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"Chan, G."
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Across Asia and the Islamic world : movement and mobility in the arts of East Asian, South and Southeast Asian, and Islamic cultures
\"The Walters Art Museum is among America's most distinctive museums, forging connections between people and art from cultures around the world that span seven millennia. The museum holds a stunning array of objects, from richly illuminated Qur'ans and images of the Buddha to captivating narrative paintings and artfully crafted ceramics and metalworks. Highlighting the strengths, variety, and sheer wonder of the Walters Art Museum's unique Asian and Islamic collections, Across Asia and the Islamic World is the first volume in a series of titles that break away from the traditional academic approach. It is built around themes that transcend period, form, locale, and medium, and showcases the museum's initiative to develop new ways of interpreting its collections\"-- Provided by publisher.
BOOK
Mechanical Control of Spin States in Spin-1 Molecules and the Underscreened Kondo Effect
The ability to make electrical contact to single molecules creates opportunities to examine fundamental processes governing electron flow on the smallest possible length scales. We report experiments in which we controllably stretched individual cobalt complexes having spin S = 1, while simultaneously measuring current flow through the molecule. The molecule's spin states and magnetic anisotropy were manipulated in the absence of a magnetic field by modification of the molecular symmetry. This control enabled quantitative studies of the underscreened Kondo effect, in which conduction electrons only partially compensate the molecular spin. Our findings demonstrate a mechanism of spin control in single-molecule devices and establish that they can serve as model systems for making precision tests of correlated-electron theories.
Journal Article
Maritime cooperation and security in the Indo-Pacific region : essays in honour of Sam Bateman
\"More than twenty Indo-Pacific scholars and emerging experts come together in this definitive volume to deliver fresh perspectives and original research on maritime cooperation and security. With subjects ranging from the Philippines to Antarctica, Coast Guards to climate change, these essays pay tribute to the late Commodore Sam Bateman (PhD) while laying the academic groundwork for the improved policies and behaviours that provide for improved good order at sea\"-- Provided by publisher.
BOOK
Viscous control of cellular respiration by membrane lipid composition
In bacteria, energy production by the electron transport chain occurs at cell membranes and can be influenced by the lipid composition of the membrane. Budin et al. used genetic engineering to influence the concentration of unsaturated branched-chain fatty acids and thus control membrane viscosity (see the Perspective by Schon). Experimental measurements and mathematical modeling indicated that rates of respiratory metabolism and rates of cell growth were dependent on membrane viscosity and its effects on diffusion. Experiments on yeast mitochondria also showed similar effects. Maintaining efficient respiration may thus place evolutionary constraints on cellular lipid composition. Science , this issue p. 1186 ; see also p. 1114 Metabolic engineering of membrane viscosity can regulate respiration rates in Escherichia coli and in yeast mitochondria. Lipid composition determines the physical properties of biological membranes and can vary substantially between and within organisms. We describe a specific role for the viscosity of energy-transducing membranes in cellular respiration. Engineering of fatty acid biosynthesis in Escherichia coli allowed us to titrate inner membrane viscosity across a 10-fold range by controlling the abundance of unsaturated or branched lipids. These fluidizing lipids tightly controlled respiratory metabolism, an effect that can be explained with a quantitative model of the electron transport chain (ETC) that features diffusion-coupled reactions between enzymes and electron carriers (quinones). Lipid unsaturation also modulated mitochondrial respiration in engineered budding yeast strains. Thus, diffusion in the ETC may serve as an evolutionary constraint for lipid composition in respiratory membranes.
Journal Article
A microbial supply chain for production of the anti-cancer drug vinblastine
Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine
1
. As MIAs are difficult to chemically synthesize, the world’s supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant
Catharanthus roseus
, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale
2
,
3
. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.
De novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast and in vitro chemical coupling to vinblastine is carried out, positioning yeast as a scalable platform to produce many monoterpene indole alkaloids.
Journal Article
Novel insights from a multiomics dissection of the Hayflick limit
The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single-cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by t YAP1/TEAD1 and TGF-β2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.
Journal Article
Industrial brewing yeast engineered for the production of primary flavor determinants in hopped beer
Flowers of the hop plant provide both bitterness and “hoppy” flavor to beer. Hops are, however, both a water and energy intensive crop and vary considerably in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Here, we report that brewer’s yeast can be engineered to biosynthesize aromatic monoterpene molecules that impart hoppy flavor to beer by incorporating recombinant DNA derived from yeast, mint, and basil. Whereas metabolic engineering of biosynthetic pathways is commonly enlisted to maximize product titers, tuning expression of pathway enzymes to affect target production levels of multiple commercially important metabolites without major collateral metabolic changes represents a unique challenge. By applying state-of-the-art engineering techniques and a framework to guide iterative improvement, strains are generated with target performance characteristics. Beers produced using these strains are perceived as hoppier than traditionally hopped beers by a sensory panel in a double-blind tasting.
Production of aromatic monoterpene molecules in hop flowers is affected by genetic, environmental, and processing factors. Here, the authors engineer brewer’s yeast for the production of linalool and geraniol, and show pilot-scale beer produced by engineered strains reconstitutes some qualities of hop flavor.
Journal Article
Different cohort, disparate results: Selection bias is a key factor in autopsy cohorts
INTRODUCTION Research‐oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter‐cohort differences. METHODS The National Alzheimer's Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit. RESULTS Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups. DISCUSSION The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non‐AD pathologies. Highlights Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research‐oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts.
Journal Article
Biosynthesis and secretion of the microbial sulfated peptide RaxX and binding to the rice XA21 immune receptor
The rice immune receptor XA21 is activated by the sulfated microbial peptide required for activation of XA21-mediated immunity X (RaxX) produced by Xanthomonas oryzae pv. oryzae (Xoo). Mutational studies and targeted proteomics revealed that the RaxX precursor peptide (proRaxX) is processed and secreted by the protease/transporter RaxB, the function of which can be partially fulfilled by a noncognate peptidase-containing transporter component B (PctB). proRaxX is cleaved at a Gly–Gly motif, yielding a mature peptide that retains the necessary elements for RaxX function as an immunogen and host peptide hormone mimic. These results indicate that RaxX is a prokaryotic member of a previously unclassified and understudied group of eukaryotic tyrosine sulfated ribosomally synthesized, posttranslationally modified peptides (RiPPs). We further demonstrate that sulfated RaxX directly binds XA21 with high affinity. This work reveals a complete, previously uncharacterized biological process: bacterial RiPP biosynthesis, secretion, binding to a eukaryotic receptor, and triggering of a robust host immune response.
Journal Article
Heterohexamers Formed by CcmK3 and CcmK4 Increase the Complexity of Beta Carboxysome Shells
Bacterial microcompartments (BMCs) encapsulate enzymes within a selectively permeable, proteinaceous shell. Carboxysomes are BMCs containing ribulose-1,5-bisphosphate carboxylase oxygenase and carbonic anhydrase that enhance carbon dioxide fixation. The carboxysome shell consists of three structurally characterized protein types, each named after the oligomer they form: BMC-H (hexamer), BMC-P (pentamer), and BMC-T (trimer). These three protein types form cyclic homooligomers with pores at the center of symmetry that enable metabolite transport across the shell. Carboxysome shells contain multiple BMC-H paralogs, each with distinctly conserved residues surrounding the pore, which are assumed to be associated with specific metabolites. We studied the regulation of β-carboxysome shell composition by investigating the BMC-H genes ccmK3 and ccmK4 situated in a locus remote from other carboxysome genes. We made single and double deletion mutants of ccmK3 and ccmK4 in Synechococcus elongatus PCC7942 and show that, unlike CcmK3, CcmK4 is necessary for optimal growth. In contrast to other CcmK proteins, CcmK3 does not form homohexamers; instead CcmK3 forms heterohexamers with CcmK4 with a 1:2 stoichiometry. The CcmK3-CcmK4 heterohexamers form stacked dodecamers in a pH-dependent manner. Our results indicate that CcmK3-CcmK4 heterohexamers potentially expand the range of permeability properties of metabolite channels in carboxysome shells. Moreover, the observed facultative formation of dodecamers in solution suggests that carboxysome shell permeability may be dynamically attenuated by \"capping\" facet-embedded hexamers with a second hexamer. Because β-carboxysomes are obligately expressed, heterohexamer formation and capping could provide a rapid and reversible means to alter metabolite flux across the shell in response to environmental/growth conditions.
Journal Article