminopyrine, benzphetamine, 7-ethoxycoumarin and benzo[alpha]pyrene were measured in adults of the Canton-S, Oregon-R and Hikone-R strains of Drosophila melanogaster. The expression of these activities is both genotype and age dependent.

Studies on the relationship between dimethylnitrosamine-demethylase activity and dimethylnitrosamine-dependent mutagenesis in Drosophila melanogaster.

The relationship between dimethylnitrosamine (DMN) demethylase activity and DMN-induced mutagenesis was investigated in Drosophila melanogaster. The activity of DMN-demethylase was at least 10-fold greater in the Hikone-R strain than in three other Drosophila strains. However, the sex-linked recessive lethal (SLRL) mutations induced by DMN in the four strains differed by less than 2-fold.

Preparation of oils for bacterial mutagenicity testing.

4 procedures used to prepare fossil-derived oils for bacterial mutagenicity testing have been examined. These are, (a) dewaxing by partitioning the oil between dimethyl sulfoxide (DMSO) and cyclohexane, (b) incorporating a surfactant to increase compatibility of the oil with the bioassay media, (c) directly slurrying the oil in DMSO, and (d) computing the mutagenicity of the oil by summing the contributions of individual chemical class fractions. DMSO slurries generally exhibit higher mutagenicities than computed by summing the contributions of chemical class fractions.

Enhancement of mutagenic activity in Salmonella by contraceptive steroids.

Two oral contraceptive steroids, mestranol and norethynodrel, were evaluated for mutagenicity in the Salmonella histidine reversion assay. The pure forms of the hormones were not mutagenic when tested with either missense (TA1535, TA100) or frameshift (TA98, TA1538, TA1537) strains. In vitro activation of the hormones with liver homogenates from rats induced either with phenobarbital or Aroclor did not influence these results.