Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones.

Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.

Integrating family planning promotion into the work of environmental volunteers: a population, health and environment initiative in Kenya.

Voluntary use of family planning is instrumental to the health and social well-being of women, families and communities.Although contraceptive use in Sub-Saharan Africa is increasing, unmet need for family planning remains high. Even within countries that have achieved increases in contraceptive prevalence, use remains low among some population subgroups. Contraceptive prevalence is generally lower in rural areas than in cities, and is consistently lower among women in the lowest wealth quintile than among those in the highest. Achieving progress in health and social indicators, such as those captured by the Millennium Development Goals, depends on expanding family planning services to poor, remote rural areas in Africa.

Integrating family planning messages into immunization services: a cluster-randomized trial in Ghana and Zambia.

OBJECTIVE: To determine whether integrating family planning (FP) messages and referrals into facility-based, child immunization services increase contraceptive uptake in the 9- to 12-month post-partum period. METHODS: A cluster-randomized trial was used to test an intervention where vaccinators were trained to provide individualized FP messages and referrals to women presenting their child for immunization services. In each of 2 countries, Ghana and Zambia, 10 public sector health facilities were randomized to control or intervention groups. Shortly after the introduction of the intervention, exit interviews were conducted with women 9-12 months postpartum to assess contraceptive use and related factors before and after the introduction of the intervention. In total, there were 8892 participants (Control Group Ghana, 1634; Intervention Group Ghana, 1129; Control Group Zambia, 3751; Intervention Group Zambia, 2468). Intervention effects were evaluated using logistic mixed models that accounted for clustering in data. In addition, in-depth interviews were conducted with vaccinators, and a process assessment was completed mid-way through the implementation of the intervention. RESULTS: In both countries, there was no significant effect on non-condom FP method use (Zambia, P = 0.56 and Ghana, P = 0.86). Reported referrals to FP services did not improve nor did women's knowledge of factors related to return of fecundity. Some providers reported having made modifications to the intervention; they generally provided FP information in group talks and not individually as they had been trained to do. CONCLUSION: Rigorous evidence of the success of integrated immunization services in resource poor settings remains weak.

Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat.

In infants, respiratory infection elicits tachypnea. To begin to evaluate the role of brainstem cytokine expression in modulation of breathing pattern changes, we compared the pattern generated after endotracheal instillation of lipopolysaccharide (LPS) in in vivo rat pups to local pro-inflammatory cytokine injection in the nucleus tractus solitarius (nTS) in an in vitro en bloc brainstem spinal cord preparation. We hypothesized that both challenges would elicit similar changes in patterning of respiration. In anesthetized, spontaneously breathing rat pups, lipopolysaccharide (LPS) or saline was instilled in the airway of urethane-anesthetized rats (postnatal days 10-11). We recorded diaphragm EMG over the subsequent 2h and saw a 20-30% decrease in interburst interval (Te) at 20-80min post-injection in LPS-instilled animals with no significant change in Ti. In contrast, IL-1ß injections into the nTS of en bloc in vitro brainstem-spinal cord preparations from 0 to 5 day-old pups maintained Ti and caused an increase in Te as early as 20min later, decreasing frequency for 80-120min after injection. Our results suggest that the neonatal respiratory response to the cytokine IL-1ß mediated inflammatory response depends on the site of the inflammatory stimulus and that the direct effect of IL-1ß in the nTS is to slow rather than increase rate.

Microtubule disruption stimulates P-body formation.

Processing bodies (P-bodies) are subcellular ribonucleoprotein (RNP) granules that have been hypothesized to be sites of mRNA degradation, mRNA translational control, and/or mRNA storage. Importantly, P-bodies are conserved from yeast to mammals and contain a common set of evolutionarily conserved protein constituents. P-bodies are dynamic structures and their formation appears to fluctuate in correlation with alterations in mRNA metabolism. Despite these observations, little is understood about how P-body structures are formed within the cell. In this study, we demonstrate a relationship between P-bodies and microtubules in the budding yeast, Saccharomyces cerevisiae. First, we demonstrate that disruption of microtubules by treatment with the drug benomyl leads to aggregation of P-body components. Consistent with this finding, we also demonstrate that disruption of microtubules by a temperature-sensitive allele of the major alpha tubulin, TUB1 (tub1-724) stimulates P-body formation. Second, we find that the alpha-tubulin protein Tub1 colocalizes with P-bodies upon microtubule destabilization. Third, we determine that a putative tubulin tyrosine ligase, encoded by YBR094W, is a protein component of P-bodies, providing additional evidence for a physical connection between P-bodies and microtubules. Finally, we establish that P-bodies formed by microtubule destabilization fail to correlate with global changes in the stability of mRNA or in general mRNA translation. These findings demonstrate that the aggregation of P-body components is linked to the intracellular microtubule network, and, further, that P-bodies formed by disruption of microtubules aggregate independent of broad alterations in either mRNA decay or mRNA translation.