Synthesis and identification of novel indolo[2,3-a]pyrimido[5,4-c]carbazoles as a new class of anti-cancer agents.

A range of 5,6-bisindole and 5-indole-6-(7-azaindole)pyrimidinones were synthesised via a β-keto ester intermediate and a screen of cyclisation conditions undertaken. The optimised route to this new class of indolocarbazoles and azaindolocarbazoles involved photocyclisation, with typical yields of 50-60%. These derivatives were screened for anti-cancer activity via topo II inhibition and the NCI-60 cell line assay, with the screening indicating a lack of topo II inhibition, but significant in vitro growth inhibition within this new chemical class, in the low micromolar range against renal cancer, melanoma and colon cancer cell lines.

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons.

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect.

Nomegestrol acetate sequentially or continuously combined to estradiol did not negatively affect membrane-receptor associated progestogenic effects in human breast cancer cells.

Objectives: Recently the first monophasic contraceptive pill containing estradiol has been developed which is thought to be a milestone in contraception. Nomegestrol acetate (NOM) is the progestogenic component. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in the tissue of breast cancer patients, and can predict a progestogen dependent risk of breast cancer.

Spatially restricted actin-regulatory signaling contributes to synapse morphology.

The actin cytoskeleton in dendritic spines is organized into microdomains, but how signaling molecules that regulate actin are spatially governed is incompletely understood. Here we examine how the localization of the RacGEF kalirin-7, a well-characterized regulator of actin in spines, varies as a function of post-synaptic density area and spine volume. Using serial section electron microscopy, we find that extrasynaptic, but not synaptic, expression of kalirin-7 varies directly with synapse size and spine volume.

Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells.

Objectives: Evidence is accumulating that progestogens may play a crucial role in the development of breast cancer under contraception and hormone therapy in reproductive and menopausal women. Progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer may be important in tumorigenesis and thus may increase breast cancer risk. The aim of this project was to investigate the influence of progesterone and nine synthetic progestins on MCF-7 breast cancer cells overexpressing PGRMC1.

Deconstructing signal transduction pathways that regulate the actin cytoskeleton in dendritic spines.

Dendritic spines are the sites of most excitatory synapses in the central nervous system. Recent studies have shown that spines function independently of each other, and they are currently the smallest known processing units in the brain. Spines exist in an array of morphologies, and spine structure helps dictate synaptic function.

Self-reported knowledge, attitudes and behaviour towards evidence-based practice of occupational therapy students in Ireland.

It is widely accepted that the occupational therapy profession needs to incorporate research findings into clinical practice so as to improve client outcomes. The purpose of this study was to investigate the knowledge and attitudes toward evidence-based practice (EBP) of occupational therapy students in the Republic of Ireland. A validated questionnaire was used to survey the population of final-year students from the four universities in Ireland in 2008.

Increased expression of Kalirin-9 in the auditory cortex of schizophrenia subjects: its role in dendritic pathology.

Reductions in dendritic arbor length and complexity are among the most consistently replicated changes in neuronal structure in post mortem studies of cerebral cortical samples from subjects with schizophrenia, however, the underlying molecular mechanisms have not been identified. This study is the first to identify an alteration in a regulatory protein which is known to promote both dendritic length and arborization in developing neurons, Kalirin-9. We found Kalirin-9 expression to be paradoxically increased in schizophrenia.

Balance interventions for diabetic peripheral neuropathy: a systematic review.

Diabetic Peripheral Neuropathy (DPN) is a complication of diabetes experienced by more than 30% of all diabetic patients. It causes decreased sensation, proprioception, reflexes, and strength in the lower extremities, leading to balance dysfunction. The purpose of this study was to assess the effectiveness of interventions used by physical therapists to minimize balance dysfunction in people with DPN.

Dissociative effects of orthographic distinctiveness in pure and mixed lists: an item-order account.

We apply the item-order theory of list composition effects in free recall to the orthographic distinctiveness effect. The item-order account assumes that orthographically distinct items advantage item-specific encoding in both mixed and pure lists, but at the expense of exploiting relational information present in the list. Experiment 1 replicated the typical free recall advantage of orthographically distinct items in mixed lists and the elimination of that advantage in pure lists.

The presence of a membrane-bound progesterone receptor sensitizes the estradiol-induced effect on the proliferation of human breast cancer cells.

Objective: Breast cancer risk is still an important topic regarding hormone therapy as well as oral contraception. Evidence that progestogens may play a crucial role is accumulating. Progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer may be important in tumorigenesis and thus may increase breast cancer risk.

Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition.

Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood.

New insight on a possible mechanism of progestogens in terms of breast cancer risk.

Objectives: Progestogens influence mammary gland development and probably breast cancer tumorigenesis by regulating a broad spectrum of physiological processes. We investigated receptor membrane-initiated actions of progestogens in MCF-7 breast cancer cells overexpressing progesterone receptor membrane component 1 (PGRMC1).

Design: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (MCF-7/PGRMC1-3HA) and overexpression of PGRMC1 was verified by immune fluorescent analysis and Western blot.

Semi-automated liquid chromatography-mass spectrometry (LC-MS/MS) method for basic pesticides in wastewater effluents.

Effluent from wastewater treatment plants have been identified as an important source of micro-organic contaminants in the environment. An online high-performance liquid chromatography-heated electrospray ionization tandem mass spectrometric method was developed and validated for the determination of basic pesticides in effluent wastewaters. Most available methods for pesticide analysis of wastewater samples are time-consuming, require complex clean-up steps and are difficult to automate.

Dendritic spine pathology in neuropsychiatric disorders.

Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets.

A bifunctional role for group IIA secreted phospholipase A2 in human rheumatoid fibroblast-like synoviocyte arachidonic acid metabolism.

Human group IIA-secreted phospholipase A(2) (sPLA(2)-IIA) is an important regulator of cytokine-mediated inflammatory responses in both in vitro and in vivo models of rheumatoid arthritis (RA). However, treatment of RA patients with sPLA(2)-IIA inhibitors shows only transient benefit. Using an activity-impaired sPLA(2)-IIA mutant protein (H48Q), we show that up-regulation of TNF-dependent PGE(2) production and cyclooxygenase-2 (COX-2) induction by exogenous sPLA(2)-IIA in RA fibroblast-like synoviocytes (FLSs) is independent of its enzyme function.

Cognitive exertion and subsequent intention execution in older adults.

Objectives: Previous studies have demonstrated that increasing the demands of a prospective memory task is detrimental to older adults' performance; however, no studies have investigated how prior cognitive demands influence subsequent prospective memory. The present study sought to address this gap by using a resource depletion paradigm.

Methods: A sample of 107 older adults whose ages ranged from 60 to 85 years (M=71.

Hippocampal phenotypes in kalirin-deficient mice.

Regulation of forebrain cellular structure and function by small GTPase pathways is crucial for normal and pathological brain development and function. Kalirin is a brain-specific activator of Rho-like small GTPases implicated in neuropsychiatric disorders. We have recently demonstrated key roles for kalirin in cortical synaptic transmission, dendrite branching, spine density, and working memory.

Elucidation of the mass fragmentation pathways of potato glycoalkaloids and aglycons using Orbitrap mass spectrometry.

The mass fragmentation of potato glycoalkaloids, α-solanine and α-chaconine, and the aglycons, demissidine and solasodine were studied using the Orbitrap Fourier transform (FT) mass spectrometer. Using the linear ion trap (LIT) mass spectrometry, multistage collisional-induced dissociation (CID) experiments (MS(n)) on the [M + H](+) precursor ions were performed to aid the elucidation of the mass fragmentation pathways. In addition, higher energy collisional-induced dissociation (HCD) mass spectra were generated for these toxins at a high resolution setting [100,000 FWHM (full width at half maximum)] using the Orbitrap.

Read length and repeat resolution: exploring prokaryote genomes using next-generation sequencing technologies.

Background: There are a growing number of next-generation sequencing technologies. At present, the most cost-effective options also produce the shortest reads. However, even for prokaryotes, there is uncertainty concerning the utility of these technologies for the de novo assembly of complete genomes.

Professional coaching as an effective strategy to retaining frontline managers.

Historically, executive coaching has been reserved only for the c-suite in healthcare organizations. Expanding this resource to directors and managers has been assumed to be cost-prohibitive. The authors describe an intervention whereby executive coaching was expanded beyond the c-suite, during a critical transition time for the organization in an attempt to positively impact management turnover, staff turnover, and employee satisfaction.

Transcriptional response of Rhodococcus aetherivorans I24 to polychlorinated biphenyl-contaminated sediments.

We used a microarray targeting 3,524 genes to assess the transcriptional response of the actinomycete Rhodococcus aetherivorans I24 in minimal medium supplemented with various substrates (e.g., PCBs) and in both PCB-contaminated and non-contaminated sediment slurries.

Phase I/II safety study of transfusion of prion-filtered red cell concentrates in transfusion-dependent patients.

Background And Objectives: Variant Creutzfeldt-Jakob (vCJD) is a fatal transfusion transmissible prion infection. No test for vCJD in the donor population is currently available. Therefore, prion removal by filtration of red cell concentrate (RCC) is an attractive option for prevention.