all Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics By feedproxy.google.com Published On :: 2012-11-01 Amelia C. PetersonNov 1, 2012; 11:1475-1488Technological Innovation and Resources Full Article
all In Vivo Identification of Human Small Ubiquitin-like Modifier Polymerization Sites by High Accuracy Mass Spectrometry and an in Vitro to in Vivo Strategy By feedproxy.google.com Published On :: 2008-01-01 Ivan MaticJan 1, 2008; 7:132-144Research Full Article
all PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life By feedproxy.google.com Published On :: 2012-08-01 M. WangAug 1, 2012; 11:492-500Technological Innovation and Resources Full Article
all Absolute Quantification of Proteins by LCMSE: A Virtue of Parallel ms Acquisition By feedproxy.google.com Published On :: 2006-01-01 Jeffrey C. SilvaJan 1, 2006; 5:144-156Research Full Article
all Exponentially Modified Protein Abundance Index (emPAI) for Estimation of Absolute Protein Amount in Proteomics by the Number of Sequenced Peptides per Protein By feedproxy.google.com Published On :: 2005-09-01 Yasushi IshihamaSep 1, 2005; 4:1265-1272Research Full Article
all DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension. Full Article
all Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development. Full Article
all Alice Billon-Galland By feedproxy.google.com Published On :: Fri, 01 Nov 2019 15:13:31 +0000 Research Associate, Europe Programme Biography Alice Billon-Galland is a research associate in the Europe programme, covering security and defence issues. Prior to joining Chatham House in October 2019, she led the European defence programme at the European Leadership Network (ELN) in London.Her research focuses on European security and defence issues, transatlantic burden-sharing, and the implementation of the new EU defence package. She also follows developments at NATO and in French foreign and defence policy, and regularly comments on defence issues for international media from Deutsche Welle to the Wall Street Journal.Alice is part of the Leadership Team of Women in International Security UK (WIIS UK) and a member of the Younger Generation Leaders Network on Euro-Atlantic Security (YGLN). She is also a 2018 GLOBSEC Young Leader.A graduate of France’s Ecole Normale Supérieure and holder of an agrégation of English language, Alice completed a Master’s degree in Public Policy at University College London and was a visiting scholar at Northwestern University in Chicago. Areas of expertise European security and defenceEU Common Security and Defence Policy (CSDP)NATO and EU-NATO relationsFrench foreign and defence policy Past experience 2017-19Policy fellow, European Leadership Network2017Researcher, European Leadership Network +44 (0)20-7314-3611 Email @alicebillon LinkedIn Full Article
all In Next Round of EU Negotiations, Britain Faces Familiar Pitfalls By feedproxy.google.com Published On :: Fri, 31 Jan 2020 14:33:27 +0000 31 January 2020 Thomas Raines Director, Europe Programme @TomHRaines Google Scholar Professor Richard G Whitman Associate Fellow, Europe Programme @RGWhitman Google Scholar Despite being free of the constraints and the theatre of a hung parliament, there is a risk that over the coming year the British government repeats too many of the mistakes of the withdrawal negotiations. 2020-01-31-Ldn.jpg The Elizabeth Tower remains under renovation on 31 January 2020. Photo: Getty Images. Whether feared or longed for, Brexit day has arrived. It is positive for all sides that the process is thus far managed and ordered, with debts paid, rights guaranteed and borders still invisible on the island of Ireland. But in a difficult new phase of negotiations, as the UK and EU try to hammer out the terms of their relationship after 2020, Britain is at risk of repeating many of its mistakes from the withdrawal talks.First, the government, through the negotiation timeline, has reduced its own room for manoeuvre. The failure of the initial withdrawal agreement and subsequent turbulent politics have reduced a planned 21-month transition to an 11-month one. Even though half the original negotiation time has been lost, 31 December 2020 remains in place and indeed has been written into UK law as the date the transition arrangement ends. Boris Johnson has followed Theresa May in investing symbolism and significance in an arbitrary date.By promising not to extend negotiations, the UK is boxing itself in, creating domestic political barriers where it may well need flexibility. The familiar face of Michel Barnier, who proved adept in leading the withdrawal negotiations for the EU side, will be back in phase two to tell Britain the clock is ticking. This new timeline is intended to focus minds but more likely it will limit ambitions. Second, this government has continued the pattern of its predecessor in making no effort to manage public expectations about the consequences of Brexit. It is naïve to have followed the last years of British politics and expect an outbreak of sobriety and levelheadedness. The entrenched positions of each side have offered little political space or electoral incentive for realism.During the 2020 transition period, the UK will lose the political rights of EU membership but it will retain the benefits and obligations. Most citizens and business will not be able to tell the difference. But a reckoning is inevitable. There will come a moment when the effects of this slow-motion political revolution – particularly in the hard form envisioned by Boris Johnson – become real, when the trade-offs and compromises, especially for business and the economy, will bite. The public deserve some realism about the price of sovereignty.Third, there is a risk that government remains underprepared. While its headline goals are clear – at least in terms of what it does not want – the UK government will need thorough, realistic and coherent proposals on what it wants in every area of negotiations, and crucially develop a process by which to make political trade-offs between the demands of different sectors and issues. The government must also then prepare for their implementation in every area. This would be a huge challenge even if the final destination was already known, which it is not. Fourth, the continued uncertainty in the process means businesses and civil servants will again be left with little time to adapt to what will face them in January 2021 and must prepare for multiple outcomes.‘Transition’ has always been a misleading term, since it implies clarity about the destination to which the UK–EU relationship will be transitioning. The government’s red lines for that future relationship provide a sketch: outside of the single market and the jurisdiction of the European Court of Justice, with an independent trade policy and free movement ended.But businesses and civil servants are not likely to know until very late in the process if the basis for future trade with the EU will be in the form of a free trade agreement, to be negotiated and implemented by the end of the year, or no trade deal at all. This last outcome is a realistic prospect. Michel Barnier speaks in the European Parliament on 29 January. Photo: Getty Images. During withdrawal negotiations, the extensions were both unlimited in number and required decisions only at the last moment. In this phase, the talks may only be extended once, and that decision must be taken six months from the final deadline. It is difficult to see circumstances in which Boris Johnson agrees to break a political promise and manifesto pledge when he still has six more months to achieve his desired outcome.The UK, it is often noted, is already fully compliant with EU law and this shared starting point is often cited as a reason this negotiation will be simple, since the parties begin in alignment. But this novel negotiation will create new trade barriers in goods and services rather than remove them. Trade deals are often politically difficult since they create winners and losers. The Brexit negotiations, in terms of UK–EU trade at least, will generally create only different levels of losers, on both sides of the Channel.That means difficult politics, challenging negotiations and hard compromises, another reason to expect some ugly politics along the way and accept that failure is a plausible outcome.We do not yet know how Brexit will change Britain in the long term, whether a settled majority will ever come to view it as political folly or liberation, choice or inevitability. If its politically fragile union can withstand the pressures of the next few years, the UK may yet find a new stable position on the EU’s periphery and, after a period of economic adjustment, begin to address the many pressing domestic challenges which have suffered from neglect amid the all-consuming Brexit saga.But whatever happens in this next chapter, the EU can no longer be an excuse for national problems. As the UK takes back control it also returns accountability. In the future, there will be no one else to credit or to blame. Full Article
all Webinar: Turkey’s Challenging Post-COVID 19 Outlook By feedproxy.google.com Published On :: Fri, 17 Apr 2020 13:05:01 +0000 Invitation Only Research Event 7 May 2020 - 1:00pm to 2:00pm Event participants Dr Murat Ucer, Turkey Country Analyst, GlobalSource Partners Chair: Fadi Hakura, Manager, Turkey Project, Europe Programme, Chatham House Turkish President Recep Tayyip Erdogan has so far refused to impose a nation-wide lockdown to suppress the spread of coronavirus in the country. In late March, Turkish health officials announced that they expect the virus to peak in three weeks' time and for Turkey to overcome it quickly. At the same time, Turkey has ruled out turning to the IMF for help in dealing with the crisis despite growing pressures on the Lira and the wider economy. The country's relations with its traditional allies, the US and Europe, remain thorny. This event will focus on the likely impact of the epidemic on Turkey's economy and politics. What are the reasons behind Erdogan’s reluctance to implement a comprehensive lockdown to break the chain of virus transmission? Why is Turkey resolutely opposed to agreeing a funding package with the IMF? What is the macro outlook for 2020 and beyond for the country's economy? And how may the government's long-term popularity be affected? Event attributes Chatham House Rule Department/project Europe Programme, Turkey Project Alina Lyadova Europe Programme Coordinator Email Full Article
all Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases. Full Article
all Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 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. Full Article
all A single amino acid substitution uncouples catalysis and allostery in an essential biosynthetic enzyme in Mycobacterium tuberculosis [Enzymology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and allostery. Full Article
all The recalibration of Chinese assertiveness: China's responses to the Indo-Pacific challenge By feedproxy.google.com Published On :: Wed, 08 Jan 2020 11:14:26 +0000 8 January 2020 , Volume 96, Number 1 Read online Feng Liu In response to the changing geopolitical landscape in Asia, both China and the United States attempt to alter the regional order in their own favour, both in the economic and security realms. This article shows how diverging views on future arrangements are leading to strategic shifts and increasing tension between these two Great Powers. As part of its quest for Great-Power status, China has been actively pushing its regional initiatives such as the Belt and Road Initiative (BRI) and the Asian Infrastructure Investment Bank (AIIB), as well as adopting assertive security policies towards its neighbours. In contrast, in order to counter China's growing influence America's regional strategy is undergoing a subtle shift from ‘rebalancing to Asia’ to focusing on the ‘Indo-Pacific’ region. However, amid an intensifying trade war and other challenges facing the region, China has chosen to moderate its proactive foreign policy-orientation in the past few years. In particular, China has made attempts to downplay its domestic rhetoric, rebuild strategic relationship with India and Japan, and to reassure ASEAN states in the South China Sea. In response to the Indo-Pacific strategy, it would be more effective for China to articulate a more inclusive regional vision and promote an institutional framework that also accommodates a US presence in the region. Full Article
all Security Challenges in the Mediterranean Region By feedproxy.google.com Published On :: Mon, 20 Jan 2020 15:15:01 +0000 Members Event 5 March 2020 - 1:00pm to 2:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants HE George Vella, President, Republic of MaltaChair: Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme, Chatham House The president of Malta discusses the current security challenges in the Mediterranean region, reflecting on the role of international cooperation in addressing climate change, migration and refugee flows. Members Events Team Email Full Article
all POSTPONED: Working Towards Cyber Resilience in the GCC: Opportunities and Challenges By feedproxy.google.com Published On :: Fri, 14 Feb 2020 14:10:01 +0000 Invitation Only Research Event 12 March 2020 - 9:00am to 5:00pm Muscat, Oman The GCC states have invested significantly in cybersecurity and have made large strides in protecting governments, businesses and individuals from cyber threats, with the aim of delivering on their ambitious national strategies and future visions. However, several challenges to cybersecurity and cyber resilience in the region persist, putting those ambitious plans at risk.These challenges include the uneven nature of cybersecurity protections, the incomplete implementation of cybersecurity strategies and regulations, and the issues around international cooperation. Such challenges mean that GCC states need to focus on the more difficult task of cyber resilience, in addition to the simpler initial stages of cybersecurity capacity-building, to ensure they harness the true potential of digital technologies and mitigate associated threats.Set against this background, this workshop will explore opportunities and challenges to cyber resilience in the GCC focusing on four main pillars:1. Cyber resilience: in concept and in practice2. Building an effective cybersecurity capacity3. The potential of regional and international cooperation to cyber resilience4. Deterrence and disruption: different approachesThis event will be held in collaboration with the Arab Regional Cybersecurity Centre (ARCC) and OMAN CERT.PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE. Event attributes Chatham House Rule Department/project International Security Programme Esther Naylor Research Assistant, International Security Programme +44 (0)20 7314 3628 Email Full Article
all Online Study Group: All Lukashenka’s Men: The Belarusian Ruling Elite and Why It Matters By feedproxy.google.com Published On :: Thu, 16 Apr 2020 07:50:01 +0000 Invitation Only Research Event 22 April 2020 - 2:30pm to 4:00pm Event participants Ryhor Astapenia, Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme, Chatham HouseChair: James Nixey, Programme Director, Russia and Eurasia, Chatham House Soon after assuming power in 1994, President Aliaksandr Lukashenka turned his back on democratic norms and overpowered the Belarusian political elite. However, the influence of the governing elite in Belarus is growing again. It seems likely that the current governing class could rule the country after Lukashenka leaves. It is thus important to study Belarusian elites not only to understand the current regime, but also to better forecast and navigate the political system that will one day replace it. This study group aims to disentangle how the Belarusian political system works, outline the types of individuals that make up the Belarusian ruling elite, assess the interaction of the elite and institutions with the West, and suggest changes that Western political actors might make to their approach to the Belarusian ruling class. Event attributes Chatham House Rule Department/project Russia and Eurasia Programme Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
all Webinar: Turkey’s Challenging Post-COVID 19 Outlook By feedproxy.google.com Published On :: Fri, 17 Apr 2020 13:05:01 +0000 Invitation Only Research Event 7 May 2020 - 1:00pm to 2:00pm Event participants Dr Murat Ucer, Turkey Country Analyst, GlobalSource Partners Chair: Fadi Hakura, Manager, Turkey Project, Europe Programme, Chatham House Turkish President Recep Tayyip Erdogan has so far refused to impose a nation-wide lockdown to suppress the spread of coronavirus in the country. In late March, Turkish health officials announced that they expect the virus to peak in three weeks' time and for Turkey to overcome it quickly. At the same time, Turkey has ruled out turning to the IMF for help in dealing with the crisis despite growing pressures on the Lira and the wider economy. The country's relations with its traditional allies, the US and Europe, remain thorny. This event will focus on the likely impact of the epidemic on Turkey's economy and politics. What are the reasons behind Erdogan’s reluctance to implement a comprehensive lockdown to break the chain of virus transmission? Why is Turkey resolutely opposed to agreeing a funding package with the IMF? What is the macro outlook for 2020 and beyond for the country's economy? And how may the government's long-term popularity be affected? Event attributes Chatham House Rule Department/project Europe Programme, Turkey Project Alina Lyadova Europe Programme Coordinator Email Full Article
all Webinar: Egypt and the Gulf: Allies and Rivals By feedproxy.google.com Published On :: Tue, 21 Apr 2020 08:25:01 +0000 Research Event 23 April 2020 - 1:00pm to 2:00pm Event participants Speaker: David Butter, Associate Fellow, Middle East and North Africa Programme, Chatham HouseModerator: Mohamed El Dahshan, Associate Fellow, Middle East and North Africa Programme, Chatham House The webinar will be livestreamed on the MENA Programme Facebook page.Egypt and the Gulf Arab region have long been important poles of political, military, economic and cultural power and influence in the Middle East. A recently published Chatham House paper examines the strategic and economic relationship between Egypt and the Gulf, focusing in particular on the period since Abdel-Fattah el-Sisi came to power in Egypt. Author David Butter offers a detailed evaluation of these economic relationships, in the broader context of a strategic alliance that, since 2013, has been informed by a common commitment between Egypt and the UAE in particular to keep in check the Muslim Brotherhood and its regional state supporters, primarily Turkey and Qatar.In this webinar, the author will discuss the paper’s main argument, namely, that the degree of Egypt’s dependence on Gulf countries has fluctuated, and that by 2019, Egypt’s direct financial dependence on the Gulf was significantly reduced by comparison with the initial three years of the Sisi era, although other economic linkages such as investment, trade, remittances and tourism remained strong, with potential for growth. The speaker will also discuss the impact of the global crisis caused by the COVID-19 pandemic on Egypt’s and Gulf countries’ economies and will explore the implications for the relationship between Egypt and the Gulf.This webinar is part of the Chatham House Middle East and North Africa Programme's Online Event Series. The event will be held on the record. Department/project Middle East and North Africa Programme Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email Full Article
Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email
all Webinar: Russian Disinformation's Golden Moment: Challenges and Responses in the COVID-19 Era By feedproxy.google.com Published On :: Tue, 21 Apr 2020 23:55:01 +0000 Invitation Only Research Event 7 May 2020 - 3:00pm to 4:30pm Event participants Anneli Ahonen, Head, StratCom East Task Force, European External Action ServiceKeir Giles, Senior Consulting Fellow, Russia and Eurasia Programme, Chatham HouseThomas Kent, Adjunct Associate Professor, Harriman Institute, Columbia University; Senior Fellow, the Jamestown FoundationChairs:James Nixey, Programme Director, Russia and Eurasia, Chatham HouseGlen Howard, President, The Jamestown Foundation The COVID-19 pandemic provides the ideal environment for malign influence to thrive as it feeds on fear and a vacuum of authoritative information. What are the current challenges posed by Russian disinformation, and how should Western nations be responding? In this discussion, jointly hosted by the Jamestown Foundation and the Chatham House Russia and Eurasia Programme, the speakers will consider what best practice looks like in safeguarding Western societies against the pernicious effects of disinformation. This event will be held on the record. Department/project Russia and Eurasia Programme, Russia's Domestic Politics Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
all Lesotho’s Domestic Priorities and Global Interests: Small Country Levers for International Influence By feedproxy.google.com Published On :: Tue, 01 Apr 2014 14:57:42 +0000 Research Event 7 April 2014 - 3:00pm to 4:00pm Chatham House, London Meeting Summarypdf | 59.43 KB Event participants HE Dr Motsoahae Thomas Thabane, Prime Minister of LesothoChair: Ian Lucas MP, Shadow Minister for Africa and the Middle East The landlocked southern African nation of Lesotho faces a number of domestic challenges in 2014. Reducing reliance on the agricultural sector, containing the prevalence of HIV and improving service delivery are all important issues that must be addressed to ensure sustainable growth. However, social achievements including literacy rates and levels of gender parity among the highest in Africa, the country’s potential for electricity exports, and the booming relationship between its textile industry and the United States, could mean Lesotho is well-placed for future growth and development. HE Prime Minister Tom Thabane will discuss how his government seeks to address the Lesotho’s domestic issues and how the country seeks to exert its influence in the regional Southern African Development Community. Full Article
all Nowhere to Call Home: Ethnic Minorities in China By feedproxy.google.com Published On :: Mon, 26 Jan 2015 11:15:01 +0000 Members Event 18 February 2015 - 6:00pm to 7:15pm Chatham House, London Transcriptpdf | 147.75 KB Transcript Q&Apdf | 160.08 KB Event participants Jocelyn Ford, Journalist and Filmmaker, Nowhere to Call Home: A Tibetan in BeijingDr Reza Hasmath, Lecturer in Chinese Politics, University of OxfordChair: Rob Gifford, Correspondent, The Economist Jocelyn Ford will share her experiences and insights from documenting the struggles of a widowed Tibetan facing ethnic discrimination in Beijing and gender discrimination in her village. The panel will then have a wider discussion about national identity and the issues facing ethnic minorities in China. This discussion coincides with the UK screening of Nowhere to Call Home: A Tibetan in Beijing and will include clips from the film. Full Article
all The Road to Gender Equality: Achievements and Challenges in China By feedproxy.google.com Published On :: Tue, 31 May 2016 14:15:01 +0000 Invitation Only Research Event 23 May 2016 - 1:00pm to 3:00pm Beijing, China Following 21 years since the adoption of the Beijing declaration by 189 states, China has the opportunity to lead the way in prioritizing gender-inclusive growth policies on the G20 agenda, as it is hosting the G20 this year.This roundtable will examine specific challenges in China, a country with a high heterogeneity in the labour force and among its population. The event will bring together representatives of government, business and civil society to continue the dialogue that Chatham House started one year ago in Beijing. Taking stock of the progress achieved so far, the participants will analyse what type of recommendations can have a positive impact in both rural and high- density populated areas.Attendance at this event is by invitation only.The Chatham House Rule To enable as open a debate as possible, this event will be held under the Chatham House Rule. Event attributes Chatham House Rule Department/project Global Economy and Finance Programme, Putting Gender Equality on the G20 Agenda Michele Bazzano Research Assistant, International Economics +44 (0)20 7314 3684 Email Full Article
all Challenges to Freedom of Expression By feedproxy.google.com Published On :: Tue, 21 Jun 2016 10:00:01 +0000 Research Event 20 July 2016 - 6:00pm to 7:15pm Chatham House, London Meeting Summarypdf | 107.63 KB Event participants Sherif Elsayed-Ali, Head of Technology and Human Rights, Amnesty InternationalProfessor David Kaye, UN Special Rapporteur on the Promotion and Protection of the Right to Freedom of Opinion and ExpressionChair: Sonya Sceats, Associate Fellow, International Law Programme, Chatham House The digital age has seen an extraordinary transformation in how individuals can exercise their right to freedom of expression. What are the proper limits of state interference in online communication in pursuit of national security and public order? What does this mean for privacy? And away from the digital world, to what extent is free speech being affected by counterterrorism measures and actions to prevent hate crimes? How do all of these challenges affect the space for civil society action? Department/project International Law Programme, Rights, Accountability and Justice, International Law Discussion Group Chanu Peiris Programme Manager, International Law +44 (0)20 7314 3686 Email Full Article
all A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent By feedproxy.google.com Published On :: 1989-04-01 M el-SaadaniApr 1, 1989; 30:627-630Articles Full Article
all Direct transesterification of all classes of lipids in a one-step reaction By feedproxy.google.com Published On :: 1986-01-01 G LepageJan 1, 1986; 27:114-120Articles Full Article
all Virtual Roundtable: America’s China Challenge By feedproxy.google.com Published On :: Fri, 03 Apr 2020 14:50:01 +0000 Research Event 17 April 2020 - 2:00pm to 3:00pm Event participants Robert Zoellick, President of the World Bank Group, 2007 - 12Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House This event is part of the Chatham House Global Trade Policy Forum. We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the forum. Department/project US and the Americas Programme, Global Trade Policy Forum US and Americas Programme Email Full Article
all Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development. Full Article
all Coronavirus Vaccine: Available For All, or When it's Your Turn? By feedproxy.google.com Published On :: Mon, 04 May 2020 15:39:19 +0000 4 May 2020 Professor David Salisbury CB Associate Fellow, Global Health Programme LinkedIn Despite high-level commitments and pledges to cooperate to ensure equitable global access to a coronavirus vaccine, prospects for fair distribution are uncertain. 2020-05-04-Vaccine-COVID-Brazil Researcher in Brazil working on virus replication in order to develop a vaccine against the coronavirus. Photo by DOUGLAS MAGNO/AFP via Getty Images. When the H1N1 influenza pandemic struck in 2009, some industrialized countries were well prepared. Many countries’ preparedness plans had focused on preparing for an influenza pandemic and based on earlier alerts over the H5N1 ‘bird flu’ virus, countries had made advanced purchase or ‘sleeping’ contracts for vaccine supplies that could be activated as soon as a pandemic was declared. Countries without contracts scrambled to get supplies after those that already had contracts received their vaccine.Following the 2009 pandemic, the European Union (EU) developed plans for joint-purchase vaccine contracts that any member state could join, guaranteeing the same price per dose for everyone. In 2009, low-income countries were unable to get the vaccine until manufacturers agreed to let 10 per cent of their production go to the World Health Organization (WHO).The situation for COVID-19 could be even worse. No country had a sleeping contract in place for a COVID-19 vaccine since nobody had anticipated that the next pandemic would be a coronavirus, not an influenza virus. With around 80 candidate vaccines reported to be in development, choosing the right one will be like playing roulette.These candidates will be whittled down as some will fail at an early stage of development and others will not get to scale-up for manufacturing. All of the world’s major vaccine pharmaceutical companies have said that they will divert resources to manufacture COVID-19 vaccines and, as long as they choose the right candidate for production, they have the expertise and the capacity to produce in huge quantities.From roulette to a horse raceOur game now changes from roulette to a horse race, as the probability of winning is a matter of odds not a random chance. Countries are now able to try to make contracts alone or in purchasing consortia with other states, and with one of the major companies or with multiple companies. This would be like betting on one of the favourites.For example, it has been reported that Oxford University has made an agreement with pharmaceutical company AstraZeneca, with a possibility of 100 million doses being available by the end of 2020. If the vaccine works and those doses materialize, and are all available for the UK, then the UK population requirements will be met in full, and the challenge becomes vaccinating everyone as quickly as possible.Even if half of the doses were reserved for the UK, all those in high-risk or occupational groups could be vaccinated rapidly. However, as each major manufacturer accepts more contracts, the quantity that each country will get diminishes and the time to vaccinate the at-risk population gets longer.At this point, it is not known how manufacturers will respond to requests for vaccine and how they will apportion supplies between different markets. You could bet on an outsider. You study the field and select a biotech that has potential with a good production development programme and a tie-in with a smaller-scale production facility.If other countries do not try to get contracts, you will get your vaccine as fast as manufacturing can be scaled up; but because it is a small manufacturer, your supplies may take a long time. And outsiders do not often win races. You can of course, depending on your resources, cover several runners and try to make multiple contracts. However, you take on the risk that some will fail, and you may have compromised your eventual supply.On April 24, the WHO co-hosted a meeting with the president of France, the president of the European Commission and the Bill & Melinda Gates Foundation. It brought together heads of state and industry leaders who committed to ‘work towards equitable global access based on an unprecedented level of partnership’. They agreed ‘to create a strong unified voice, to build on past experience and to be accountable to the world, to communities and to one another’ for vaccines, testing materials and treatments.They did not, however, say how this will be achieved and the absence of the United States was notable. The EU and its partners are hosting an international pledging conference on May 4 that aims to raise €7.5 billion in initial funding to kick-start global cooperation on vaccines. Co-hosts will be France, Germany, Italy, the United Kingdom, Norway and Saudi Arabia and the priorities will be ‘Test, Treat and Prevent’, with the latter dedicated to vaccines.Despite these expressions of altruism, every government will face the tension between wanting to protect their own populations as quickly as possible and knowing that this will disadvantage poorer countries, where health services are even less able to cope. It will not be a vote winner to offer a share in available vaccine to less-privileged countries.The factories for the biggest vaccine manufacturers are in Europe, the US and India. Will European manufacturers be obliged by the EU to restrict sales first to European countries? Will the US invoke its Defense Production Act and block vaccine exports until there are stocks enough for every American? And will vaccine only be available in India for those who can afford it?The lessons on vaccine availability from the 2009 influenza pandemic are clear: vaccine was not shared on anything like an equitable basis. It remains to be seen if we will do any better in 2020. Full Article
all Algeria’s Perfect Storm: COVID-19 and Its Fallout By feedproxy.google.com Published On :: Wed, 06 May 2020 19:19:54 +0000 6 May 2020 Adel Hamaizia Associate Fellow, Middle East and North Africa Programme Yahia H. Zoubir Senior Professor of International Studies, KEDGE Business School; Visiting Fellow, Brookings Doha Center Coronavirus is a godsend for Algeria’s government to introduce restrictive measures beyond those needed to contain COVID-19. But its new leaders are missing a chance to gain legitimacy, which will offset the socio-economic fallout of the drop in oil prices. 2020-05-06-Algeria-Health-Covid Algerian volunteers prepare personal protection equipment (PPE) to help combat the coronavirus epidemic in the capital Algiers. Photo by RYAD KRAMDI/AFP via Getty Images. Although protests successfully ended Abdelaziz Bouteflika’s 20-year sultanistic rule a little over one year ago, demands have been continuing to dismantle the system, get rid of the old personnel, and institute democracy.The controversial election in December of Abdelmadjid Tebboune — who has inherited a disastrous situation — has not tempered the determination of the Hirak protest movement. As a former minister and prime minister under Bouteflika, the new president has won little legitimacy, and protests have continued.Now COVID-19 is worsening already dire economic conditions, such as a sharp drop in oil prices. By the beginning of May, statistics showed 10% of confirmed cases have ended in fatality, the highest percentage in the region.Maintaining an authoritarian styleHirak had already called for the suspension of the marches — mobilising online instead — before the government’s measures, which include curfews and lockdowns, demonstrating a high sense of duty. But instead of appeasing Hirak’s demands, the government has maintained the authoritarian style of its predecessors.Tebboune released more than 5,000 prisoners on March 31 but kept prisoners of conscience and leaders of the hirak imprisoned, then subsequently imprisoned journalists and activists. It even passed a controversial penal law, that also covers fake news, and may be used to justify actions against journalists.The regime wishes to see an end to the Hirak, and rejects accusations of totalitarianism by insisting freedom and a democratic climate exist in Algeria.Tebboune’s actions contradict his praise for the ‘blessed’ hirak and his promises of instituting the rule of law. In proclaiming the measures, the government has shown disappointing leadership, acting in an authoritarian fashion.Tebboune also declared proudly that Algeria was fully prepared to fight the coronavirus epidemic, an optimistic claim given the country has only 400 intensive care unit (ICU) beds, or one per 100,000 people. Despite hundreds of billions of hydrocarbon dollars accumulating during the Bouteflika-era, Algeria’s health system ranks 173 out of 195 countries.Algerians often refer to hospitals as ‘mouroirs’, meaning ‘places for the dying’. Not only has the state failed to build modern hospitals but basic hygienic conditions are lacking, and government officials prefer being treated overseas. A 2014 project to build five university hospitals was abandoned, leaving the health sector in deplorable shape.Before Chinese assistance arrived, the glaring lack of equipment to protect caregivers and care for the sick was evident. Prime Minister Abdelaziz Djerad admitted the health system required a ‘total overhaul’. The president recently stated Algeria’s doctors are among the 'best in the world' but didn't address why almost 15,000 Algerian doctors practice in France.Strict containment measures are in sync with most countries but implementation is challenging when most people live in overcrowded urban dwellings (the average household consists of 5.9 members).Water shortages in many areas makes good hygiene and decontamination impossible, while schools and universities find online teaching difficult when many students do not possess laptops or internet connections. And only 20% of Algerians have debit cards in a cash-dominated economy because of low trust in the public-dominated banking sector, making online shopping capability low.An already declining macroeconomic situation is worsening due to COVID-19. The IMF revised its 2020 estimates for Algeria, forecasting a catastrophic contraction of -5.2% in a country where hydrocarbons account for 93% of export revenues and 60% of its budget.Foreign currency reserves are now an estimated $55 billion (expected to fall to $44billion by the end of 2020), down from $200 billion in 2014, and Algerian crude has recently traded close to production costs, with the fiscal breakeven oil price at $157.In line with its historic aversion to external borrowing, Tebboune recently ruled out seeking financial support from the ‘IMF or other foreign banks’, as he argued such borrowing undermines sovereign foreign policy because - when indebted - ‘we cannot talk about either Palestine or Western Sahara’, two causes dear to Algeria. ‘Friendly countries’ - most likely a reference to China - are said to have offered to grant loans which have been declined for now.The government is forecasted to face a 20% budget shortfall this year, but Algeria’s fiscal response to COVID-19 is actually the largest among the regional hydrocarbon exporters at an estimated 8% of GDP, compared to an average of 3.2%. However, the government revised downwards its 2020 public spending by 50% (a second cut in a month, from an initial 30% reduction), halting state projects and slashing its $41 billion import bill by 25% while expanding agricultural production. National oil company SONATRACH will also cut planned investment by half to $7 billion but plans have been revealed to develop other natural resources including gold, uranium and phosphates.But recent growth rates are insufficient to create jobs for those entering the labour market. Despite government attempts to support a rather anaemic ‘formal’ private sector, estimates are 700,000 jobs could be lost due to potential bankruptcies from reduced activity and a loss of markets abroad.Facing potential social unrest and the quasi-preservation of a tired social contract, the government has committed to upholding public sector wages - including for 50% of the civil servants told to stay home - protecting sacrosanct, unsustainable subsidies, and increasing health expenditure to strengthen the capacity to combat COVID-19.A supplementary finance law will include various measures that support businesses and the economic fallout. However, while the government is to be commended for its efforts to aid businesses, supporting large swathes of the population is challenging as approximately 50% of the workforce operate in the informal economy.Weak administrative capacity and insufficient data to implement cash transfers makes the planned ‘solidarity allowance’ of 10,000 dinars ($80) for Ramadan difficult to allocate to those who most need it (especially those in the informal sector). Families, communities, and religious organisations continue to be a social safety net.So COVID-19 has not created new problems, it has merely magnified and exacerbated the numerous inequalities and failures of the Bouteflika regime to sufficiently invest in human security (economic, food, health environmental, personal, community, and political). Typically, whenever oil prices and related earnings dwindle, the political system promises to reform and diversify the economy. Tebboune is repeating this same old tune.There are positive elements, such as the government’s realization it must initiate genuine reforms. And local enterprises have been successfully producing artificial respirators, surgical masks, and other materials. Algerians, including the Hirak, are showing great social solidarity.But the government must capitalize on these positive actions by introducing real change. Because, if not, Hirak will certainly be back in force once the crisis is over, and operating in an environment of worsening socioeconomic problems. The medicine of the past will not work. Full Article
all Chatham House Forum: Are Humans Psychologically Wired to Fight? By feedproxy.google.com Published On :: Tue, 05 Jun 2018 00:00:00 +0100 Full Article
all Drugs and Organized Crime: The Challenges Facing Southeast Asia By feedproxy.google.com Published On :: Wed, 06 Jun 2018 00:00:00 +0100 Full Article
all The Failed Marshall Plan: Learning from US Foreign Policy Missteps By feedproxy.google.com Published On :: Mon, 10 Sep 2018 00:00:00 +0100 Full Article
all Managing the Real and Perceived Challenges Facing the World By feedproxy.google.com Published On :: Mon, 24 Sep 2018 00:00:00 +0100 Full Article
all Undercurrents: Episode 19 - Green Building Projects in Jordan, and Qatar's Football World Cup By feedproxy.google.com Published On :: Thu, 18 Oct 2018 00:00:00 +0100 Full Article
all Iran’s New Foreign Policy Challenges By feedproxy.google.com Published On :: Tue, 06 Nov 2018 00:00:00 +0000 Full Article
all Indo-UK Collaboration: Opportunities and Challenges By feedproxy.google.com Published On :: Tue, 27 Nov 2018 00:00:00 +0000 Full Article
all The Transatlantic Relationship: Challenges and Opportunities By feedproxy.google.com Published On :: Wed, 30 Jan 2019 00:00:00 +0000 Full Article
all The Challenge of Ambition? Unlocking Climate Action and the Outcomes of COP24 By feedproxy.google.com Published On :: Fri, 01 Mar 2019 00:00:00 +0000 Full Article
all Sustainable Solutions to Challenges Faced by Displaced People and Refugees By feedproxy.google.com Published On :: Wed, 03 Apr 2019 00:00:00 +0100 Full Article
all The Paradox of Progress: Health Challenges of the Future By feedproxy.google.com Published On :: Wed, 03 Apr 2019 00:00:00 +0100 Full Article
all Africa’s Economic Outlook in a Challenging External Environment By feedproxy.google.com Published On :: Mon, 10 Jun 2019 00:00:00 +0100 Full Article
all Undercurrents: Summer Special - Allison Gardner on Artificial Intelligence By feedproxy.google.com Published On :: Thu, 08 Aug 2019 00:00:00 +0100 Full Article
all Challenges and Opportunities in the Fight Against Corruption By feedproxy.google.com Published On :: Mon, 09 Dec 2019 00:00:00 +0000 Full Article
all France, the UK and Europe: New Partnerships and Common Challenges By feedproxy.google.com Published On :: Fri, 28 Feb 2020 00:00:00 +0000 Full Article
all Security Challenges in the Mediterranean Region By feedproxy.google.com Published On :: Thu, 05 Mar 2020 00:00:00 +0000 Full Article
all Atomic force microscopy-based characterization of the interaction of PriA helicase with stalled DNA replication forks [DNA and Chromosomes] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 In bacteria, the restart of stalled DNA replication forks requires the DNA helicase PriA. PriA can recognize and remodel abandoned DNA replication forks, unwind DNA in the 3'-to-5' direction, and facilitate the loading of the helicase DnaB onto the DNA to restart replication. Single-stranded DNA–binding protein (SSB) is typically present at the abandoned forks, but it is unclear how SSB and PriA interact, although it has been shown that the two proteins interact both physically and functionally. Here, we used atomic force microscopy to visualize the interaction of PriA with DNA substrates with or without SSB. These experiments were done in the absence of ATP to delineate the substrate recognition pattern of PriA before its ATP-catalyzed DNA-unwinding reaction. These analyses revealed that in the absence of SSB, PriA binds preferentially to a fork substrate with a gap in the leading strand. Such a preference has not been observed for 5'- and 3'-tailed duplexes, suggesting that it is the fork structure that plays an essential role in PriA's selection of DNA substrates. Furthermore, we found that in the absence of SSB, PriA binds exclusively to the fork regions of the DNA substrates. In contrast, fork-bound SSB loads PriA onto the duplex DNA arms of forks, suggesting a remodeling of PriA by SSB. We also demonstrate that the remodeling of PriA requires a functional C-terminal domain of SSB. In summary, our atomic force microscopy analyses reveal key details in the interactions between PriA and stalled DNA replication forks with or without SSB. Full Article
all Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections. Full Article
all Tracking isotopically labeled oxidants using boronate-based redox probes [Methods and Resources] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 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. Full Article
all Templated folding of intrinsically disordered proteins [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding. Full Article