Molecular, isotopic and <i>in situ</i> analytical approaches to the study of meteoritic organic material

Organic materials isolated from carbonaceous meteorites provide us with a record of pre-biotic chemistry in the early Solar System. Molecular, isotopic and in situ studies of these materials suggest that a number of extraterrestrial environments have contributed to the inventory of organic matter in the early Solar System including interstellar space, the Solar nebula and meteorite parent bodies. There are several difficulties that have to be overcome in the study of the organic constituents of meteorites. Contamination by terrestrial biogenic organic matter is an ever-present concern and a wide variety of contaminant molecules have been isolated and identified including essential plant oils, derived from either biological sources or common cleaning products, and aliphatic hydrocarbons, most probably derived from petroleum-derived pollutants. Only 25% of the organic matter in carbonaceous chondrites is amenable to extraction with organic solvents; the remainder is present as a complex macromolecular aromatic network that has required the development of analytical approaches that can yield structural and isotopic information on this highly complex material. Stable isotopic studies have been of paramount importance in understanding the origins of meteoritic organic matter and have provided evidence for the incorporation of interstellar molecules within meteoritic material. Extending isotopic studies to the molecular level is yielding new insights into both the sources of meteoritic organic matter and the processes that have modified it. Organic matter in meteorites is intimately associated with silicate minerals and the in situ examination of the relationships between organic and inorganic components is crucial to our understanding of the role of asteroidal processes in the modification of organic matter and, in particular, the role of water as both a solvent and a reactant on meteorite parent bodies

Vaccination with Schistosoma mansoni cholinesterases reduces the parasite burden and egg viability in a mouse model of Schistosomiasis

Schistosomiasis is a neglected tropical disease caused by parasitic blood flukes of the genus Schistosoma, which kills 300,000 people every year in developing countries, and there is no vaccine. Recently, we have shown that cholinesterases (ChEs)—enzymes that regulate neurotransmission—from Schistosoma mansoni are expressed on the outer tegument surface and present in the excretory/secretory products of larval schistosomula and adult worms, and are essential for parasite survival in the definitive host, highlighting their utility as potential schistosomiasis vaccine targets. When treated in vitro with anti-schistosome cholinesterase (SmChE) IgG, both schistosomula and adult worms displayed significantly decreased ChE activity, which eventually resulted in parasite death. Vaccination with individual SmChEs, or a combination of all three SmChEs, significantly reduced worm burdens in two independent trials compared to controls. Average adult worm numbers and liver egg burdens were significantly decreased for all vaccinated mice across both trials, with values of 29–39% and 13–46%, respectively, except for those vaccinated with SmAChE1 in trial 1. Egg viability, as determined by egg hatching from liver homogenates, was significantly reduced in the groups vaccinated with the SmChE cocktail (40%) and SmAChE2 (46%). Furthermore, surviving worms from each vaccinated group were significantly stunted and depleted of glycogen stores, compared to controls. These results suggest that SmChEs could be incorporated into a vaccine against schistosomiasis to reduce the pathology and transmission of this debilitating disease

Identification of lead chemotherapeutic agents from medicinal plants against blood flukes and whipworms

Schistosomiasis and trichuriasis are two of the most common neglected tropical diseases (NTD) that affect almost a billion people worldwide. There is only limited number of effective drugs to combat these NTD. Medicinal plants are a viable source of parasiticides. In this study, we have investigated six of the 19 phytochemicals isolated from two Bhutanese medicinal plants, Corydalis crispa and Pleurospermum amabile, for their anthelmintic properties. We used xWORM technique and Scanning Electron Microscope-based imaging to determine the activity of the compounds. Of the six compounds tested, isomyristicin and bergapten showed significant anthelmintic activity against Schistosoma mansoni and Trichuris muris with bergapten being the most efficacious one against both parasites (S. mansoni IC50 = 8.6 μg/mL and T. muris IC50 = 10.6 μg/mL) and also against schistosomula stage of S. mansoni. These two compounds induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. The efficacy against multiple phylogenetically distinct parasites and different life stages, especially the schistosomulum where praziquantel is ineffective, makes isomyristicin and bergapten novel scaffolds for broad-spectrum anthelmintic drug development that could be used for the control of helminths infecting humans and animals

Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration

Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson's disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer's disease and Huntington's disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders

Of monkeys and men: immunomic profiling of sera from humans and non-human primates resistant to schistosomiasis reveals novel potential vaccine candidates.

Schistosoma haematobium affects more than 100 million people throughout Africa and is the causative agent of urogenital schistosomiasis. The parasite is strongly associated with urothelial cancer in infected individuals and as such is designated a group I carcinogen by the International Agency for Research on Cancer. Using a protein microarray containing schistosome proteins, we sought to identify antigens that were the targets of protective IgG1 immune responses in S. haematobium-exposed individuals that acquire drug-induced resistance (DIR) to schistosomiasis after praziquantel treatment. Numerous antigens with known vaccine potential were identified, including calpain (Smp80), tetraspanins, glutathione-S-transferases, and glucose transporters (SGTP1), as well as previously uncharacterized proteins. Reactive IgG1 responses were not elevated in exposed individuals who did not acquire DIR. To complement our human subjects study, we screened for antigen targets of rhesus macaques rendered resistant to S. japonicum by experimental infection followed by self-cure, and discovered a number of new and known vaccine targets, including major targets recognized by our human subjects. This study has further validated the immunomics-based approach to schistosomiasis vaccine antigen discovery and identified numerous novel potential vaccine antigens

Protection against LPS-induced cartilage inflammation and degradation provided by a biological extract of Mentha spicata

<p>Abstract</p> <p>Background</p> <p>A variety of mint [<it>Mentha spicata</it>] has been bred which over-expresses Rosmarinic acid (RA) by approximately 20-fold. RA has demonstrated significant anti-inflammatory activity <it>in vitro </it>and in small rodents; thus it was hypothesized that this plant would demonstrate significant anti-inflammatory activity <it>in vitro</it>. The objectives of this study were: a) to develop an <it>in vitro </it>extraction procedure which mimics digestion and hepatic metabolism, b) to compare anti-inflammatory properties of High-Rosmarinic-Acid <it>Mentha spicata </it>(HRAM) with wild-type control <it>M. spicata </it>(CM), and c) to quantify the relative contributions of RA and three of its hepatic metabolites [ferulic acid (FA), caffeic acid (CA), coumaric acid (CO)] to anti-inflammatory activity of HRAM.</p> <p>Methods</p> <p>HRAM and CM were incubated in simulated gastric and intestinal fluid, liver microsomes (from male rat) and NADPH. Concentrations of RA, CA, CO, and FA in simulated digest of HRAM (HRAM_sim) and CM (CM_sim) were determined (HPLC) and compared with concentrations in aqueous extracts of HRAM and CM. Cartilage explants (porcine) were cultured with LPS (0 or 3 μg/mL) and test article [HRAM_sim(0, 8, 40, 80, 240, or 400 μg/mL), or CM_sim(0, 1, 5 or 10 mg/mL), or RA (0.640 μg/mL), or CA (0.384 μg/mL), or CO (0.057 μg/mL) or FA (0.038 μg/mL)] for 96 h. Media samples were analyzed for prostaglandin E₂(PGE₂), interleukin 1β (IL-1), glycosaminoglycan (GAG), nitric oxide (NO) and cell viability (differential live-dead cell staining).</p> <p>Results</p> <p>RA concentration of HRAM_simand CM_simwas 49.3 and 0.4 μg/mL, respectively. CA, FA and CO were identified in HRAM_simbut not in aqueous extract of HRAM. HRAM_sim(≥ 8 μg/mL) inhibited LPS-induced PGE₂and NO; HRAM_sim(≥ 80 μg/mL) inhibited LPS-induced GAG release. RA inhibited LPS-induced GAG release. No anti-inflammatory or chondroprotective effects of RA metabolites on cartilage explants were identified.</p> <p>Conclusions</p> <p>Our biological extraction procedure produces a substance which is similar in composition to post-hepatic products. HRAM_simis an effective inhibitor of LPS-induced inflammation in cartilage explants, and effects are primarily independent of RA. Further research is needed to identify bioactive phytochemical(s) in HRAM_sim.</p

Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signaling and drug detoxification and are essential for parasite survival

Cholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 -smp_154600 and Smache2 -smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 -smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor 2,2- dichlorovinyl dimethyl phosphate-dichlorvos (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.Funding: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was funded by NHMRC program grant APP1037304, an NHMRC Senior Principal Research Fellowship (APP1117504) to A.L. and a James Cook University Postgraduate Scholarship to B.T

Law, politics and the governance of English and Scottish joint-stock companies 1600-1850

This article examines the impact of law on corporate governance by means of a case study of joint-stock enterprise in England and Scotland before 1850. Based on a dataset of over 450 company constitutions together with qualitative information on governance practice, it finds little evidence to support the hypothesis that common-law regimes such as England were more supportive of economic growth than civil-law jurisdictions such as Scotland: indeed, levels of shareholder protection were slightly stronger in the civil-law zone. Other factors, such as local political institutions, played a bigger role in shaping organisational forms and business practice

Channel Scour at Bridges in the United States

DTFH61-87-Y-00123Scour of the channel bed around bridge foundations is the leading cause of failure among more than 487,000 bridges over water in the United States. Field measurements of scour at bridges are needed to improve the understanding of scour processes and the ability to predict scour depths accurately. This report documents methods to measure and interpret bridge scour data, presents an extensive pier scour measurement data base, evaluates scour processes in an analysis of these data, and compares observed and predicted scour depths for several scour prediction equations. More than 380 measurements of local scour around bridge piers have been compiled from 56 bridges in 14 States in a cooperative investigation of the U.S. Geological Survey and the Federal Highway Administration. The data are stored in an interactive bridge scour data base management system developed in this study. Improved planning for scour measurements during floods and advances in scour measurement instrumentation and techniques have improved the quantity and quality of measured scour data. Consistent and representative methods are used to interpret scour measurement data that were compiled from several investigations. The relation of scour depth to several explanatory variables, including effective pier width, flow depth, flow intensity, and sediment parameters, is investigated. The data distributions of individual scour variables are typically right skewed. The effective pier width generally has the greatest influence on scour depth. Flow depth has a positive relation with scour depth over the range of measured data; but the influence of flow depth decreases with increasing scour. The positive relation of flow intensity to scour depth is apparent when bed-load transport is negligible, but appears insignificant for active bed-load transport conditions. The influence of sediment size and gradation on local scour depth is inconclusive on the basis of this analysis. Selected local scour prediction equations are evaluated and compared based on the field data. None of the selected equations accurately predict the depth of scour for all the measured conditions. Several equations did better than others when evaluated as design equations. The information in this report is provided to contribute to the improved design and evaluation of bridges, and to the safety of the traveling public