Unlike other variants of transition-metal-catalyzed cross-coupling reactions, those based on organosilicon donors have not been used extensively in natural product synthesis. However, recent advances ...such as: 1) the development of mild reaction conditions, 2) the expansion of substrate scope, 3) the development of methods to stereoselectively and efficiently introduce the silicon-containing moiety, 4) the development of a large number of sequential processes, and 5) the advent of bifunctional bis(silyl) linchpin reagents, signify the coming of age of silicon-based cross-coupling reactions. The following case studies illustrate how silicon-based cross-coupling reactions play a strategic role in constructing carbon-carbon bonds in selected target molecules.
Higher education is becoming destabilized in the face of extraordinarily rapid change. The composition of the academy's most valuable asset--the faculty--and the essential nature of faculty work are ...being transformed. Jack H. Schuster and Martin J. Finkelstein describe the transformation of the American faculty in the most extensive and ambitious analysis of the American academic profession undertaken in a generation. A century ago the American research university emerged as a new organizational form animated by the professionalized, discipline-based scholar. The research university model persisted through two world wars and greatly varying economic conditions. In recent years, however, a new order has surfaced, organized around a globalized, knowledge-based economy, powerful privatization and market forces, and stunning new information technologies. These developments have transformed the higher education enterprise in ways barely imaginable in generations past. At the heart of that transformation, but largely invisible, has been a restructuring of academic appointments, academic work, and academic careers--a reconfiguring widely decried but heretofore inadequately described. This volume depicts the scope and depth of the transformation, combing empirical data drawn from three decades of national higher education surveys. The authors' portrait, at once startling and disturbing, provides the context for interpreting these developments as part of a larger structural evolution of the national higher education system. They outline the stakes for the nation and the challenging work to be done. Appended are: (1) The National Faculty Surveys; (2) Selected National Faculty Surveys: A Concordance of Contents; (3) Interpreting Faculty Surveys: Challenges and Strategies; (4) Variables for Classifying Faculty Subgroups; (5) Definitions of Terms Used in Tables and Figures; (6) Academic Appointments: Historical Milestones; (7) Faculty Compensation: Data Sources; (8) Note on Accessing the Survey Instruments; (9) Faculty Diversity: Race and Ethnic Categories; and (10) Appendix Tables. A bibliography and an index are included. (Contains 37 line drawings.)
Mixed ionic‐electronic conducting (MIEC) membranes have gained growing interest recently for various promising environmental and energy applications, such as H2 and O2 production, CO2 reduction, O2 ...and H2 separation, CO2 separation, membrane reactors for production of chemicals, cathode development for solid oxide fuel cells, solar‐driven evaporation and energy‐saving regeneration as well as electrolyzer cells for power‐to‐X technologies. The purpose of this roadmap, written by international specialists in their fields, is to present a snapshot of the state‐of‐the‐art, and provide opinions on the future challenges and opportunities in this complex multidisciplinary research field. As the fundamentals of using MIEC membranes for various applications become increasingly challenging tasks, particularly in view of the growing interdisciplinary nature of this field, a better understanding of the underlying physical and chemical processes is also crucial to enable the career advancement of the next generation of researchers. As an integrated and combined article, it is hoped that this roadmap, covering all these aspects, will be informative to support further progress in academics as well as in the industry‐oriented research toward commercialization of MIEC membranes for different applications.
The roadmap involving multidisciplinary research fields, presented by various global experts in their fields, is intended to give an overview on the status and breakthroughs of this evolving and growing interdisciplinary field and provide insights into the challenges driven by the research needs and opportunities in the diverse and rich field of using mixed ionic‐electronic conducting membranes.
Research to develop highly versatile, chiral, heterogeneous catalysts for asymmetric organic transformations, without quenching the catalytic reactivity, has met with limited success. While chiral ...supramolecular structures, connected by weak bonds, are highly active for homogeneous asymmetric catalysis, their application in heterogeneous catalysis is rare. In this work, asymmetric catalyst was prepared by encapsulating metallic nanoclusters in chiral self-assembled monolayer (SAM), immobilized on mesoporous SiO2 support. Using olefin cyclopropanation as an example, it was demonstrated that by controlling the SAM properties, asymmetric reactions can be catalyzed by Au clusters embedded in chiral SAM. Up to 50% enantioselectivity with high diastereoselectivity were obtained while employing Au nanoclusters coated with SAM peptides as heterogeneous catalyst for the formation of cyclopropane-containing products. Spectroscopic measurements correlated the improved enantioselectivity with the formation of a hydrogen-bonding network in the chiral SAM. These results demonstrate the synergetic effect of the catalytically active metallic sites and the surrounding chiral SAM for the formation of a mesoscale enantioselective catalyst.
FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half-life of active, circulating, human FGF-21 ...has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-specific inhibitor, ARI-3099, blocks the activity in mouse, monkey and human plasma and prolongs the half-life of circulating human FGF-21 in mice. Mouse FGF-21, however, lacks the FAP cleavage site and is not cleaved by FAP. These findings indicate FAP may function in the regulation of metabolism and that FAP inhibitors may prove useful in the treatment of diabetes and metabolic disorders in humans, but pre-clinical proof of concept studies in rodents will be problematic.
There are many fields where it is of interest to measure the elastic moduli of tiny fragile fibers, such as filamentous bacteria, actin filaments, DNA, carbon nanotubes, and functional microfibers. ...The elastic modulus is typically deduced from a sophisticated tensile test under a microscope, but the throughput is low and limited by the time-consuming and skill-intensive sample loading/unloading. Here, we demonstrate a simple microfluidic method enabling the high-throughput measurement of the elastic moduli of microfibers by rope coiling using a localized compression, where sample loading/unloading are not needed between consecutive measurements. The rope coiling phenomenon occurs spontaneously when a microfiber flows from a small channel into a wide channel. The elastic modulus is determined by measuring either the buckling length or the coiling radius. The throughput of this method, currently 3,300 fibers per hour, is a thousand times higher than that of a tensile tester. We demonstrate the feasibility of the method by testing a nonuniform fiber with axially varying elastic modulus. We also demonstrate its capability for in situ inline measurement in a microfluidic production line. We envisage that high-throughput measurements may facilitate potential applications such as screening or sorting by mechanical properties and real-time control during production of microfibers.
Pulsed electron spin resonance (ESR) dipolar spectroscopy (PDS) in combination with site-directed spin labeling is unique in providing nanometer-range distances and distributions in biological ...systems. To date, most of the pulsed ESR techniques require frozen solutions at cryogenic temperatures to reduce the rapid electron spin relaxation rate and to prevent averaging of electron–electron dipolar interaction due to the rapid molecular tumbling. To enable measurements in liquid solution, we are exploring a triarylmethyl (TAM)-based spin label with a relatively long relaxation time where the protein is immobilized by attachment to a solid support. In this preliminary study, TAM radicals were attached via disulfide linkages to substituted cysteine residues at positions 65 and 80 or 65 and 76 in T4 lysozyme immobilized on Sepharose. Interspin distances determined using double quantum coherence (DQC) in solution are close to those expected from models, and the narrow distance distribution in each case indicates that the TAM-based spin label is relatively localized.
Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of ...mechanistic understanding, Val-boroPro has attracted substantial interest as a potential anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.
Mutations in
, the gene that encodes lamin A and C, causes LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy. LMNA is expressed in endothelial cells (ECs); however, little is known about ...the EC-specific phenotype of LMNA-related DCM. Here, we studied a family affected by DCM due to a frameshift variant in
Human induced pluripotent stem cell (iPSC)-derived ECs were generated from patients with LMNA-related DCM and phenotypically characterized. Patients with LMNA-related DCM exhibited clinical endothelial dysfunction, and their iPSC-ECs showed decreased functionality as seen by impaired angiogenesis and nitric oxide (NO) production. Moreover, genome-edited isogenic iPSC lines recapitulated the EC disease phenotype in which LMNA-corrected iPSC-ECs showed restoration of EC function. Simultaneous profiling of chromatin accessibility and gene expression dynamics by combining assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) as well as loss-of-function studies identified Krüppel-like factor 2 (KLF2) as a potential transcription factor responsible for the EC dysfunction. Gain-of-function studies showed that treatment of LMNA iPSC-ECs with KLF2 agonists, including lovastatin, rescued the EC dysfunction. Patients with LMNA-related DCM treated with lovastatin showed improvements in clinical endothelial dysfunction as indicated by increased reactive hyperemia index. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from patients exhibiting the DCM phenotype showed improvement in CM function when cocultured with iPSC-ECs and lovastatin. These results suggest that impaired cross-talk between ECs and CMs can contribute to the pathogenesis of LMNA-related DCM, and statin may be an effective therapy for vascular dysfunction in patients with cardiolaminopathy.
Animals and plants are increasingly suffering from diseases caused by fungi and oomycetes. These emerging pathogens are now recognized as a global threat to biodiversity and food security. Among ...oomycetes, Saprolegnia species cause significant declines in fish and amphibian populations. Fish eggs have an immature adaptive immune system and depend on nonspecific innate defences to ward off pathogens. Here, meta-taxonomic analyses revealed that Atlantic salmon eggs are home to diverse fungal, oomycete and bacterial communities. Although virulent Saprolegnia isolates were found in all salmon egg samples, a low incidence of Saprolegniosis was strongly correlated with a high richness and abundance of specific commensal Actinobacteria, with the genus Frondihabitans (Microbacteriaceae) effectively inhibiting attachment of Saprolegniato salmon eggs. These results highlight that fundamental insights into microbial landscapes of fish eggs may provide new sustainable means to mitigate emerging diseases.
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