The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

BACKGROUND:Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control. METHODOLOGY/ PRINCIPLE FINDINGS:Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. CONCLUSIONS/ SIGNIFICANCE:7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

Ashfall Tephra in the Ogallala Group of the Great Plains: Characteristics and Significance

The Miocene Ogallala Group blankets the Great Plains east of the Rocky Mountains. This sheet of largely fluvial deposits, lying downwind of major silicic volcanic fields to the west, was ideally located to receive and preserve tephra from these fields. This investigation brings modern methods of tephrochronlogy to bear on the age and identity of Ogallala tephra. Results indicate that ~40 separate tephra layers, ranging in age from ~16.5–5.0 Ma, in the Ogallala. Most tephra came from Yellowstone hotspot sources. The relative frequency of hotspot tephra in the Ogallala matches that in more proximal regions to the west with peak intensities in the intervals ~16.5−15 Ma nd ~13.0−8.5 Ma. About 30 of the Ogallala tephra are correlated with tephra of known age the the Basin and Range to the west. Using the ages of correlative tephra to the west insight into the age of the Ogallala, the correlation of Ogallala tephra from region to region in the Great Plains, and sedimentation rates within the Ogallala. In the Ogallala sedimentation rates vary. The rates are lowest (3–9 m/Ma) in the Cap Rock Mbr. of the Ash Hollow Fm. along the Niobrara River and in undifferentiated Ogallala strata and in the undifferentiated Ogalala Gp. in NW Kansas. Rates of 40–80 m/Ma characterize the Valentine Fm. beneath the Cap Rock Mbr. Finally, one tephra, the 11.37 Ma Cougar Point Tuff XI, is recognized at 6 localies. This key horizon provides the first detailed structure contours within the Ogallala. These contours show a sharply increasing slope of the Ogallala west of 101° W that reflects the post–6 Ma tilt along the western edge of the Ogallala. East of 101º W the gradients mirror the gradients of the major rivers (1.3 to 1.6 m/km.). West of 101º W gradients increase and reach a maximun of 4.6 m/km at the crest of the Gangplank

Iminosugar idoBR1 isolated from Cucumber Cucumis sativus reduces inflammatory activity

Cucumbers have been anecdotally claimed to have anti-inflammatory activity for a long time, but the active principle was not identified. idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, is an iminosugar amino acid isolated from fruits of certain cucumbers, Cucumis sativus (Cucurbitaceae). It has no chromophore and analytically behaves like an amino acid making detection and identification difficult. It has anti-inflammatory activity reducing lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) in THP-1 cells and ex vivo human blood. It showed selective inhibition of human α-l-iduronidase and sialidases from both bacteria (Tannerella forsythia) and human THP-1 cells. idoBR1 and cucumber extract reduced the binding of hyaluronic acid (HA) to CD44 in LPS-stimulated THP-1 cells and may function as an anti-inflammatory agent by inhibiting induced sialidase involved in the production of functionally active HA adhesive CD44. Similar to the related iminosugars, idoBR1 is excreted unchanged in urine following consumption. Its importance in the diet should be further evaluated

Retention of function without normal disc morphogenesis occurs in cone but not rod photoreceptors

It is commonly assumed that photoreceptor (PR) outer segment (OS) morphogenesis is reliant upon the presence of peripherin/rds, hereafter termed Rds. In this study, we demonstrate a differential requirement of Rds during rod and cone OS morphogenesis. In the absence of this PR-specific protein, rods do not form OSs and enter apoptosis, whereas cone PRs develop atypical OSs and are viable. Such OSs consist of dysmorphic membranous structures devoid of lamellae. These tubular OSs lack any stacked lamellae and have reduced phototransduction efficiency. The loss of Rds only appears to affect the shape of the OS, as the inner segment and connecting cilium remain intact. Furthermore, these structures fail to associate with the specialized extracellular matrix that surrounds cones, suggesting that Rds itself or normal OS formation is required for this interaction. This study provides novel insight into the distinct role of Rds in the OS development of rods and cones

Lowering the bar: options for the automotive industry to achieve 80g/km CO2 by 2020 in Europe

Transport is the fastest growing sector for greenhouse gas emissions in the EU. In 2007, transport accounted for 28% of the EU’s overall emissions and passenger cars are responsible for over half of these. Recognising the problem, European Commission President José Manuel Barroso has singled out the transport sector, alongside the power sector, as a priority area for climate action during his second term in office. Executive summary: In April 2010, the European Commission proposed a European strategy on clean and energy efficient vehicles. The Commission recognised that “Ambitious emission targets will be crucial in driving innovations in the long-term and will take account of their contribution to achieving the overall level of greenhouse gas reduction needed in the transport sector.” Under EU legislation adopted in 2009, the average new passenger car sold in 2015 should comply with a CO2 target of 130 grammes per kilometre (g/km). By 2020, the target is 95g/km. A review of this legislation is scheduled no later than the end of 2012, to agree the modalities of how carmakers should reach the 2020 target. The first studies have been carried out for the European Commission into the feasibility of the 95g/km target as well as others. These studies have focused on technology improvements as a solitary means of achieving the reduction, ignoring other means such as lowering performance and a shift toward smaller cars. Unsurprisingly, a target of 85g/km has been identified as “the maximum attainable target under the assumptions in the study,” (AEA 2009: 23). Greenpeace has commissioned a separate study to demonstrate the feasibility of reaching an even lower target of 80g/km by 2020. This target would increase the emissions savings from the legislation to 100 million tons (Mt) CO2 by 2020, instead of 80 Mt CO2 saved with a target of 95g/km by 2020, according to earlier research carried out for Greenpeace. The study is released as EU ministers discuss the regulatory framework, as part of the European strategy on clean and energy efficient vehicles

Synthesis of (+)-(R)-Tiruchanduramine

The absolute stereochemistry of the marine alkaloid (+)-(R)-tiruchanduramine was established via a convergent total synthesis in six steps and 15.5% overall yield from Fmoc-D-Dab(Boc)-OH