Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total ...synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
Enantioselective Organocatalysis Using SOMO Activation Beeson, Teresa D; Mastracchio, Anthony; Hong, Jun-Bae ...
Science (American Association for the Advancement of Science),
04/2007, Letnik:
316, Številka:
5824
Journal Article
Recenzirano
The asymmetric α-addition of relatively nonpolar hydrocarbon substrates, such as allyl and aryl groups, to aldehydes and ketones remains a largely unsolved problem in organic synthesis, despite the ...wide potential utility of direct routes to such products. We reasoned that well-established chiral amine catalysis, which activates aldehydes toward electrophile addition by enamine formation, could be expanded to this important reaction class by applying a single-electron oxidant to create a transient radical species from the enamine. We demonstrated the concept of singly occupied molecular orbital (SOMO) activation with a highly selective α-allylation of aldehydes, and we here present preliminary results for enantioselective heteroarylations and cyclization/halogenation cascades.
Perceived and objectively-assessed aspects of the neighbourhood physical environment have been postulated to be key contributors to regular engagement in active travel (AT) in older adults. We ...systematically reviewed the literature on neighbourhood physical environmental correlates of AT in older adults and applied a novel meta-analytic approach to statistically quantify the strength of evidence for environment-AT associations.
Forty two quantitative studies that estimated associations of aspects of the neighbourhood built environment with AT in older adults (aged ≥ 65 years) and met selection criteria were reviewed and meta-analysed. Findings were analysed according to five AT outcomes (total walking for transport, within-neighbourhood walking for transport, combined walking and cycling for transport, cycling for transport, and all AT outcomes combined) and seven categories of the neighbourhood physical environment (residential density/urbanisation, walkability, street connectivity, access to/availability of services/destinations, pedestrian and cycling infrastructure, aesthetics and cleanliness/order, and safety and traffic).
Most studies examined correlates of total walking for transport. A sufficient amount of evidence of positive associations with total walking for transport was found for residential density/urbanisation, walkability, street connectivity, overall access to destinations/services, land use mix, pedestrian-friendly features and access to several types of destinations. Littering/vandalism/decay was negatively related to total walking for transport. Limited evidence was available on correlates of cycling and combined walking and cycling for transport, while sufficient evidence emerged for a positive association of within-neighbourhood walking with pedestrian-friendly features and availability of benches/sitting facilities. Correlates of all AT combined mirrored those of walking for transport. Positive associations were also observed with food outlets, business/institutional/industrial destinations, availability of street lights, easy access to building entrance and human and motorised traffic volume. Several but inconsistent individual- and environmental-level moderators of associations were identified.
Results support strong links between the neighbourhood physical environment and older adults' AT. Future research should focus on the identification of types and mixes of destinations that support AT in older adults and how these interact with individual characteristics and other environmental factors. Future research should also aim to clarify dose-response relationships through multi-country investigations and data-pooling from diverse geographical regions.
Activity-friendly neighbourhood physical environments with access to recreational facilities are hypothesised to facilitate leisure-time physical activity (LTPA) among older adults (≥ 65 years old). ...The aim of the current study was to systematically review and quantitatively summarise study findings on the relationships between physical environmental attributes and LTPA among older adults.
An extensive search of literature, including grey literature, yielded 72 articles eligible for inclusion. The reported associations between seven categories of environmental attributes and six LTPA outcomes were extracted, weighted by sample size and study quality, and quantitatively summarised. Reported moderating effects of individual and environmental characteristics and neighbourhood definition were also examined.
We observed positive associations for walkability (p = 0.01), land-use mix-access (p = 0.02) and aesthetically pleasing scenery (p < 0.001) with leisure-time walking. For leisure-time walking within the neighbourhood, evidence was found for positive associations with land-use mix-access (p = 0.03) and access to public transit (p = 0.05), and a negative association with barriers to walking/cycling (p = 0.03). Evidence for positive relationships between overall LTPA and access to recreational facilities (p = 0.01) and parks/open space (p = 0.04) was found. Several environmental attribute-LTPA outcome combinations were insufficiently studied to draw conclusions. No consistent moderating effects were observed for individual and environmental characteristics and neighbourhood definition.
The observed significant relationships can be used to inform policy makers and planners on how to (re-)design neighbourhoods that promote LTPA among older adults. Many environmental attribute-LTPA outcome relationships have been studied insufficiently and several methodological issues remain to be addressed.
PROSPERO 2016:CRD42016051180.
Type II CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems use an RNA-guided DNA endonuclease, Cas9, to generate double-strand breaks in invasive DNA ...during an adaptive bacterial immune response. Cas9 has been harnessed as a powerful tool for genome editing and gene regulation in many eukaryotic organisms. We report 2.6 and 2.2 angstrom resolution crystal structures of two major Cas9 enzyme subtypes, revealing the structural core shared by all Cas9 family members. The architectures of Cas9 enzymes define nucleic acid binding clefts, and single-particle electron microscopy reconstructions show that the two structural lobes harboring these clefts undergo guide RNA-induced reorientation to form a central channel where DNA substrates are bound. The observation that extensive structural rearrangements occur before target DNA duplex binding implicates guide RNA loading as a key step in Cas9 activation.
Identifying attributes of the built environment associated with health-enhancing levels of physical activity (PA) in older adults (≥65 years old) has the potential to inform interventions supporting ...healthy and active ageing. The aim of this study was to first systematically review and quantify findings on built environmental correlates of older adults' PA, and second, investigate differences by type of PA and environmental attribute measurement.
One hundred articles from peer-reviewed and grey literature examining built environmental attributes related to total PA met inclusion criteria and relevant information was extracted. Findings were meta-analysed and weighted by article quality and sample size and then stratified by PA and environmental measurement method. Associations (p < .05) were found in relation to 26 individual built environmental attributes across six categories (walkability, residential density/urbanisation, street connectivity, access to/availability of destinations and services, infrastructure and streetscape, and safety) and total PA and walking specifically. Reported individual- and environmental-level moderators were also examined.
Positive environmental correlates of PA, ranked by strength of evidence, were: walkability (p < .001), safety from crime (p < .001), overall access to destinations and services (p < .001), recreational facilities (p < .001), parks/public open space (p = .002) and shops/commercial destinations (p = .006), greenery and aesthetically pleasing scenery (p = .004), walk-friendly infrastructure (p = .009), and access to public transport (p = .016). There were 26 individual differences in the number of significant associations when the type of PA and environmental measurement method was considered. No consistent moderating effects on the association between built environmental attributes and PA were found.
Safe, walkable, and aesthetically pleasing neighbourhoods, with access to overall and specific destinations and services positively influenced older adults' PA participation. However, when considering the environmental attributes that were sufficiently studied (i.e., in ≥5 separate findings), the strength of evidence of associations of specific categories of environment attributes with PA differed across PA and environmental measurement types. Future research should be mindful of these differences in findings and identify the underlying mechanisms. Higher quality research is also needed.
Apoptosis is a highly regulated form of cell death that controls normal homeostasis as well as the antitumor activity of many chemotherapeutic agents. Commitment to death via the mitochondrial ...apoptotic pathway requires activation of the mitochondrial pore-forming proteins BAK or BAX. Activation can be effected by the activator BH3-only proteins BID or BIM, which have been considered to be functionally redundant in this role. Herein, we show that significant activation preferences exist between these proteins: BID preferentially activates BAK while BIM preferentially activates BAX. Furthermore, we find that cells lacking BAK are relatively resistant to agents that require BID activation for maximal induction of apoptosis, including topoisomerase inhibitors and TRAIL. Consequently, patients with tumors that harbor a loss of BAK1 exhibit an inferior response to topoisomerase inhibitor treatment in the clinic. Therefore, BID and BIM have nonoverlapping roles in the induction of apoptosis via BAK and BAX, affecting chemotherapy response.
•BID and BIM preferentially activate BAK and BAX, respectively•BID-dependent cell death correlates with BAK-dependent cell death•Patients with tumors lacking BAK respond poorly to topoisomerase inhibitors
Stress granules are higher order assemblies of nontranslating mRNAs and proteins that form when translation initiation is inhibited. Stress granules are thought to form by protein–protein ...interactions of RNA-binding proteins. We demonstrate RNA homopolymers or purified cellular RNA forms assemblies in vitro analogous to stress granules. Remarkably, under conditions representative of an intracellular stress response, the mRNAs enriched in assemblies from total yeast RNA largely recapitulate the stress granule transcriptome. We suggest stress granules are formed by a summation of protein–protein and RNA–RNA interactions, with RNA self-assembly likely to contribute to other RNP assemblies wherever there is a high local concentration of RNA. RNA assembly in vitro is also increased by GR and PR dipeptide repeats, which are known to increase stress granule formation in cells. Since GR and PR dipeptides are involved in neurodegenerative diseases, this suggests that perturbations increasing RNA–RNA assembly in cells could lead to disease.
Sustainable management of agricultural water resources requires improved understanding of irrigation patterns in space and time. We produced annual, high‐resolution (30 m) irrigation maps for ...1999–2016 by combining all available Landsat satellite imagery with climate and soil covariables in Google Earth Engine. Random forest classification had accuracies from 92 to 100% and generally agreed with county statistics (r2 = 0.88–0.96). Two novel indices that integrate plant greenness and moisture information show promise for improving satellite classification of irrigation. We found considerable interannual variability in irrigation location and extent, including a near doubling between 2002 and 2016. Statistical modeling suggested that precipitation and commodity price influenced irrigated extent through time. High prices incentivized expansion to increase crop yield and profit, but dry years required greater irrigation intensity, thus reducing area in this supply‐limited region. Data sets produced with this approach can improve water sustainability by providing consistent, spatially explicit tracking of irrigation dynamics over time.
Plain Language Summary
Irrigated agriculture is the world's largest consumer of global freshwater. In order to effectively use limited water supplies, managers need to understand when and where irrigation occurs. We fill this knowledge gap by using satellite images to produce annual maps of irrigation for 1999–2016 in a large, economically important agricultural region in the central United States that must manage its water supply for multiple users. We then used these maps to study changes in irrigation over time. We were surprised to find that the total area and individual locations of irrigated fields changed substantially from year to year. Our analysis suggests that farmers expanded irrigation when crop prices were high to increase crop yield and profit. We initially expected to also see increases in drought years to compensate for lack of rainfall, but instead, we found the opposite: irrigated area decreased in dry years. Looking closer, we realized that this happened because farmers had to irrigate more heavily over each field, which reduced the number of fields they could irrigate due to limited water supply. These irrigation maps consistently track irrigation over time and are freely available for others to use to help manage water sustainably and meet food needs.
Key Points
Sustainable management of agricultural water resources requires improved understanding of dynamic irrigation patterns
We produced high‐resolution irrigation maps for 18 years using the full annual Landsat record and advances in cloud computing
Irrigated area had considerable spatiotemporal variability driven by changes in commodity prices, precipitation, and water accessibility
Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations ...in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.
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