The alkaloids of Artabotrys suaveolens, Blume (N. O. Anonaceae)

The bark of the Philippine species of Artabotrs suaveolens, Blume, has been re- examined and has been shown to yield, in addition to the principal alkaloid "Artabotrine ", two new alkaloids, viz., "Suaveoline" and "Artabotrinine ".From a detailed study of artabotrine, the probable structural formula has been determined; and such facts as have been ascertained regarding the structures of the other two alkaloids are also included.a. Artabotrine. 1. From analytical data obtained with the purified base as well as with various derivatives, the empirical formula C20H2304N is preferred to that of C21H2504N. 2. The previously unknown function of the fourth oxygen atom in artabotrine has been determined and shown to be due to an alcoholic group possessing slightly acidic properties. The hydroxyl group can/ -115- can be methylated either with nascent diazomethane or by means of dimethyl sulphate; in the latter case the nitrogen atom is also methylated. 3. The product obtained from the action of chlorethyl carbonate on artabotrine was neutral and optically inactive; a tetrahydro- isoquinoline ring system is therefore indicated. 4. The first stage of the Hofmann degradation yielded a crystalline, optically active, unsaturated methine -base. Further methylation of the methine base and treatment with alkali resulted in the elimination of trimethylamine, and in the formation of a non -nitrogenous vinyl compound which exhibited properties similar to those of 10- phenanthrol. The elimination of trimethylamine after the second methylation indicates that the nitrogen belongs to one ring. That a vinyl group was present was shown by the rapid absorption of one mol of hydrogen, but owing to the instability of the resulting compound, it could not be isolated. Attempts to oxidize the non -nitrogenous vinyl compound to the corresponding carboxylic acid were unsuccessful. 5. Oxidation of artabotrine with chromic acid yielded a small quantity of deep coloured substance with properties resembling those of an ortho -quinone. 6. Oxidation of artabotrine with aqueous potassium permanganate yielded a small amount of a lactone acid which possesses two methoxyl groups. In an attempt to synthesize the substance, three isomeric lactone acids were prepared but found not to be identical with the natural acid. 7. The ultra-violet absorption spectra of artabotrine has been found to be similar to that of pukateine. 8. The crystallographic analysis of artabotrine has contra-indicated a double -molecule structure for the base. 9. The pharmacological activity of artabotrine has been re-examined and compared with that of thebaine.b. Suaveoline. 1. The empirical formula of this new phenolic alkaloid has been shown to be C1.H2104N. 2, The alkaloid is optically active and possesses two methoxyl groups, one N- methyl group, and a Zerewitinoff estimation showed two active hydrogen atoms. 3. The alkaloid gives a positive rellagri reaction, indicating that the para position to the phenolic hydroxyl group is probably free. 4. The alkaloid can be completely methylated with nascent diazomethane to an oily base which readily forms a crystalline methiodide. A mixed melting point has indicated that this methiodide is probably identical with that obtained from fully methylated artabotrine.c. Artabotrinine. 1. This new, non -phenolic alkaloid possesses the empirical formula C 1 eH 1.p3 N, ard is amorphous. 2. The alkaloid is an optieally active secondary base, and possesses one methoxyl as well as a methylene dioxy group; the latter two groups therefore account for all three oxygen atoms. A Zerewitinoff estimation showed one active hydrogen. 3. The alkaloid can be methylated to the corresponding crystalline N- methyl derivative by means of formaldehyde and formic acid. 4. N- methyl artabotrinine is isomeric, but not identical, with 0- methyl pukateine. 5. The methylene -dioxy group was hydrolysed by means of phloroglucinol and sulphuric acid and the resulting dihydroxy compound methylated with nascent diazometh.a.ne. 6. The ultra -violet absorption spectra of artabotrinine hydrochloride has been examined and compared with that of dicentrine

Letter from Seargent Smith Prentiss to Albert Pike, April 25, 1846.

In this letter, Seargent Smith Prentiss writes on the subject of a claim sold to Albert Pike and requests the names and residences for witnesses, dated April 25, 1846.https://digitalcommons.wofford.edu/littlejohnmss/1190/thumbnail.jp

Towards social impact assessment of copper-nickel mining in Botswana

This research study is more of an initiative towards Social Impact Assessment of copper-nickel mining in Botswana. The specific objectives of the study were centred on the assessment of the social impacts of copper-nickel mining in Botswana from the initial mining stage of exploration, surveying and mine site development to mine closure. The study was carried out under the broad hypotheses that mining influences population movement that impact on areas of mining; mining activities have both economic benefits and deleterious social impacts on the local communities found in the areas where mining is taking place; and mine closure has far reaching socio-economic, investment and developmental implications over and above the obvious interests of project owners. To achieve the broad aim as summarised above, the research study used a multi-disciplinary methodology and approach that required several kinds of expertise and sources of information. Hence it used both primary and secondary sources centred on interactive informative interviews, site visits and observations, questionnaires, census data records, mining companies’ publications, published textbooks and journal articles. The research study comprised of three different mines operated by three different mining companies in three varied socio-cultural and ethnic regions of Botswana. First was a detailed Social Impact Assessment of the initial phase of exploration, surveying and mine site development represented by Mowana mine project operated by African Copper in the rural areas of Dugwi and Mosetse. This case study yielded results showing that the social impacts of mining in the area are diverse and extensive. The findings suggest that the impacts relate not only to the possible economic benefits of foreign exchange, employment, the optimal use of available mineral resources and the possible development of Dugwi and Mosetse villages, but extends to the deleterious social impacts. The results also indicated that the social impacts have just begun in the two communities. Hence they point towards a possible disruption within the socio-cultural system of the local people if serious mitigation measures are not put in place; thus suggesting that the early stages of exploration and mine site development results in the most conflict between the mine and the local people. Second was a comprehensive Social Impact Assessment of Tati-Nickel Phoenix mining project in the peri-urban areas of Matshelagabedi and Matsiloje areas representing the mining stage of mine production and expansion. The results from this case study suggest that during vi mine production and expansion, many people were relocated. However, the overriding impression gained from the case study was Tati-Nickel Mining Company’s elaborate corporate policies that suggested good corporate governance and best practices that promote sustainable development. A notable milestone on good corporate governance and best practice that the other two case studies (mining company) could benchmark on is Tati-Nickel’s corporate social responsibility programme that has been designed to ensure that the communities within a fifty kilometre mine radius benefit from the mine. The results from the case study also distinguished the mining stage of production and expansion from the other two because it is associated with the deep entrenchment of the social impacts into the communities near to mining areas. Third was a detailed Social Impact Assessment on Bamangwato Concession Limited mine in the industrial town of Selebi-Phikwe. The case study represented the stage of mine closure. Through the findings of this case study, it became apparent that the economic dependence of Selebi-Phikwe on mining has seen the town developing into a mining town, increasing its vulnerability at mine closure. The results from the case study further suggest that mine closure will degrade the socio-economic sector of the town with ever far reaching socio-economic implications as many people lose their gainful employment, hence suggesting that a possible complete mine closure will be the most traumatic phase leading to major social conflict within the area. Thus the results suggest that at mine closure, the deleterious social impacts will overspill to other areas in Botswana with disastrous effects for the economy of the country. The results yielded through this study established in clear and passionate language that copper-nickel mining in Botswana influences population movements that lead to positive and negative impacts on the communities found in mining areas. Another major finding of the study is that copper-nickel mining activities have both economic benefits and deleterious social impacts on the local communities, hence the recommendation that the copper-nickel mining companies should embrace the concept of sustainable mining for sustainable development to avoid most of the negative impacts of their operations on the local communities

Comet C/2011 W3 (Lovejoy): Orbit Determination, Outbursts, Disintegration of Nucleus, Dust-Tail Morphology, and Relationship to New Cluster of Bright Sungrazers

We describe the physical and orbital properties of C/2011 W3. After surviving perihelion, the comet underwent major changes (permanent loss of nuclear condensation, formation of spine tail). The process of disintegration culminated with an outburst on December 17.6 (T+1.6 d) and this delayed response is inconsistent with the rubble pile model. Probable cause was thermal stress from the heat pulse into the nucleus after perihelion, which could also produce fragmentation of sungrazers far from the Sun. The spine tail was a synchronic feature, made up of dust released at <30 m/s. Since the nucleus would have been located on the synchrone, we computed the astrometric positions of the missing nucleus as the coordinates of the points of intersection of the spine tail's axis with lines of forced orbital-period variation, derived from orbital solutions based on preperihelion astrometry from the ground. The resulting osculating orbital period was 698+/-2 years, which proves that C/2011 W3 is the first major member of the predicted new, 21st-century cluster of bright Kreutz-system sungrazers. The spine tail's tip contained dust 1-2 mm in diameter. The bizarre appearance of the dust tail in images taken hours after perihelion with coronagraphs on SOHO and STEREO is readily understood. The disconnection of the comet's head from the preperihelion tail and the apparent activity attenuation near perihelion are both caused by sublimation of all dust at heliocentric distances smaller than ~1.8 solar radii. The tail's brightness is strongly affected by forward scattering of sunlight by dust. The longest-imaged grains had a radiation-pressure parameter beta ~ 0.6, probably submicron-sized silicate grains. The place of C/2011 W3 within the hierarchy of the Kreutz system and its genealogy via a 14th century parent suggest that it is indirectly related to the celebrated sungrazer X/1106 C1.Comment: Submitted to Astrophysical Journal; 35 pages, 18 figures, 8 table

Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARγ, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARγ signaling could also play an anti-neoplastic role in several <it>in vitro </it>models, although conflicting results are reported from <it>in vivo </it>models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes.</p> <p>Methods</p> <p>A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs.</p> <p>Results</p> <p>In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, <it>P </it>= 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, <it>P </it>= 0.02), and among women (OR = 2.07, <it>P </it>= 0.01).</p> <p>Conclusion</p> <p>These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.</p

Effect of troglitazone on tumor growth and pulmonary metastasis development of the mouse osteosarcoma cell line LM8

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma often develops micrometastases in the lung prior to diagnosis, causing a fatal outcome. Therefore, the prevention of pulmonary metastases is critical for the improvement of the prognosis of patients with osteosarcoma. The purpose of this study was to investigate whether troglitazone (TGZ) is considered as possible therapeutics in the treatment of growth and metastasis of osteosarcoma.</p> <p>Methods</p> <p>LM8 cells were treated for 3 days with various concentrations of TGZ. The effect of TGZ on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2'-deoxyuridine incorporation study. The assay of cell invasion and motility was performed using either the Matrigel-coated cell culture inserts or the uncoated cell culture inserts in the invasion chambers. The effect of TGZ on Akt signaling was assessed by Western blot analysis of Akt and p-Akt. The effects of oral administration of either TGZ (TGZ group) or ethanol (control group) on the growth of primary tumor and the development of pulmonary metastasis were examined in nude mice implanted with LM8 cells on their backs. The expression and activity of matrix metalloproteinase 2 (MMP-2) within the tumor were determined by immunohistochemistry and zymography. The microvessel density (MVD) within the tumor was determined by immunohistochemistry for CD34.</p> <p>Results</p> <p>TGZ dose-dependently inhibits cell proliferation. TGZ-treated cells were less invasive and less motile than untreated cells. The activity of MMP-2 secreted by TGZ-treated cells was lower than that secreted by untreated cells. TGZ decreased the level of p-Akt. The primary tumor mass was smaller in the TGZ group than in the control group. The TGZ group had less metastatic tumors in the lung compared with the control group. The expression and activity of MMP-2 within the tumor of the TGZ group were lower than those of the control group. The MVD within the tumor of the TGZ group was lower than that of the control group.</p> <p>Conclusions</p> <p>Inhibition of Akt signaling by TGZ may decrease the secretion of MMP-2, resulting in the decrease of invasiveness and motility in LM8 cells. Treatment of tumor-bearing mice with TGZ decreases the expression and activity of MMP-2 within the tumor, and inhibits primary tumor growth and pulmonary metastasis development. TGZ may offer a new approach in chemotherapy for osteosarcoma.</p

Specific Thiazolidinediones Inhibit Ovarian Cancer Cell Line Proliferation and Cause Cell Cycle Arrest in a PPARγ Independent Manner

Peroxisome Proliferator Activated Receptor gamma (PPARγ) agonists, such as the thiazolinediones (TZDs), have been studied for their potential use as cancer therapeutic agents. We investigated the effect of four TZDs--Rosiglitazone (Rosi), Ciglitazone (CGZ), Troglitazone (TGZ), and Pioglitazone (Pio)--on ovarian cancer cell proliferation, PPARγ expression and PPAR luciferase reporter activity. We explored whether TZDs act in a PPARγ dependent or independent manner by utilizing molecular approaches to inhibit or overexpress PPARγ activity.Treatment with CGZ or TGZ for 24 hours decreased proliferation in three ovarian cancer cell lines, Ovcar3, CaOv3, and Skov3, whereas Rosi and Pio had no effect. This decrease in Ovcar3 cell proliferation was due to a higher fraction of cells in the G(0)/G(1) stage of the cell cycle. CGZ and TGZ treatment increased apoptosis after 4 hours of treatment but not after 8 or 12 hours. Treatment with TGZ or CGZ increased PPARγ mRNA expression in Ovcar3 cells; however, protein levels were unchanged. Surprisingly, luciferase promoter assays revealed that none of the TZDs increased PPARγ activity. Overexpression of wild type PPARγ increased reporter activity. This was further augmented by TGZ, Rosi, and Pio indicating that these cells have the endogenous capacity to mediate PPARγ transactivation. To determine whether PPARγ mediates the TZD-induced decrease in proliferation, cells were treated with CGZ or TGZ in the absence or presence of a dominant negative (DN) or wild type overexpression PPARγ construct. Neither vector changed the TZD-mediated cell proliferation suggesting this effect of TZDs on ovarian cancer cells may be PPARγ independent.CGZ and TGZ cause a decrease in ovarian cancer cell proliferation that is PPARγ independent. This concept is supported by the finding that a DN or overexpression of the wild type PPARγ did not affect the changes in cell proliferation and cell cycle

Molecular Predictors of 3D Morphogenesis by Breast Cancer Cell Lines in 3D Culture

Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARγ has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARγ has been validated through two supporting biological assays

p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

Background: The tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs. Methodology/Principal Findings: To clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 downregulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells. Conclusions: These comparative studies suggest that, depending on the specific cell type and the specific differentiatio