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'I gave everything to boxing and still have nothing'

Heather Hardy tells BBC Sport how she is adapting to life outside of boxing after the former world champion was left with a life-threatening injury.




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Nature presenter Chris Packham settles case over axing of green policy

The TV presenter says the previous Tory administration was "reckless" to scale back climate policy.




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Norris calls Verstappen 'dangerous' as Sainz wins in Mexico

Lando Norris cuts Max Verstappen’s lead to 47 points and labels his rival “dangerous” as the championship battle reaches boiling point at the Mexico City Grand Prix.




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Van Gerwen exits Grand Slam but Littler progresses

Michael van Gerwen fails to make it through to the Grand Slam of Darts last 16 but Luke Littler breezes through to the knockout stage.




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Brown exits St Mirren as John added as replacement

Jaden Brown leaves St Mirren by mutual consent "to be closer to his family", the club announce as they sign Declan John as a replacement.




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You're the boss - pick your Northern Ireland starting XI

It's time for you to be the boss as you select your Northern Ireland starting XI to take on Belarus in Belfast on Friday.




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The new TOXIC AVENGER comic book is great

It's been just over a year since director Macon Blair premiered his new reboot of The Toxic Avenger at Fantastic Fest in Austin, Texas. The new film stars Peter Dinklage as the eponymous hideously deformed creature of superhuman size and strength, along with Elijah Wood, Kevin Bacon, and more—but has unfortunately struggled to find support for a wider distribution, according to The Hollywood Reporter. — Read the rest

The post The new TOXIC AVENGER comic book is great appeared first on Boing Boing.




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Technology, Humanity, and the Existential Test

I’m still digging through some of the pieces I posted at the now defunct NewCo Shift, and found this piece, adapted from a talk I gave at the Thrival Humans X Tech conference in Pittsburgh back in September of 2018. I was alarmed by trends that I saw intensifying – a push by the tech … Continue reading "Technology, Humanity, and the Existential Test"





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China Party Congress: Xi’s political blueprint

China Party Congress: Xi’s political blueprint The World Today rescobales.drupal 28 September 2022

In the second of her three-part series on the 20th National Congress of the Chinese Communist Party, Yu Jie outlines two key policy themes we can expect Xi to define: ‘common prosperity’ and ‘self-reliance’.

What can we expect from the Party Congress?

In mid-October five years ago, the 19th Party Congress opened with Xi Jinping delivering a political report lasting three-and-a-half hours. He will repeat the performance on October 16, the opening day of this year’s 20th Party congress.

Bland as its name may be, this political report is one of the Party Congress’s core items of business. It remains the most authoritative public account of the Chinese Communist Party’s path on all major policy fronts, containing a laundry list of policies undertaken by the outgoing Central Committee in the past five years, while putting forward guidance for future policy.

It represents the view of the current Politburo Standing Committee and that of the CCP. The 20th Congress report is a collegial effort and should not be considered Xi’s personal manifesto, nor should it be counted as another of his speeches to his comrades.

However, as general-secretary of the party for the past decade, it will most probably reflect many of the elements that Xi has influenced.

What are China’s political priorities?

No matter how complicated the geopolitics of the world becomes, Xi sticks to the conservative approach that has served his country well for past centuries: that China prioritizes the management of its own affairs.

Since the Cold War ended, two recurring themes have dominated the political report: the economy and security. For the 20th session, Xi will use the phrases ‘common prosperity’ as shorthand for the economy and ‘self-reliance’ for security.

Xi introduced the slogan ‘common prosperity’ at the start of his third term in August 2021. His aim was to close the income gap, address regional economic inequality and improve social welfare provision. Rebalancing social inequality was seen as essential to avoid the social disruption witnessed in other parts of the world.

Xi’s concept of ‘common prosperity’ was influenced by his childhood experiences living in exile in a remote village in Shanxi Province, in northwest China, during the Cultural Revolution. The ensuing upheaval was to prove a tragedy for his family and a disaster for the country.

His ambition is to define progress not in terms of producing double-digit growth but in dealing with the long-standing challenge of scarcities across different sections of society to meet ‘people’s ever-growing needs for a better life’. This direction was indicated at the 19th Party Congress by the term ‘shifting the principal contradiction’.

What state is the Chinese economy in?

Xi may have arrived at the right diagnosis but he has so far failed to find a cure that invokes ‘common prosperity’. After sweeping regulatory measures, the CCP has clamped down on its most successful private companies and spooked investors. While providing 80 per cent of China’s jobs, private enterprises are worried that the ‘common prosperity’ initiative may jeopardize their business.

Equally, Beijing’s zero-Covid policy has discouraged much-needed investment and failed to win the hearts and minds of Chinese youth, who have suffered most, both economically and socially.

The challenge facing Xi over the next five years will be to manage the financial risks in downsizing China’s property sector while coming out of a rigidly imposed Covid lockdown without reducing economic growth to such an extent that it damages the personal wealth of millions of people.

One hopes that Xi’s policies in future will be based on an innovative reading of the first-century phrase ‘seeking truth from facts’ adopted by Mao Zedong and last promoted as the political philosophy of Deng Xiaoping in the Seventies. A healthy market economy is not only essential for China’s development but as the only means of maintaining the party’s legitimacy, something vital for Xi.

Does China need more security?

China’s weakened export markets and less-friendly relations with the United States have encouraged it to become more self-reliant. Expect an emphasis on greater self-sufficiency in sectors of strategic importance to form a substantial part of this year’s political report.

In view of increased international hostility, Xi and his lieutenants have publicly recognized the need to take control of production and supply chains. These supply chains need to become ‘self-determined, self-controlled’ they have said, voicing frustration that the highest value-added elements of the Chinese tech sector remain reliant on overseas suppliers and vulnerable to geopolitical tensions.

Equally, on food and energy security, Russia’s invasion in Ukraine has exacerbated China’s already fragile food supplies as both countries are vital sources of food imports. Xi has already called for a ‘comprehensive thrift strategy’ to manage China’s food and energy needs.

Beijing is equally worried about the increase in oil and commodity prices which is driving up the cost of living. This may push parts of Chinese society out of ‘common prosperity’ and into ‘common poverty’, as it threatens to in some parts of Europe.

For the next five years, Xi needs to strike a balance between ‘common prosperity’ and ‘self-reliance’ to mitigate the storms ahead. He cannot afford to lockdown the world’s second largest economy indefinitely.

The hope is that the 20th Party congress will bring much-needed course corrections.

Read the two further articles in this series: the first provides a guide to why the Chinese Communist Party Congress matters; the third analyses the foreign policy issues likely to be discussed at the congress.  

 




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Xi Jinping shows the world he is taking a tougher line

Xi Jinping shows the world he is taking a tougher line Expert comment NCapeling 16 October 2022

Xi opens the 20th National Congress of the Chinese Communist Party with a political report which demonstrates both change and continuity in the approach of his leadership.

The 20th Party Congress report is significantly shorter than the 19th, which is a clear indication of Xi’s success in centralizing power. The report acts as a summary of the party’s achievements and its plans – expressed as the lowest common denominator of consensus between competing factions. A shorter political report would seem to represent fewer factions now seeking consensus.

In the 20th Party Congress report, the language on Taiwan has been revised, reflecting the changes in tone and the policies of the CCP senior leadership. In addition to the conventional ‘peaceful reunification’ term, there is also an addition of more hawkish language on Taiwan to ‘not exclude the use of force as a last resort’.

Xi also suggested that ‘resolving Taiwan Question should be in hands of the Chinese’, sending a further warning to the US and other Western allies which are perceived as interfering in Taiwan affairs.

In his remarks, Xi suggested the ‘zero-COVID’ strategy has worked for China although he gave no clear timeline on when the policy will end. He also proposed building a healthcare system able to cope with future pandemics. This implies that China is still in short supply of sufficient healthcare resources to cope with a disease like COVID.

Economic policy reveals anxiety

On economic policy, much of the emphasis is given to the extent to which security and economic growth should go hand in hand, which illustrates Beijing’s deep anxieties on supply chains and the high-tech sector. These supply chains need to become more ‘self-determined, self-controlled’, voicing frustration that the highest value-added elements of the Chinese tech sector remain reliant on overseas suppliers and vulnerable to geopolitical tensions.

Much of the emphasis is given to the extent to which security and economic growth should go hand in hand, which illustrates Beijing’s deep anxieties on supply chains and the high-tech sector

Also, he expected the Common Prosperity Initiative will further adjust uneven income distribution to increase the amount of middle-income population. He gave little favours for financial services and fin-tech companies but insisted that China should remain as a manufacturing-led economy with qualitative growth. That implies Beijing will tolerate much slower growth so long as the income gap between the rich and poor is closing.

On foreign affairs, Xi has completely abandoned the ‘new types of great power relations’ – instead he has stressed that China should further develop its ties with the Global South through the Global Development Initiative and the Global Security Initiative.




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Xi Jinping prepares the Communist party for new reality

Xi Jinping prepares the Communist party for new reality Expert comment NCapeling 20 October 2022

Political report reflects a worsened economic and diplomatic position as Xi knows his unprecedented third term as leader will be judged on results.

In stark contrast to the aura of triumphant glory that greeted Xi Jinping at the last National Congress of the Chinese Communist Party in 2017, this week’s convocation opened with an air of sobriety.

Amid a domestic economic downturn and a return to enmity with Western liberal democracies, Xi offered his own recipe for party legitimacy and the country’s economic survival in the lengthy executive summary of his political report to the CCP congress. The prime keyword was security, with some 73 mentions, underscored with a message of self-reliance.

The periodic report acts as a summary of the party’s achievements and of its future plans, with both expressed as the lowest common denominator of consensus between competing voices in the CCP. It thus typically sheds some light on relationships among senior party members and insights into the political fortunes of important intraparty groups.

Beijing is indeed turning to domestic consumption and homegrown technological prowess as the means to provide the rising wealth that the Chinese people have come to expect

Most portions of the new report combined Xi’s personal preferences with concessions to the reality of what is necessary for China’s economic survival. Both ends point to an urgent prioritization of economic and political self-reliance for Xi’s third term as party general secretary.

Holistic concept of security

On the domestic front, much emphasis was given to enhancing national security and promoting equitable growth.

Since even before COVID-19, Xi has advocated a holistic conceptualization of security that includes food, the internet, energy and manpower. Reflecting Beijing’s deep anxieties about high-tech development and its frustrations with dependence on overseas suppliers vulnerable to the vagaries of geopolitical tensions, the political report noted the need for China’s supply chains to become more “self-determined and self-controlled.”

Xi, though, went further to stress the importance of improving scientific education and grooming and attracting the necessary talent to accelerate China’s quest to achieve breakthroughs in semiconductor production and overcome development choke points created by Western technological monopolies.

As China has traditionally relied on connectivity with the rest of the world to support innovation and attract talent, a turn toward autarky is not a viable option, given Xi’s technological priorities. Yet the renewed mention of his ‘dual circulation’ strategy in the report signals that Beijing is indeed turning to domestic consumption and homegrown technological prowess as the means to provide the rising wealth that the Chinese people have come to expect from the Communist Party.

Worsening Sino-US relations and tightening access to overseas markets for Chinese companies have prompted party leaders not only to reconsider the country’s sources of economic growth but have also forced them to reconfigure their approach to foreign affairs.

Judging by his report summary, Xi has completely abandoned the ‘new type of great power relations’ concept used repeatedly in the last two editions of his congressional update to refer to his preferred approach to relations with the US-led West.

The omission shows that Beijing has concluded that its fraught relationship with advanced developed nations is here to stay, with little prospect of improvement soon. To this end, China needs to prepare for the worst of decoupling and become more self-reliant in terms of markets and technologies.

With the central government grappling with the country’s domestic economic woes, its spending spree on development assistance has had to come to an end

In place of the discarded concept, Xi stressed that China should further develop its ties with the global South through the Global Development Initiative and the Global Security Initiative he announced earlier this year. These efforts aim to reshape the global governance agenda in multilateral forums and to project Beijing’s influence on the developing world.

Meanwhile, the party’s latest official rhetoric about the Belt and Road Initiative shows it is no longer a one-size-fits-all slogan but on its way to becoming a genuine tool of trade and investment promotion with China’s near neighbors but with provincial governments taking the lead rather than Beijing.

With the central government grappling with the country’s domestic economic woes, its spending spree on development assistance has had to come to an end. The new political report clearly signals this change.

A modern socialist society is still the aim

The current economic downturn and dangerous geopolitical tensions have not dented the CCP’s ambitions to build a modern socialist society by 2035 and thus join the world’s club of upper middle-income countries, but this is easier said than done.




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Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the {alpha}/{beta}-fold epoxide hydrolase Alp1U [Enzymology]

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.




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Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity [Methods and Resources]

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.




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Reply to Sysel et al.: Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor]

In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,...




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Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor]

After a thorough read of this paper (1), we wish to clarify that the authors' anaerobic method of synthesis for the production of nitrocobalamin results in the transient formation of nitrosylcobalamin, an unstable intermediate upon exposure to air. We concur that the authors' method results in the production of nitrocobalamin based on the UV-visible data as shown. The authors' adapted anaerobic method consists of mixing hydroxocobalamin hydrochloride with diethylamine NONOate diethylammonium salt in aqueous solution. Of concern, the UV spectrum of nitric oxide overlaps that of all cobalamin species under anaerobic conditions, making any assignments of the binding of nitric oxide to hydroxocobalamin suspect (2). Additionally, the use of acetone to precipitate the authors' product causes precipitation of diethylamine NONOate, resulting in an impure product. As a result, its utility for drawing experimental conclusions is faulty.The product from the authors' anaerobic synthetic method has not been assessed for purity, and the synthetic method itself has not been validated using a stability-indicating method as required by the International Conference on Harmonization (ICH) (ICH Q2B, Validation of Analytical Procedures) methodology, which is a hallmark for analytical characterization. Our nitrosylcobalamin synthesis involves reacting nitric oxide gas with hydroxocobalamin acetate as a heterogeneous mixture in a non-electron-donating solvent followed by rotary evaporation. Our nitrosylcobalamin product is stable in air, releases nitric oxide gas in situ (3), and meets ICH stability guidelines (4). Additionally, our nitrosylcobalamin product demonstrates biological activity, which has not been observed for nitrocobalamin (3, 5).




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Brexit: Implications for EU–China Relations

Brexit: Implications for EU–China Relations Research paper sysadmin 10 May 2017

For Beijing, the EU–China relationship will take priority over UK–China ties – with China’s relative focus on Germany becoming even more significant.

Containers are loaded onto a freight train at a depot in Corringham, east of London, en route to Yiwu, China, on 10 April 2017. Photo: Getty Images.

Summary

  • The extent of current UK relations with China means that Brexit will notably reduce the scale and diversity of overall EU–China economic and commercial interactions. But the impact will vary across different areas.
  • In policy terms, liberal voices on economic policy towards China will be somewhat weaker among the post-Brexit EU27. Brexit will not be the most important factor determining the future level of strategic coherence in EU policy towards China.
  • The impact on post-Brexit EU27 trade with China will be felt both in the volume of trade and its composition. Following Brexit the EU will no longer be China’s largest trading partner.
  • There will be some relative shift in Chinese investment in Europe away from the UK, though over time the impact of Europe-wide policy approaches to Chinese investment will have more impact than Brexit per se.
  • EU–China educational exchanges will be weakened after Brexit, but inbound Chinese tourism will be less affected by Brexit.
  • By 2025, the EU will have compensated for Brexit’s impact in some areas, but much depends on the EU’s own trajectory over the next decade.
  • For Beijing, the EU–China relationship will take priority over UK–China ties. Within the EU, China’s relative focus on Germany will be even more significant.




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Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology




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Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources




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Undercurrents: Episode 15 - Brexit Update, and Corruption in the World of the Global Super-Rich




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Red Flags: The Outlook for Xi Jinping's China




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The European Union Before, During and After Brexit




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Can and Should Brexit Be Stopped?




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Undercurrents: Episode 17 - Alastair Campbell on New Labour and Brexit, Alistair Darling on the Financial Crisis




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Radical Change? New Political Paradigms in Brazil and Mexico




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Podcast: Examining The Post-Brexit Japan-UK Partnership




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Brexit: In Search of A Solution - The Common Market 2.0 Option




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UK–EU Defence and Security Cooperation after Brexit




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The State of Brexit on ‘Brexit Day’




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What Brexit Satisfies the Democratic Will of the People?




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Britain, Brexit and the Future of NATO




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Screening Room: Brexit - Behind Closed Doors




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Undercurrents: Summer Special - Andrés Rozental on Mexican Politics




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Brexit in a Historical Context: Pursuing a Global Vision at the Expense of Domestic Harmony?




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Tackling Toxic Air Pollution in Cities




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A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent

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




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Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews




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Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death

Nica M. Borradaile
Dec 1, 2006; 47:2726-2737
Research Articles




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Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles




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Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles




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Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression

K Schoonjans
May 1, 1996; 37:907-925
Reviews




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A novel stress-inducible CmtR-ESX3-Zn2+ regulatory pathway essential for survival of Mycobacterium bovis under oxidative stress [Microbiology]

Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.




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Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells [Gene Regulation]

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.





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Biochemical and biophysical analyses of hypoxia sensing prolyl hydroxylases from Dictyostelium discoideum and Toxoplasma gondii [Molecular Biophysics]

In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.





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Existence and uniqueness result for reaction-diffusion model of diffusive population dynamics

A. Kh. Khachatryan, Kh. A. Khachatryan and A. Zh. Narimanyan
Trans. Moscow Math. Soc. 83 (), 183-200.
Abstract, references and article information





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Flexible Distribution Systems: New Services, Actors and Technologies

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.




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The Impact of Brexit on Energy Transformation in the UK and EU

The Impact of Brexit on Energy Transformation in the UK and EU 28 March 2019 — 8:15AM TO 9:45AM Anonymous (not verified) 3 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

The UK’s decision to leave the EU will fundamentally reshape many of the UK’s policies and its relations with countries around the world. For energy and climate, the changes could be significant and will need to be managed carefully to secure ongoing investment, stable energy prices and ambitious climate objectives. The UK’s departure will also affect the balance of political support for climate and energy policies with the EU institutions and potentially impact upon regional initiatives.

This roundtable will discuss:

  • The impact on the energy sector of Brexit during the transition period through until December 2020 including the operation of interconnectors and access to the Internal energy market, ongoing engagement in European research collaboration and the replacement of European financial resources.
  • The possible opportunities and risks for the UK’s energy sector in 2021 and beyond.
  • The implications of Brexit on the EU’s energy and climate policy.

The roundtable will discuss the role of the public and business in shaping the future deal as it will need to be ratified by the parliaments of all member states.

Attendance at this event is by invitation only.