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Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway. Copyright © 2020 the Author(s). Published by PNAS.Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation of EHD2 in mice leads to increased lipid droplet size in fat tissue. This organismic phenotype was paralleled at the cellular level by increased fatty acid uptake via a caveolae- and CD36-dependent pathway that also involves dynamin. Concomitantly, elevated numbers of detached caveolae were found in brown and white adipose tissue lacking EHD2, and increased caveolar mobility in mouse embryonic fibroblasts. EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway and imply that low EHD2 expression levels are linked to obesity. Copyright © 2020 the Author(s). Published by PNAS.Consciousness is currently a thriving area of research in psychology and neuroscience. While this is often attributed to events that took place in the early 1990s, consciousness studies today are a continuation of research that started in the late 19th century and that continued throughout the 20th century. From the beginning, the effort built on studies of animals to reveal basic principles of brain organization and function, and of human patients to gain clues about consciousness itself. Particularly important and our focus here is research in the 1950s, 1960s, and 1970s involving three groups of patients-amnesia, split brain, and blindsight. Across all three groups, a similar pattern of results was found-the patients could respond appropriately to stimuli that they denied seeing (or in the case of amnesiacs, having seen before). These studies paved the way for the current wave of research on consciousness. The field is, in fact, still grappling with the implications of the findings showing that the ability to consciously know and report the identity of a visual stimulus can be dissociated in the brain from the mechanisms that underlie the ability to behave in a meaningful way to the same stimulus. Copyright © 2020 the Author(s). Published by PNAS.Lens transparency is established by abundant accumulation of crystallin proteins and loss of organelles in the fiber cells. It requires an efficient translation of lens messenger RNAs (mRNAs) to overcome the progressively reduced transcriptional activity that results from denucleation. Inappropriate regulation of this process impairs lens differentiation and causes cataract formation. However, the regulatory mechanism promoting protein synthesis from lens-expressed mRNAs remains unclear. Here we show that in zebrafish, the RNA-binding protein Rbm24 is critically required for the accumulation of crystallin proteins and terminal differentiation of lens fiber cells. In the developing lens, Rbm24 binds to a wide spectrum of lens-specific mRNAs through the RNA recognition motif and interacts with cytoplasmic polyadenylation element-binding protein (Cpeb1b) and cytoplasmic poly(A)-binding protein (Pabpc1l) through the C-terminal region. Loss of Rbm24 reduces the stability of a subset of lens mRNAs encoding heat shock proteins and shortens the poly(A) tail length of crystallin mRNAs encoding lens structural components, thereby preventing their translation into functional proteins. This severely impairs lens transparency and results in blindness. Consistent with its highly conserved expression in differentiating lens fiber cells, the findings suggest that vertebrate Rbm24 represents a key regulator of cytoplasmic polyadenylation and plays an essential role in the posttranscriptional control of lens development. Copyright © 2020 the Author(s). Published by PNAS.Crises in science concern not only methods, statistics, and results but also, theory development. Beyond the indispensable refinement of tools and procedures, resolving crises would also benefit from a deeper understanding of the concepts and processes guiding research. Usually, theories compete, and some lose, incentivizing destruction of seemingly opposing views. This does not necessarily contribute to accumulating insights, and it may incur collateral damage (e.g., impairing cognitive processes and collegial relations). To develop a more constructive model, we built on adversarial collaboration, which integrates incompatible results into agreed-on new empirical research to test competing hypotheses [D. Kahneman, Am. Psychol. 58, 723-730 (2003)]. Applying theory and evidence from the behavioral sciences, we address the group dynamic complexities of adversarial interactions between scientists. We illustrate the added value of considering these in an "adversarial alignment" that addressed competing conceptual frameworks from five different theories of social evaluation. buy TAK-242 Negotiating a joint framework required two preconditions and several guidelines. First, we reframed our interactions from competitive rivalry to cooperative pursuit of a joint goal, and second, we assumed scientific competence and good intentions, enabling cooperation toward that goal. Then, we applied five rules for successful multiparty negotiations 1) leveling the playing field, 2) capitalizing on curiosity, 3) producing measurable progress, 4) working toward mutual gain, and 5) being aware of the downside alternative. Together, these guidelines can encourage others to create conditions that allow for theoretical alignments and develop cumulative science.Among CO2-fixing metabolic pathways in nature, the linear Wood-Ljungdahl pathway (WLP) in phylogenetically diverse acetate-forming acetogens comprises the most energetically efficient pathway, requires the least number of reactions, and converts CO2 to formate and then into acetyl-CoA. Despite two genes encoding glycine synthase being well-conserved in WLP gene clusters, the functional role of glycine synthase under autotrophic growth conditions has remained uncertain. Here, using the reconstructed genome-scale metabolic model iSL771 based on the completed genome sequence, transcriptomics, 13C isotope-based metabolite-tracing experiments, biochemical assays, and heterologous expression of the pathway in another acetogen, we discovered that the WLP and the glycine synthase pathway are functionally interconnected to fix CO2, subsequently converting CO2 into acetyl-CoA, acetyl-phosphate, and serine. Moreover, the functional cooperation of the pathways enhances CO2 consumption and cellular growth rates via bypassing reducing power required reactions for cellular metabolism during autotrophic growth of acetogens.
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