The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Efficacy of Herbicides When Spray Solution Application Is Delayed

Information is limited concerning the impact of delaying applications of pesticides after solution preparation on efficacy. Experiments were conducted to determine weed control when diclosulam, dimethenamid-P, flumioxazin, fomesafen, imazethapyr, pendimethalin, and S-metolachlor were applied preemergence the day of solution preparation or 3, 6, and 9 days after solution preparation. Herbicide solutions were applied on the same day regardless of when prepared. Control of broadleaf signalgrass, common lambsquarters, entireleaf morningglory, and Palmer amaranth by these herbicides was not reduced regardless of when herbicide solutions were prepared. Surprisingly entireleaf morningglory control by all herbicides increased when herbicide application was delayed by 9 days. In separate experiments, control of broadleaf signalgrass by clethodim, common ragweed by glyphosate and lactofen, entireleaf morningglory by lactofen, Italian rye grass by glyphosate and paraquat, and Palmer amaranth by atrazine, dicamba, glufosinate, glyphosate, imazethapyr, lactofen, and 2,4-D was affected more by increase in weed size due to delayed application than the time between solution preparation and application

On the origin of non-monotonic doping dependence of the in-plane resistivity anisotropy in Ba(Fe1−xTx_{1-x}T_x)2_2As2_2, TT = Co, Ni and Cu

The in-plane resistivity anisotropy has been measured for detwinned single crystals of Ba(Fe$_{1-x}$Ni$_x$)$_2$As$_2$ and Ba(Fe$_{1-x}$Cu$_x$)$_2$As$_2$. The data reveal a non-monotonic doping dependence, similar to previous observations for Ba(Fe$_{1-x}$Co$_x$)$_2$As$_2$. Magnetotransport measurements of the parent compound reveal a non-linear Hall coefficient and a strong linear term in the transverse magnetoresistance. Both effects are rapidly suppressed with chemical substitution over a similar compositional range as the onset of the large in-plane resistivity anisotropy. It is suggested that the relatively small in-plane anisotropy of the parent compound in the spin density wave state is due to the presence of an isotropic, high mobility pocket of reconstructed Fermi surface. Progressive suppression of the contribution to the conductivity arising from this isotropic pocket with chemical substitution eventually reveals the underlying in-plane anisotropy associated with the remaining FS pockets.Comment: 12 pages, 9 figure

Processes leading to concentration of platinum-group elements in chromite rich rocks

Platinum-group elements are enriched in the ultramafic parts of the Stillwater, Bushveld and Great Dyke Complexes. Processes whereby this enrichment may occur are considered

Brief Metacognitive Therapy for Emotional Distress in Adult Cancer Survivors

Background: Adult cancer survivors often experience substantial psychological morbidity following the completion of acute cancer treatment. Unfortunately, current psychological interventions are of limited efficacy. This study explored if metacognitive therapy (MCT); a brief transdiagnostic psychological intervention was potentially efficacious and could be delivered effectively to adult cancer survivors with psychological morbidity.Methods: An open trial with 3- and 6-month follow-up evaluated the treatment effects of MCT in 27 consecutively referred individuals to a clinical psychology health service specializing in psycho-oncology. Each participant received a maximum of six 1-hour sessions of MCT. Levels of anxiety, depression, fear of cancer recurrence, post-traumatic stress symptoms, health related quality of life, and metacognitive beliefs and processes were assessed using self-report questionnaires.Results: MCT was associated with statistically significant reductions across all outcome measures which were maintained through to 6-month follow-up. In the ITT sample on the primary treatment outcome measure, the Hospital Anxiety and Depression Scale-Total, 59% of participants met recovery criteria at post-treatment and 52% at 6-month follow-up, respectively. No participants significantly deteriorated. In the completer sample (N = 20), 80% recovered at post-treatment and 70% at 6-month follow-up. MCT was acceptable to patients with approximately 75% of patients completing all treatment sessions.Conclusion: MCT, a brief transdiagnostic psychological intervention can be delivered effectively to a heterogenous group of cancer survivors with promising treatment effects. Examining the efficacy of brief MCT against the current gold standard psychological intervention would be a valuable advance toward improving the quality of life of cancer survivors