Elucidating the biosynthetic pathway of taxol

1996 Spring.Includes bibliographical references.The total synthesis of (±)-taxa-4(5),11(12)-diene, (±)-taxa-4(20),11(12)-diene, (±)-taxa-4(20), 11(12)-diene-5(β)-ol, and (±)-taxa-4(20),11(12)-diene-5(α)-ol is described. The syntheses rely upon selenium-based methodology developed by Krief for the introduction of the tetrasubstituted double bond in diene 201 and an intramolecular Diels-Alder reaction, methodology developed by Shea and Jenkins, to form the AB ring system of taxol in compound 208. The synthetic route was used to introduce stable and radiolabeled atoms into the target compounds. The incubation of 13C labeled (±)-taxa-4(20),11(12)-diene with taxadiene synthase has helped confirm the first committed biosynthetic step to taxol, in Taxus brevifolia, as being the direct cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. The incubation of tritium labeled (±)-taxa-4(5),11(12)-diene with a cytochrome P-450 microsomal cell-free extract produced a new mono-oxygenated product that had the same g.l.c. retention time and mass spectral fragmentation pattern as taxa-4(20),11(12)-diene-S(α)-ol. Taxa-4(20),11(12)-diene-5(β)-ol could not be found in this assay. Tritium labeled taxa-4(20),11(12)-diene-S(a)-ol was subsequently incubated with Taxus brevifolia stem discs and was incorporated into taxol. In addition, taxa-4(20),11(12)-diene-S(α)-acetate acted as a better substrate than taxa-4(20),11(12)-diene-5(α)-ol in the conversion to the more polar product(s) when incubated with the cytochrome P-450 microsomal cell-free extract. The more polar product(s) is/are presumed to be more highly hydroxylated biosynthetic intermediates enroute to taxol

Steps to a Political Ecology of Amazonia

Many recent studies of Amazonia have documented the ways in which agents of the state or capital seek to colonize not only indigenous land and labor, but indigenous desires as well. This colonization of the third kind has disastrous consequences: recently, William Fisher asked, “Why ... did it seem that Xikrin would sell their grandchildren’s environmental birthright just at the moment when reservations were finally being demarcated and boundaries guaranteed for generations to come?” Here I argue that this sort of question must become one of the central concerns of Amazonian ethnology. Drawing on work by Fisher and others, I review the value of political ecology approaches to answering such questions. I argue that political ecology must be informed by a broad notion of politics, one that centers on complex operations of power, especially the relationship between power and desire. Such a political ecology, informed both by poststructuralist concerns, a commitment to grounded ethnography, and a sophisticated theory of agency is well-equipped to make a serious contribution to our understanding of this problem, and is especially timely for Amazonian ethnography. Muchos estudios recientes de Amazonia han documentado las maneras a través de las cuales agentes del estado o del capital procuran colonizar no sólo la tierra y el trabajo indígenas sino también los deseos de los indígenas. Esta colonización tiene consecuencias desastrosas: recientemente, William Fisher preguntó “¿por qué … parecía que los Xikrin venderían los patrimonios ambientales de sus nietos justo en el momento en que las reservas estaban finalmente siendo demarcadas y sus fronteras garantizadas para las generaciones por venir?” En este ensayo, propongo que esta cuestión debe convertirse en una preocupación central de la etnología amazónica. Utilizando el trabajo de Fisher y otros, repaso la importancia del enfoque sobre ecología política para responder a preguntas como la de Fisher. Propongo que la ecología política debe incluir un concepto amplio de la política, uno que se centre en las operaciones complejas del poder, especialmente en la relación entre poder y deseo. Una ecología política que incluya preocupaciones pos-estructuralistas, una etnografía bien fundamentada, y una teoría sofisticada de la agencia, se adecuaría para hacer una contribución seria a nuestro entendimiento de este problema, y sería especialmente oportuna para la etnografía amazónica actual

Border Crossings: Transnational Americanist Anthopology

For anthropologists and social scientists working in North and South America, the past few decades have brought considerable change as issues such as repatriation, cultural jurisdiction, and revitalization movements have swept across the hemisphere. Today scholars are rethinking both how and why they study culture as they gain a new appreciation for the impact they have on the people they study. Key to this reassessment of the social sciences is a rethinking of the concept of borders: not only between cultures and nations but between disciplines such as archaeology and cultural anthropology, between past and present, and between anthropologists and indigenous peoples. Border Crossings is a collection of fourteen essays about the evolving focus and perspective of anthropologists and the anthropology of North and South America over the past two decades. For a growing number of researchers, the realities of working in the Americas have changed the distinctions between being a “Latin,” “North,” or “Native” Americanist as these researchers turn their interests and expertise simultaneously homeward and out across the globe

Comparing strategies for United States veterans' mortality ascertainment

BACKGROUND: We aimed to determine optimal strategies for complete mortality ascertainment comparing death certificates and United States (US) Veterans Administration (VA) records. METHODS: We constructed a cohort of California veterans who died in fiscal year (FY) 2000 and used VA services the year before death. We determined decedent status using California death certificates linked to VA utilization data and the VA Beneficiary Identification and Records Locator System (BIRLS) death file. We compared the characteristics of decedents who would not have been identified by either single source (e.g., VA BIRLS alone or California death certificates alone) with the rest of the cohort. RESULTS: A total of 8,813 veteran decedents were identified from both VA decedent files and death certificates. Of all decedents, 5,698 / 8,813 (65%) veterans were identified in both source files, but 2,426 / 8,813 (28%) decedents were not identified in VA BIRLS, and 689 / 8,813 (8%) were not identified in death certificates. Compared to the rest of the cohort, decedents whose mortality status was ascertained through either single source differed by race / ethnicity, marital status, and California residence. Clinically, veterans identified from either single source had less comorbidity and were less likely to have been users of VA inpatient or long term care, but equally or more likely to have been users of VA outpatient services. CONCLUSION: As single sources, VA decedent files and death certificates each provided an incomplete record, and death ascertainment was improved by using both source files. Potential bias may vary depending on analytic interest

Analysis of four DLX homeobox genes in autistic probands

BACKGROUND: Linkage studies in autism have identified susceptibility loci on chromosomes 2q and 7q, regions containing the DLX1/2 and DLX5/6 bigene clusters. The DLX genes encode homeodomain transcription factors that control craniofacial patterning and differentiation and survival of forebrain inhibitory neurons. We investigated the role that sequence variants in DLX genes play in autism by in-depth resequencing of these genes in 161 autism probands from the AGRE collection. RESULTS: Sequencing of exons, exon/intron boundaries and known enhancers of DLX1, 2, 5 and 6 identified several nonsynonymous variants in DLX2 and DLX5 and a variant in a DLX5/6intragenic enhancer. The nonsynonymous variants were detected in 4 of 95 families from which samples were sequenced. Two of these four SNPs were not observed in 378 undiagnosed samples from North American populations, while the remaining 2 were seen in one sample each. CONCLUSION: Segregation of these variants in pedigrees did not generally support a contribution to autism susceptibility by these genes, although functional analyses may provide insight into the biological understanding of these important proteins

Preventing Falls in Older Californians: State of the Art

In February 2003, the Foundation convened over 150 leaders in academic, legislative, community-based services, consumer advocates, aging network, housing, public health, public safety, and other leaders who worked for two days on a statewide blueprint on fall prevention.  In preparation for the convening, a Preconference White Paper was created and used to build the blueprint.  The California Blueprint describes state-of-the-art approaches to reducing the risks of falls, and the challenges to implementing fall prevention in California.  One of the top recommendations from this blueprint was the creation of a coordination center that could serve as a statewide resource and lead efforts in fall prevention.  This recommendation eventually led to the creation of the Fall Prevention Center of Excellence (FPCE)

Profiling quality of care: Is there a role for peer review?

BACKGROUND: We sought to develop a more reliable structured implicit chart review instrument for use in assessing the quality of care for chronic disease and to examine if ratings are more reliable for conditions in which the evidence base for practice is more developed. METHODS: We conducted a reliability study in a cohort with patient records including both outpatient and inpatient care as the objects of measurement. We developed a structured implicit review instrument to assess the quality of care over one year of treatment. 12 reviewers conducted a total of 496 reviews of 70 patient records selected from 26 VA clinical sites in two regions of the country. Each patient had between one and four conditions specified as having a highly developed evidence base (diabetes and hypertension) or a less developed evidence base (chronic obstructive pulmonary disease or a collection of acute conditions). Multilevel analysis that accounts for the nested and cross-classified structure of the data was used to estimate the signal and noise components of the measurement of quality and the reliability of implicit review. RESULTS: For COPD and a collection of acute conditions the reliability of a single physician review was quite low (intra-class correlation = 0.16–0.26) but comparable to most previously published estimates for the use of this method in inpatient settings. However, for diabetes and hypertension the reliability is significantly higher at 0.46. The higher reliability is a result of the reviewers collectively being able to distinguish more differences in the quality of care between patients (p < 0.007) and not due to less random noise or individual reviewer bias in the measurement. For these conditions the level of true quality (i.e. the rating of quality of care that would result from the full population of physician reviewers reviewing a record) varied from poor to good across patients. CONCLUSIONS: For conditions with a well-developed quality of care evidence base, such as hypertension and diabetes, a single structured implicit review to assess the quality of care over a period of time is moderately reliable. This method could be a reasonable complement or alternative to explicit indicator approaches for assessing and comparing quality of care. Structured implicit review, like explicit quality measures, must be used more cautiously for illnesses for which the evidence base is less well developed, such as COPD and acute, short-course illnesses

Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies against the hemidesmosomal proteins BP180 and BP230. In the IgG passive transfer model of BP, blister formation is triggered by anti-BP180 IgG and depends on complement activation, mast cell degranulation, and neutrophil recruitment. Mice lacking neutrophil elastase (NE) do not develop experimental BP. Here, we demonstrated that NE degrades recombinant mouse BP180 within the immunodominant extracellular domain at amino acid positions 506 and 561, generating peptide p561 and peptide p506. Peptide p561 is chemotactic for neutrophils both in vitro and in vivo. Local injection of NE into B6 mice recruits neutrophils to the skin, and neutrophil infiltration is completely blocked by co-injection with the NE inhibitor α1-proteinase inhibitor. More importantly, NE directly cleaves BP180 in mouse and human skin, as well as the native human BP180 trimer molecule. These results demonstrate that (i) NE directly damages the extracellular matrix and (ii) NE degradation of mouse BP180 generates neutrophil chemotactic peptides that amplify disease severity at the early stage of the disease

Apparent Competition, Lion Predation, and Managed Livestock Grazing: Can Conservation Value Be Enhanced?

Predator restorations often result in apparent competition, where co-occurring prey populations experience asymmetric predation pressure driven by predator preferences. In many rangeland ecosystems, livestock share the landscape with wildlife, including ungulates and the large carnivores that consume them. We examined whether apparent competition reorganized prey communities following restoration of lions (Panthera leo) to a savanna ecosystem, and whether and how livestock management could alter this indirect interaction between lions and their prey. Three lines of evidence supported the hypothesis that Jackson's hartebeest (Alcelaphus bucelaphus lelwel; an ungulate of conservation concern) are suppressed via lion-mediated apparent competition. First, hartebeest exhibited an Allee effect where they were exposed to lions, but displayed negative density-dependent population growth where they were protected from lions. Second, spatial overlap between plains zebra (Equus burchelli; the primary prey of lions) and hartebeest further exacerbated lion predation on hartebeest. Finally, hartebeest were killed selectively by lions, whereas zebra were killed by lions in proportion to their abundance. We then tested whether glades [nutrient-rich hotspots created by abandoned cattle (Bos indicus) corrals] could be used to manipulate top-down control of hartebeest via their influence on the spatial distribution of zebra. Zebra aggregated at glades, and survival of hartebeest increased with increasing distance from glades, suggesting that corrals may be placed on the landscape away from hartebeest to create spatial refuges from lions. Our findings demonstrate how informed placement of livestock corrals can be used to manipulate the spatial distribution of primary prey (zebra), thereby reducing apparent competition suffered by hartebeest. Our work further provides an example of how integrating apparent competition theory with proactive livestock management can improve conservation efforts in multiple-use landscapes