Toward the Total Synthesis of Spirastrellolide A. Part 2: Conquest of the Northern Hemisphere

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

Toward the Total Synthesis of Spirastrellolide A. Part 1: Strategic Considerations and Preparation of the Southern Domain

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

Someone is pulling the strings: hypersensitive agency detection and belief in conspiracy theories

We hypothesized that belief in conspiracy theories would be predicted by the general tendency to attribute agency and intentionality where it is unlikely to exist. We further hypothesized that this tendency would explain the relationship between education level and belief in conspiracy theories, where lower levels of education have been found to be associated with higher conspiracy belief. In Study 1 (N=202) participants were more likely to agree with a range of conspiracy theories if they also tended to attribute intentionality and agency to inanimate objects. As predicted, this relationship accounted for the link between education level and belief in conspiracy theories. We replicated this finding in Study 2 (N=330), whilst taking into account beliefs in paranormal phenomena. These results suggest that education may undermine the reasoning processes and assumptions that are reflected in conspiracy belief

Total Synthesis of Spirastrellolide F Methyl Ester—Part 2: Macrocyclization and Completion of the Synthesis

Marvel of the sea: A concise and highly convergent total synthesis of the methyl ester of the marine macrolide spirastrellolide F (see picture), which has exquisite antimitotic properties, is reported. In this approach, the northern and the southern hemispheres of this intricate target are stitched together in only two consecutive steps (Suzuki coupling, Yamaguchi lactonization) without any interim protecting-group manipulations

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Prevalence and Risk Factors for Urinary Incontinence in Overweight and Obese Diabetic Women: Action for Health in Diabetes (Look AHEAD) study

OBJECTIVE To determine the prevalence and risk factors for urinary incontinence among different racial/ethnic groups of overweight and obese women with type 2 diabetes. RESEARCH DESIGN AND METHODS Cross-sectional analysis of baseline data from the Action for Health in Diabetes (Look AHEAD) study, a randomized clinical trial with 2,994 overweight/obese women with type 2 diabetes. RESULTS Weekly incontinence (27%) was reported more often than other diabetes-associated complications, including retinopathy (7.5%), microalbuminuria (2.2%), and neuropathy (1.5%). The prevalence of weekly incontinence was highest among non-Hispanic whites (32%) and lowest among African Americans (18%), and Asians (12%) (P \u3c 0.001). Asian and African American women had lower odds of weekly incontinence compared with non-Hispanic whites (75 and 55% lower, respectively; P \u3c 0.001). Women with a BMI of ≥35 kg/m2 had a higher odds of overall and stress incontinence (55–85% higher; P \u3c 0.03) compared with that for nonobese women. Risk factors for overall incontinence, as well as for stress and urgency incontinence, included prior hysterectomy (40–80% increased risk; P \u3c 0.01) and urinary tract infection in the prior year (55–90% increased risk; P \u3c 0.001). CONCLUSIONS Among overweight and obese women with type 2 diabetes, urinary incontinence is highly prevalent and far exceeds the prevalence of other diabetes complications. Racial/ethnic differences in incontinence prevalence are similar to those in women without diabetes, affecting non-Hispanic whites more than Asians and African Americans. Increasing obesity (BMI ≥35 kg/m2) was the strongest modifiable risk factor for overall incontinence and stress incontinence in this diverse cohort

Error determination in the photogrammetric assessment of shoreline changes

The evaluation of error or uncertainty in shoreline change studies is an issue of prime importance for providing an adequate framework for calculated rates of change and to allow the establishment of threshold values above which the rates would be significant. In this note, a practical, easy-to-use method is presented to estimate error involved in the calculation of shoreline changes on aerial photographs, including the three most used types of shoreline indicators: high water line, dune/cliff toe and cliff top. This approach takes into account the specific characteristics of each shoreline proxy, such as relief in the case of the cliff top or tidal oscillations in the case of the high water line. At the same time it includes the error components that are independent from the proxy, basically related to the technical aspects of the process such as photo scanning and georeferencing. A practical example of application of the method is provided for several types of data inputs, based on shoreline changes around the Bay of Cádiz (SW Spain)

Conspiracy theory as spatial practice: the case of the Sivas arson attack, Turkey

This article discusses the relationship between conspiratorial thinking and physical space by focusing on the ways conspiracy theories regarding political violence shape and are shaped by the environments in which it is commemorated. Conspiratorial thinking features space as a significant element, but is taken to do so mainly figuratively. In blaming external powers and foreign actors for social ills, conspiracy theorists employ the spatial metaphor of inside versus outside. In perceiving discourses of transparency as the concealment rather than revelation of mechanisms of governance, conspiracy theorists engage the trope of a façade separating the space of power’s formulations from that of its operations. Studying the case of an arson attack dating from 1990s Turkey and its recent commemorations, this article argues that space mediates conspiracy theory not just figuratively but also physically and as such serves to catalyze two of its deadliest characteristics: anonymity and non-linear causality. Attending to this mediation requires a shift of focus from what conspiracy theory is to what it does as a spatial practice

Information is Power? Transparency and fetishism in International Relations

International actors, state and non-state, have embraced transparency as a solution to all manner of political problems. Theoretical analyses of these processes present transparency in a fetishtic manner, in which the social relations that generate transparency are misrecognized as the product of information itself. This paper will outline the theoretical problems that arise when transparency promotion is fetishized in International Relations theory. Examining the fetishism of transparency, we will note problematic conception of politics, the public sphere, and rationality they articulate. Confusing the relationship between data, information and knowledge, fetishized treatments of transparency muddy the historical dynamics responsible for the emergence of transparency as a political practice. This alters our understanding of the relationship between global governance institutions, their constituents, and the nature of knowledge production itself. Realizing the normative promise of transparency requires a reorientation of theoretical practice towards sociologically and historically sensitive approaches to the politics of knowledge