Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

RK Tangirala
Nov 1, 1995; 36:2320-2328
Articles

Chatham House appoints Tim Benton as Research Director for Energy, Environment and Resources News Release sysadmin 30 May 2019

Chatham House is pleased to announce that Professor Tim Benton has been appointed as research director of the Energy, Environment and Resources Department.

Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? 9 September 2021 — 2:00PM TO 3:30PM Anonymous (not verified) 21 July 2021 Online

Exploring current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

Counter-terrorism measures  address broad forms of support to terrorist acts. Their expansion, internationally and domestically, has given rise to new points of friction with international humanitarian law. Unless the measures include adequate safeguards, they  can impede humanitarian action. Country-specific sanctions imposed for other objectives, such as ending conflicts or protecting civilians, raise similar challenges for humanitarian action. 

These problems are not new, but solutions at international and national level remain elusive. 

At this panel event, which marks the launch of a new Chatham House research paper, panellists explore current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

• What are the current dynamics and developments at Security Council level?  
• What are the opportunities now that the UK is developing its independent sanctions strategy? 
• What challenges do counter-terrorism requirements in funding agreements for humanitarian action  pose? 
• What is necessary to make progress?

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

Expert

A. V. Silantyev
Trans. Moscow Math. Soc. 83 (), 75-149.
Abstract, references and article information

Z. A. Kasumov and N. R. Akhmedzade
Trans. Moscow Math. Soc. 83 (), 67-74.
Abstract, references and article information

N. R. Ikonomov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 33-54.
Abstract, references and article information

Flexible Distribution Systems: New Services, Actors and Technologies 4 September 2018 — 9:00AM TO 10:30AM Anonymous (not verified) 31 July 2018 Chatham House, London

The pace of the energy transition is accelerating. Solar and wind are dramatically falling in cost and displacing fossil fuel generators. Simultaneously, the rapid uptake of electric vehicles and battery storage systems are beginning to send shock-waves through the electricity sector.

As the proportion of distributed energy resources (DERs) connected to the distribution network grows, a significant opportunity is beginning to present itself. What if the concerns of renewable integration and associated costs could be solved by the smart integration of these DERs?

By properly valuing the services DERs can provide, actively managing the distribution system and creating new market places, might a truly renewable electricity system capable of supporting the electrification of heat and transport be possible?

During this roundtable, Andrew Scobie, CEO of Faraday Grid, will provide an overview of the challenges and opportunities faced within the distribution network and explain why the current system is no longer fit for purpose.

This is the inaugural event in the Energy Transitions Roundtable (ETR) series.

Youth voices on climate action 22 April 2021 — 12:30PM TO 2:00PM Anonymous (not verified) 22 March 2021 Online

To celebrate Earth Day, youth activists, local change-makers, innovators and entrepreneurs discuss opportunities and challenges for youth-led climate activism.

Young people will bear the brunt of the intensifying impacts of climate change over time. Facing this challenge, youth around the world have emerged at the forefront of climate activism at an unprecedented scale.

School strikes, marches, and declarations complement youth engagement in diplomacy, technology, science, and law. Providing a platform for young people involved in climate action at the local, national and global levels is essential to promote collaboration, generate new policy ideas, and demand accountability from political and business leaders.

Panellists engage in critical conversation about COP26; global leadership in climate mitigation, adaptation, and finance; and how to develop the full potential of youth-led global initiatives going forward.

Pierre Lairez, Eric Pichon-Pharabod and Pierre Vanhove
Math. Comp. 93 (), 2985-3025.
Abstract, references and article information

Martin Ehler and Karlheinz Gröchenig
Math. Comp. 93 (), 2885-2919.
Abstract, references and article information

Sangsan Warakkagun
Conform. Geom. Dyn. 28 (), 115-130.
Abstract, references and article information

Time: 10:00 AM, Location: E1.012 (Hearing Room)

Time: 9:00 AM, Location: E1.028 (Hearing Room)

Víctor González-Aguilera, Alvaro Liendo, Pedro Montero and Roberto Villaflor Loyola
Trans. Amer. Math. Soc. 377 (), 5483-5511.
Abstract, references and article information

Ta Cong Son, Tran Manh Cuong, Le Quang Dung and Le Van Dung
Theor. Probability and Math. Statist. 111 (), 153-165.
Abstract, references and article information

Claudio Macci and Barbara Pacchiarotti
Theor. Probability and Math. Statist. 111 (), 21-43.
Abstract, references and article information

Abdessamad Dehaj and Mohamed Guessous
Theor. Probability and Math. Statist. 111 (), 1-8.
Abstract, references and article information

Lasse L. Wolf and Hong-Wei Zhang
Proc. Amer. Math. Soc. 152 (), 5445-5453.
Abstract, references and article information

Luiz Ricardo Abreu Melo
Proc. Amer. Math. Soc. 152 (), 5373-5380.
Abstract, references and article information

Ferdinand Ihringer
Proc. Amer. Math. Soc. 152 (), 5355-5365.
Abstract, references and article information

Cheng Chu
Proc. Amer. Math. Soc. 152 (), 5289-5297.
Abstract, references and article information

Sudip Ranjan Bhuia
Proc. Amer. Math. Soc. 152 (), 5249-5263.
Abstract, references and article information

Neelarnab Raha
Proc. Amer. Math. Soc. 152 (), 5067-5081.
Abstract, references and article information

N. Lebedeva and A. Petrunin
St. Petersburg Math. J. 35 (), 473-476.
Abstract, references and article information

Reggae artiste Jah Kettle says he was pleased with his recently concluded Canada tour and is now excited to release a new single, titled Nothing Gonna Take Your Love Away, done with fellow reggae act Ras Penco. "The fans were riveting and showed...

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.

TNF is a highly pro-inflammatory cytokine that contributes not only to the regulation of immune responses but also to the development of severe inflammatory diseases. TNF is synthesized as a transmembrane protein, which is further matured via proteolytic cleavage by metalloproteases such as ADAM17, a process known as shedding. At present, TNF is mainly detected by measuring the precursor or the mature cytokine of bulk cell populations by techniques such as ELISA or immunoblotting. However, these methods do not provide information on the exact timing and extent of TNF cleavage at single-cell resolution and they do not allow the live visualization of shedding events. Here, we generated C-tag TNF as a genetically encoded reporter to study TNF shedding at the single-cell level. The functionality of the C-tag TNF reporter is based on the exposure of a cryptic epitope on the C terminus of the transmembrane portion of pro-TNF on cleavage. In both denatured and nondenatured samples, this epitope can be detected by a nanobody in a highly sensitive and specific manner only upon TNF shedding. As such, C-tag TNF can successfully be used for the detection of TNF cleavage in flow cytometry and live-cell imaging applications. We furthermore demonstrate its applicability in a forward genetic screen geared toward the identification of genetic regulators of TNF maturation. In summary, the C-tag TNF reporter can be employed to gain novel insights into the complex regulation of ADAM-dependent TNF shedding.

Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune responses. C. difficile genome analysis showed that 12 genes potentially encode N-deacetylases; however, which of these N-deacetylases are involved in peptidoglycan N-deacetylation remains unknown. Here, we report the enzymes responsible for peptidoglycan N-deacetylation and their respective regulation. Through peptidoglycan analysis of several mutants, we found that the N-deacetylases PdaV and PgdA act in synergy. Together they are responsible for the high level of peptidoglycan N-deacetylation in C. difficile and the consequent resistance to lysozyme. We also characterized a third enzyme, PgdB, as a glucosamine N-deacetylase. However, its impact on N-deacetylation and lysozyme resistance is limited, and its physiological role remains to be dissected. Finally, given the influence of peptidoglycan N-deacetylation on host defense against pathogens, we investigated the virulence and colonization ability of the mutants. Unlike what has been shown in other pathogenic bacteria, a lack of N-deacetylation in C. difficile is not linked to a decrease in virulence.

VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.

Managing natural resources

Research analyzing options for the sustainable management of natural resources and how to use them in a way that enhances the resilience of ecosystems.

Areas of focus include examining what is the future for fossil fuels and other extractive industries (especially coal, oil and natural gas), forest governance in light of continued illegal logging and deforestation, and ocean governance.

Natural resources are vital for the future sustainability of major industries such as agriculture, mining, tourism, fisheries and forestry. Research is carried out in areas such as land use planning, water management, biodiversity conservation, and the scientific and technical understanding of resources governance.

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α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.

2 September 2020

10 September 2020