Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology]
3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.
Tracking isotopically labeled oxidants using boronate-based redox probes [Methods and Resources]
Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.
Christophe Bellmann
Biography
Christophe is a senior resident research associate at ICTSD with decades of experience working on international trade negotiations and policymaking from a sustainable development perspective.
He joined ICTSD in 1998 as programme officer for outreach and partnership, then became director of policy dialogues. Since 2002, he has been programmes director.
He previously worked for the Swiss Coalition of Development Organisations (SCDO) where he was responsible for activities on multilateral trade and sustainable development issues, and has also worked as a research associate at the Economic Commission for Latin America and the Caribbean (ECLAC) in Santiago, Chile on the relationship between trade and the environment.
Christophe has edited and published a wide range of books, articles and opinion pieces in English, French and Spanish on trade and sustainable development. His work focuses on international trade negotiations, development policies and environmental governance in areas such as agriculture and food security, fisheries, tariffs and non-tariff barriers, rules, regional trade, services and intellectual property rights.
He holds an MA in international relations from the Graduate Institute for International Studies in Geneva.
Closing the Global Access Gap in Palliative Care and Pain Relief: A Top Priority in Achieving Universal Health Coverage
Invitation Only Research Event
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Dr Tedros Adhanom Ghebreyesus, Director-General, World Health Organization
The Lancet Commission on Palliative Care and Pain Relief estimated that in 2015, 61 million people experienced serious health-related suffering (SHS) that could have been ameliorated by palliative care. A large proportion of this burden – more than 80 per cent – fell on low- and middle-income countries (LMICs) despite an essential package of palliative care and pain relief services being cost-effective and affordable. As the director general of the World Health Organization (WHO) argues, there cannot be UHC without palliative care and thus, closing this coverage gap should be a top priority for the global UHC movement.
The Centre on Global Health Security at Chatham House, building on the momentum of the Lancet Commission, is hosting a roundtable focused on the global unmet need for palliative care and effective pain relief. The primary purpose of this roundtable is to convene leading experts, palliative care service users and advocates with key figures from the UHC movement and global health to highlight the importance of prioritizing this vital part of the continuum of care in UHC reform processes. The roundtable will serve as a scholarly discourse in translating the recommendations of the Lancet Commission into concrete actions, focusing on the political and economic dimensions.
Department/project
Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation [Research Articles]
The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.
Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases [Thematic Reviews]
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.
A Balancing Act for Europe: Stop the Migrants, Support Greece, Assuage Turkey
Pulling Out (from) All the Stops - Visiting all of NY's subway stops in record time
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.
Going Over the Top - Designing roller coasters
Researcher: Meredith Greer, Bates College. Going Over the Top Description: Meredith Greer talks about math and roller coasters.
In Effort to Stop Faulty Goods, China Asks Importers to Ensure PPE Meets Standards
Deadlier outbreaks could follow coronavirus pandemic if people don't stop destroying nature, say experts
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.
CBD News: UN Biodiversity Convention Secretariat teams up with Europe's Bern Convention to stop the lost of biodiversity in Europe.
CBD Press Release: From words to action - key organizations team up to stop the extinction crisis.
CBD News: While 87% of consumers surveyed worldwide want companies to adopt sourcing policies that respect biodiversity, only 27% of the top 100 beauty and personal care companies actually mention biodiversity on their websites or in their corporate socia
CBD News: Reconnecting ourselves to nature is sometimes easier said than done. Many of us live in cities full of concrete and use devices such as smartphones and laptops that, while connecting us to other people, often serve to disconnect us from the simp
CBD News: No matter where we live, every other breath we take comes from the Ocean's breath - from the oxygen produced by its phytoplankton and its rich marine plant life.
Probabilistic Methods in Geometry, Topology and Spectral Theory
Dynamics: Topology and Numbers
Motivic Homotopy Theory and Refined Enumerative Geometry
Topology and Geometry of Biopolymers
Topological Phases of Matter and Quantum Computation
????-theory in Algebra, Analysis and Topology
On the group of self-homotopy equivalences of an elliptic space
Mahmoud Benkhalifa
Proc. Amer. Math. Soc. 148 (2020), 2695-2706.
Abstract, references and article information
A topology on the set of isomorphism classes of maximal Cohen–Macaulay modules
Naoya Hiramatsu and Ryo Takahashi
Proc. Amer. Math. Soc. 148 (2020), 2359-2369.
Abstract, references and article information
Decomposition-space slices are toposes
Joachim Kock and David I. Spivak
Proc. Amer. Math. Soc. 148 (2020), 2317-2329.
Abstract, references and article information
Christopher Hui visits registry
Secretary for Financial Services & the Treasury Christopher Hui today visited the Companies Registry (CR) to inspect its operation.
Mr Hui visited the New Companies Section, the Public Search Section and the Document Management Section at the registry and spoke with staff there to learn about their work conditions and the services that they provide.
He said: “The COVID-19 pandemic has dealt a heavy blow to Hong Kong's overall economy.
“To help enterprises cope with their operating pressure amid the economic downturn, the Financial Secretary announced in the 2020-21 Budget the waiver of registration fees for annual returns, except for late delivery, charged by the CR for two years.
“And with a view to encouraging the wider use of the CR's electronic services, we also propose to reduce the fees payable in relation to the incorporation of companies, including registration of non-Hong Kong companies, through electronic means by 10%."
The Companies (Fees) (Amendment) Regulation 2020 gazetted today will be tabled at the Legislative Council for negative vetting on May 13 for the waiver and reduction to take effect from October 1.
The waiver of registration fees for annual returns will benefit about 1.4 million companies.
Mr Hui added that he was pleased that the CR has been providing electronic services for filing of documents and company searches.
He appealed to the department to adopt wider use of technology, adding that a business-friendly environment is needed more than ever in the process of economic recovery.
Mr Hui also expressed gratitude to CR staff for their dedication in providing public services amid the pandemic.
Math in the Media - May 2020:John Conway, "magical mathematician", Topological analysis of zebrafish, teaching online...
Perturbation de la Dynamique de Diffeomorphismes en Topologie (C^{1})
Topology and Field Theories
Structures of the MHC-I molecule BF2*1501 disclose the preferred presentation of an H5N1 virus-derived epitope [Protein Structure and Folding]
Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens.
Catabolic degradation of endothelial VEGFA via autophagy [Glycobiology and Extracellular Matrices]
Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.
Could a polio vaccine stop the coronavirus pandemic? (video)
(American Chemical Society) The COVID-19 pandemic has scientists considering a few less-conventional options while vaccines against SARS-CoV-2 are being developed. One option might be the oral polio vaccine. We chatted with one of the researchers proposing the idea -- Robert Gallo, M.D. -- to understand why a vaccine that hasn't been used in the U.S. for two decades might provide short-term protection against this new coronavirus: https://youtu.be/Wqw4aX4c33c.
Poets&Quants’ Top MBA Startups of 2020
Police stop fewer black drivers at night when a 'veil of darkness' obscures their race
(Stanford School of Engineering) After analyzing 95 million traffic stop records, filed by officers with 21 state patrol agencies and 35 municipal police forces from 2011 to 2018, a Stanford-led research team concluded that 'police stops and search decisions suffer from persistent racial bias.'