An approach to the synthesis of ingenane diterpenes

Ingenol is the parent compound of the ingenane diterpenes. Certain C-3 fatty acid derivatives of these compounds are potent tumour promoters. Their mode of action is thought to occur through binding to and activation of the cell regulatory enzyme, protein kinase C. Central to the ingenane skeleton is a bicylo[4.4.1]undecanone-ll- one unit which is a rare example of //-a/M-intrabridgehead or inside-outside stereochemistry and is very strained. The structures are also highly oxygenated, ingenol itself is host to a cis-triol motif. To date ingenol has yet to succumb to total synthesis. Access to this system was envisaged via a tandem Birch reduction-divinylcyclopropyl (Cope) rearrangement of a phenylcyclopropane followed by a biomimetic pinacol-pinacolone skeletal shift. A model study in to the Birch reduction chemistry of phenylcyclopropanes is discussed and involves the preparation of phenylcyclopropanes substituted with methoxymethyl, vinyl and carboxylate groups. The reductive cleavage of the cyclopropane ring is observed with any functionality able to stabilise intermediate radical or anionic species or that can act as a leaving group. In the case of methoxymethyl substitution, reductive cleavage can be avoided by using proton sources; thus dihydro derivatives are readily available. The ring opening mechanism associated with vinyl substituted phenylcyclopropanes such as 2-phenyl vinylcyclopropane and 2-methoxymethyl-3-phenyl vinylcyclopropane has been shown to be particularly facile and is probably radical in nature. The possible utility of this methodology in the preparation of indenyl-type structures via 5-exo-trig cyclisation of radical intermediates has been investigated and led to the synthesis of 3-(2'-vinylcyclopropyl)-N,N, diethyl benzamide by way of Suzuki cross-coupling of the cyclopropyl boronate, ethyl 2-(4,4,5,5-tetramethyl[l,3,2]dioxaborolane)cyclopropanecarboxylate. In this case the presence of benzamide functionality allows a degree of reaction tuning (even in the presence of a vinyl group) so as to provide products of either reductive cyclopropane cleavage or those of aromatic reduction and related Cope rearrangement. The key Birch reduction substrate for ingenol synthesis, 1-(1,'2'- dihydroxycyclopentyl)-2-(2"methoxyphenyl)cyclopropane, was prepared from the cM-diene, Z-I-(cyciopent-l-ene)-2-(2'-methoxyphenyl)ethene, by dihydroxylation followed by cyclopropanation. Unfortunately the 2,5 rather than the desired 1,4- regioisomer was obtained from the Birch reduction step. Installation of electron withdrawing functionality such as an amide on the aromatic ring should overcome any such problem in the future. The 2,5 isomer forms an interesting hexacyclo acetal when heated or on contact with protic or Lewis acids

Sensitivity and Response of Bhutanese Glaciers to Atmospheric Warming

Glacierized change in the Himalayas affects river-discharge, hydro-energy and agricultural production, and Glacial Lake Outburst Flood potential, but its quantification and extent of impacts remains highly uncertain. Here we present conservative, comprehensive and quantitative predictions for glacier area and meltwater flux changes in Bhutan, monsoonal Himalayas. In particular, we quantify the uncertainties associated with the glacier area and meltwater flux changes due to uncertainty in climate data, a critical problem for much of High Asia. Based on a suite of gridded climate data and a robust glacier melt model, our results show that glacier area and meltwater change projections can vary by an order of magnitude for different climate datasets. However, the most conservative results indicate that, even if climate were to remain at the present-day mean values, almost 10% of Bhutan s glacierized area would vanish and the meltwater flux would drop by as much as 30%. Under the conservative scenario of an additional 1 C regional warming, glacier retreat is going to continue until about 25% of Bhutan s glacierized area will have disappeared and the annual meltwater flux, after an initial spike, would drop by as much as 65%. Citatio

Flipping the Model: A Values-Based Consortial Approach to Journal Negotiations

When negotiating journal pricing, the disadvantages libraries face are well documented. In addition to financially incompatible acquisition models that are out of sync with both library budgets and any predicted growth, libraries are also presented with rising inflationary costs, content added to an already overloaded system, and vendor consolidation. Pricing issues are further exacerbated by traditional negotiations, where libraries begin negotiations based on the offers made by publishers and vendors. These offers too often are predicated on historical spend and coupled with list prices that come with few explanations for their sums. Big package deals, that arguably expand access to resources and may lower costs on an article basis, have also increased overall costs and pushed out diverse resources. In attempting to move away from such deals institutions are faced with similar pricing for dramatically reduced access. The difficulties in navigating our way to a sustainable model become clear when the loss of researcher access is coupled with the increased staffing needed to manage individual subscriptions. New, and potentially viable pathways are beginning to emerge, including open access initiatives and the application of new models, such as read/publish. Although these pathways are not yet fully formed, they are promising developments that attempt to more holistically account for the contributions of the academy, the public good, and the costs of publishing. This presentation detailed the efforts of a task force within VIVA (Virginia’s academic library consortium) to create a bridge-solution between the current acquisition model and the future vision of its members. It creates a space to rethink what these deals could be and relies on consortial criteria to determine the value of content. The approach remains conscious of the real long-term institutional trust and communication risks to such endeavors, and is built on concerted, collective action

Removal of the Northern Paleo-Teton Range along the Yellowstone Hotspot Track

Classically held mechanisms for removing mountain topography (e.g., erosion and gravitational collapse) require 10-100 Myr or more to completely remove tectonically generated relief. Here, we propose that mountain ranges can be completely and rapidly (\u3c 2 Myr) removed by a migrating hotspot. In western North America, multiple mountain ranges, including the Teton Range, terminate at the boundary with the relatively low relief track of the Yellowstone hotspot. This abrupt transition leads to a previously untested hypothesis that preexisting mountainous topography along the track has been erased. We integrate thermochronologic data collected from the footwall of the Teton fault with flexural-kinematic modeling and length-displacement scaling to show that the paleo-Teton fault and associated Teton Range was much longer (min. original length 190-210 km) than the present topographic expression of the range front (~65 km) and extended across the modern-day Yellowstone hotspot track. These analyses also indicate that the majority of fault displacement (min. 11.4-12.6 km) and the associated footwall mountain range growth had accumulated prior to Yellowstone encroachment at ~2 Ma, leading us to interpret that eastward migration of the Yellowstone hotspot relative to stable North America led to removal of the paleo-Teton mountain topography via posteruptive collapse of the range following multiple supercaldera (VEI 8) eruptions from 2.0 Ma to 600 ka and/or an isostatic collapse response, similar to ranges north of the Snake River plain. While this extremely rapid removal of mountain ranges and adjoining basins is probably relatively infrequent in the geologic record, it has important implications for continental physiography and topography over very short time spans

Changes in Nascent Chromatin Structure Regulate Activation of the Pro-fibrotic Transcriptome and Myofibroblast Emergence in Organ Fibrosis

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis

Effect of Dam Emplacement and Water Level Changes on Sublacustrine Geomorphology and Recent Sedimentation in Jackson Lake, Grand Teton National Park (Wyoming, United States)

Dam installation on a deep hydrologically open lake provides the experimental framework necessary to study the influence of outlet engineering and changing base levels on limnogeological processes. Here, high-resolution seismic reflection profiles, sediment cores, and historical water level elevation datasets were employed to assess the recent depositional history of Jackson Lake, a dammed glacial lake located adjacent to the Teton fault in western Wyoming (USA). Prograding clinoforms imaged in the shallow stratigraphy indicate a recent lake-wide episode of delta abandonment. Submerged ∼11–12 m below the lake surface, these Gilbert-type paleo-deltas represent extensive submerged coarse-grained deposits along the axial and lateral margins of Jackson Lake that resulted from shoreline transgression following dam construction in the early 20th century. Other paleo-lake margin environments, including delta plain, shoreline, and glacial (drumlins, moraines) landforms were likewise inundated following dam installation, and now form prominent features on the lake floor. In deepwater, a detailed chronology was established using 137Cs, 210Pb, and reservoir-corrected 14C for a sediment core that spans ∼1654–2019 Common Era (CE). Dam emplacement (1908–1916 CE) correlates with a nearly five-fold acceleration in accumulation rates and a depositional shift towards carbonaceous sediments. Interbedded organic-rich black diatomaceous oozes and tan silts track changes in reservoir water level elevation, which oscillated in response to regional climate and downstream water needs between 1908 and 2019 CE. Chemostratigraphic patterns of carbon, phosphorus, and sulfur are consistent with a change in nutrient status and productivity, controlled initially by transgression-driven flooding of supralittoral soils and vegetation, and subsequently with water level changes. A thin gravity flow deposit punctuates the deepwater strata and provides a benchmark for turbidite characterization driven by hydroclimate change. Because the Teton fault is a major seismic hazard, end-member characterization of turbidites is a critical first step for accurate discrimination of mass transport deposits controlled by earthquakes in more ancient Jackson Lake strata. Results from this study illustrate the influence of dam installation on sublacustrine geomorphology and sedimentation, which has implications for lake management and ecosystem services. Further, this study demonstrates that Jackson Lake contains an expanded, untapped sedimentary archive recording environmental changes in the American West

SNAPSHOT USA 2019 : a coordinated national camera trap survey of the United States

This article is protected by copyright. All rights reserved.With the accelerating pace of global change, it is imperative that we obtain rapid inventories of the status and distribution of wildlife for ecological inferences and conservation planning. To address this challenge, we launched the SNAPSHOT USA project, a collaborative survey of terrestrial wildlife populations using camera traps across the United States. For our first annual survey, we compiled data across all 50 states during a 14-week period (17 August - 24 November of 2019). We sampled wildlife at 1509 camera trap sites from 110 camera trap arrays covering 12 different ecoregions across four development zones. This effort resulted in 166,036 unique detections of 83 species of mammals and 17 species of birds. All images were processed through the Smithsonian's eMammal camera trap data repository and included an expert review phase to ensure taxonomic accuracy of data, resulting in each picture being reviewed at least twice. The results represent a timely and standardized camera trap survey of the USA. All of the 2019 survey data are made available herein. We are currently repeating surveys in fall 2020, opening up the opportunity to other institutions and cooperators to expand coverage of all the urban-wild gradients and ecophysiographic regions of the country. Future data will be available as the database is updated at eMammal.si.edu/snapshot-usa, as well as future data paper submissions. These data will be useful for local and macroecological research including the examination of community assembly, effects of environmental and anthropogenic landscape variables, effects of fragmentation and extinction debt dynamics, as well as species-specific population dynamics and conservation action plans. There are no copyright restrictions; please cite this paper when using the data for publication.Publisher PDFPeer reviewe

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe