Development of a TB vaccine trial site in Africa and lessons from the Ebola experience

Tuberculosis is the deadliest infection of our time. In contrast, about 11,000 people died of Ebola between 2014 and 2016. Despite this manifest difference in mortality, there is now a vaccine licensed in the United States and by the European Medicines Agency, with up to 100% efficacy against Ebola. The developments that led to the trialing of the Ebola vaccine were historic and unprecedented. The single licensed TB vaccine (BCG) has limited efficacy. There is a dire need for a more efficacious TB vaccine. To deploy such vaccines, trials are needed in sites that combine high disease incidence and research infrastructure. We describe our twelve-year experience building a TB vaccine trial site in contrast to the process in the recent Ebola outbreak. There are additional differences. Relative to the Ebola pipeline, TB vaccines have fewer trials and a paucity of government and industry led trials. While pathogens have varying levels of difficulty in the development of new vaccine candidates, there yet appears to be greater interest in funding and coordinating Ebola interventions. TB is a global threat that requires similar concerted effort for elimination

Plasma Membrane Is the Site of Productive HIV-1 Particle Assembly

Recently proposed models that have gained wide acceptance posit that HIV-1 virion morphogenesis is initiated by targeting the major structural protein (Gag) to late endosomal membranes. Thereafter, late endosome-based secretory pathways are thought to deliver Gag or assembled virions to the plasma membrane (PM) and extracellular milieu. We present several findings that are inconsistent with this model. Specifically, we demonstrate that HIV-1 Gag is delivered to the PM, and virions are efficiently released into the extracellular medium, when late endosome motility is abolished. Furthermore, we show that HIV-1 virions are efficiently released when assembly is rationally targeted to the PM, but not when targeted to late endosomes. Recently synthesized Gag first accumulates and assembles at the PM, but a proportion is subsequently internalized via endocytosis or phagocytosis, thus accounting for observations of endosomal localization. We conclude that HIV-1 assembly is initiated and completed at the PM, and not at endosomal membranes

Identification and structural characterization of FYVE domain-containing proteins of Arabidopsis thaliana

<p>Abstract</p> <p>Background</p> <p>FYVE domains have emerged as membrane-targeting domains highly specific for phosphatidylinositol 3-phosphate (PtdIns(3)<it>P</it>). They are predominantly found in proteins involved in various trafficking pathways. Although FYVE domains may function as individual modules, dimers or in partnership with other proteins, structurally, all FYVE domains share a fold comprising two small characteristic double-stranded β-sheets, and a C-terminal α-helix, which houses eight conserved Zn²⁺ion-binding cysteines. To date, the structural, biochemical, and biophysical mechanisms for subcellular targeting of FYVE domains for proteins from various model organisms have been worked out but plant FYVE domains remain noticeably under-investigated.</p> <p>Results</p> <p>We carried out an extensive examination of all <it>Arabidopsis </it>FYVE domains, including their identification, classification, molecular modeling and biophysical characterization using computational approaches. Our classification of fifteen <it>Arabidopsis </it>FYVE proteins at the outset reveals unique domain architectures for FYVE containing proteins, which are not paralleled in other organisms. Detailed sequence analysis and biophysical characterization of the structural models are used to predict membrane interaction mechanisms previously described for other FYVE domains and their subtle variations as well as novel mechanisms that seem to be specific to plants.</p> <p>Conclusions</p> <p>Our study contributes to the understanding of the molecular basis of FYVE-based membrane targeting in plants on a genomic scale. The results show that FYVE domain containing proteins in plants have evolved to incorporate significant differences from those in other organisms implying that they play a unique role in plant signaling pathways and/or play similar/parallel roles in signaling to other organisms but use different protein players/signaling mechanisms.</p

Sustainability and Depletion Accounting for Non-Renewable Resources: The Case of Copper in Chile

&lt;p class="1Body"&gt;This research develops a framework for assessing just compensation values for mining projects, where they might contribute toward a responsible, profitable, and sustainable path to economic growth and development. More specifically, it deals with methods to determine a “sustainable” rate of mineral extraction, putting a dollar value on the environmental impacts from various levels of mineral extraction. The project focuses on an emerging political economy (Chile) and uses an interdisciplinary approach. The approach rests on the assumption that the policy objectives of environmental protection and sustainable economic development can be subsumed into the “Hartwick rule” goal of investing mining rents in natural, social, and infrastructure capital. This study aids in policy decisions relating to benefit transfer to local/regional infrastructure investment.&lt;/p&gt;</jats:p

Returns from the Management of Noble Fir Stands for Bough Production and Sawtimber

Abstract Noble fir (Abies procera Rehder) bough harvest has been part of the nontimber forest products industry in the Pacific Northwest for decades. The boughs are used for seasonal decorations and command a higher pricethan most other decorative bough species. However, noble fir boughs that are harvested in the region have been merely a byproduct of noble fir plantations managed for timber products. This article presents the results of a study assessing the financial desirability of managing noble fir plantationsin the southern Cascade Mountains of Washington State for the production of both timber and bough products. The Landscape Management System software program was used to simulate the growth of noble fir in four different plant associations on the Gifford Pinchot National Forest. Data from recentlyestablished noble fir plantations were used in the simulations. Harvestable bough weights were estimated using a previously published noble fir bough weight model. Comparisons of estimated harvest volumes for sawlogs and noble fir boughs showed positive present net worth (PNW) values for eachstand under a combined timber production and bough harvest scenario and negative PNW values for each stand with a timber production management scenario only. Bough harvest is compatible with other land use activities, and the harvest revenue can cover stand establishment and precommercialthinning costs.</jats:p

A Model to Estimate Noble Fir Bough Weight

Abstract The harvesting of noble fir (Abies procera) for the production of Christmas wreaths and related products has been a mainstay of the nontimber forest products industry in the Pacific Northwest (PNW) for decades. Although noble fir is the single most important bough product harvested in the PNW, little or no work has been published concerning the estimation of the weight of harvestable boughs from standing trees. The model presented in this article was designed specifically for use in predicting the weight of harvestable boughs from standing trees. A total of 322 noble fir were selected on the west side of the Cascades of Washington and Oregon. The stands and sites for sampling were chosen to represent a wide range of environmental and stand conditions. Sample trees were selected at fixed distances along systematical located lines at each selected site. Circular plots with a 20-ft radius centered at each sample tree were established to provide data on competition. Regression analysis was used to estimate the final model. Variables included in the final model were total tree height, merchantable bough height, dbh2, age at dbh, whorl age for each merchantable whorl, and the associated number of boughs for each whorl as well as the total number of trees within a 20-foot radius of the plot tree. In addition, an intercept shifter (0,1) to designate noble fir stands located north and South of the Marion/Clackamas County line in Oregon (South = 0, North = 1) was included in the model. The overall model was significant at the 0.0001 level with an adjusted R2 of 0.77 West. J. Appl. For. 20(1):44–49.</jats:p