Gijs den Besten
Sep 1, 2013; 54:2325-2340
Reviews

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

EJ Blanchette-Mackie
Jun 1, 1995; 36:1211-1226
Articles

Robert W. Mahley
Jan 1, 1999; 40:1-16
Reviews

Invitation Only Research Event

Event participants

Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham House
Professor Peter Trubowitz, Professor of International Relations, London School of Economics and Political Science; Associate Fellow, US and the Americas Programme, Chatham House
Amy Pope, Associate Fellow, US and the Americas Programme, Chatham House; Deputy Homeland Security Advisor, US National Security Council, 2015-17
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House

28 April 2020

Invitation Only Research Event

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity.

8 January 2020 , Volume 96, Number 1

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.

Expert

Expert

Expert

Expert

Expert

Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

Site-specific arrest of RNA polymerases (RNAPs) is fundamental to several technologies that assess RNA structure and function. Current in vitro transcription “roadblocking” approaches inhibit transcription elongation by blocking RNAP with a protein bound to the DNA template. One limitation of protein-mediated transcription roadblocking is that it requires inclusion of a protein factor extrinsic to the minimal in vitro transcription reaction. In this work, we developed a chemical approach for halting transcription by Escherichia coli RNAP. We first established a sequence-independent method for site-specific incorporation of chemical lesions into dsDNA templates by sequential PCR and translesion synthesis. We then show that interrupting the transcribed DNA strand with an internal desthiobiotin-triethylene glycol modification or 1,N6-etheno-2'-deoxyadenosine base efficiently and stably halts Escherichia coli RNAP transcription. By encoding an intrinsic stall site within the template DNA, our chemical transcription roadblocking approach enables display of nascent RNA molecules from RNAP in a minimal in vitro transcription reaction.

Trans. Moscow Math. Soc. 80 (2020), 113-122.
Abstract, references and article information

The music of most hit songs is pretty well known, but sometimes there are mysteries. One question that remained unanswered for over forty years is: What instrumentation and notes make up the opening chord of the Beatles. "A Hard Day.s Night"? Mathematician Jason Brown - a big Beatles fan - recently solved the puzzle using his musical knowledge and discrete Fourier transforms, mathematical transformations that help decompose signals into their basic parts. These transformations simplify applications ranging from signal processing to multiplying large numbers, so that a researcher doesn.t have to be "working like a dog" to get an answer. Brown is also using mathematics, specifically graph theory, to discover who wrote "In My Life," which both Lennon and McCartney claimed to have written. In his graphs, chords are represented by points that are connected when one chord immediately follows another. When all songs with known authorship are diagrammed, Brown will see which collection of graphs - McCartney.s or Lennon.s - is a better fit for "In My Life." Although it may seem a bit counterintuitive to use mathematics to learn more about a revolutionary band, these analytical methods identify and uncover compositional principles inherent in some of the best Beatles. music. Thus it.s completely natural and rewarding to apply mathematics to the Fab 4 For More Information: Professor Uses Mathematics to Decode Beatles Tunes, "The Wall Street Journal", January 30, 2009..

With 468 stops served by 26 lines, the New York subway system can make visitors feel lucky when they successfully negotiate one planned trip in a day. Yet these two New Yorkers, Chris Solarz and Matt Ferrisi, took on the task of breaking a world record by visiting every stop in the system in less than 24 hours. They used mathematics, especially graph theory, to narrow down the possible routes to a manageable number and subdivided the problem to find the best routes in smaller groups of stations. Then they paired their mathematical work with practice runs and crucial observations (the next-to-last car stops closest to the stairs) to shatter the world record by more than two hours!

Although Chris and Matt.s success may not have huge ramifications in other fields, their work does have a lot in common with how people do modern mathematics research

* They worked together, frequently using computers and often asking experts for advice;
* They devoted considerable time and effort to meet their goal; and
* They continually refined their algorithm until arriving at a solution that was nearly optimal.
Finally, they also experienced the same feeling that researchers do that despite all the hours and intense preparation, the project .felt more like fun than work.
For More Information: Math whizzes shoot to set record for traversing subway system,. Sergey Kadinsky and Rich Schapiro, New York Daily News, January 22, 2009.
Photo by Elizabeth Ferrisi.
Map New York Metropolitan Transit Authority.
The Mathematical Moments program promotes appreciation and understanding of the role mathematics plays in science, nature, technology, and human culture.

Van Wedeen talks about the geometry of the brain's communication pathways.

Researcher: Andrew Beveridge, Macalester College
Moment Title: Dis-playing the Game of Thrones
Description: Andrew Beveridge uses math to analyze Game of Thrones.

Hydel, despite trailing their rivals for two straight days, easily retained their title

Rampant deforestation, uncontrolled expansion of agriculture, infrastructure development and exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people.

Sovereign nations typically measure economic success in terms of GDP (income) but this approach is risky as it fails to track and measure the impact of this on nature. Inclusive wealth, on the other hand captures financial and produced capital, but also the skills in our workforce (human capital), the cohesion in our society (social capital) and the value of our environment (natural capital).

Research from Chazen Senior Scholar Christian Moser suggests that who gets hired and how much they get paid could make the difference between a startup’s success and its failure.

Outcomes of the Meeting of the Friends of the Co-Chairs on liability and redress, Bonn, 7-10 May 2008

The office space company has filed for an initial public offering, here are five things you need to know about one of the year's hottest IPOs