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MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates [Lipids]

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.




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Results of Primary One discretionary places to be released on Monday




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Primary One Central Allocation results to be posted to parents in early June




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LSU Health study suggests nicotine exposure alone leads to pulmonary hypertension

(Louisiana State University Health Sciences Center) A study conducted at LSU Health New Orleans has shown for the first time that chronic exposure to inhaled nicotine alone increases blood pressure in both the body's general circulation and in the lungs that can lead to pulmonary hypertension. The study also found that nicotine-induced pulmonary hypertension is accompanied by changes in the size, shape and function (remodeling) of the blood vessels in the lung and the right lower chamber of the heart.




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Study shows need for new focus in anti-vaping efforts for older teens and young adults

(Michigan Medicine - University of Michigan) They know it's addictive. They know it's linked to dangerous lung diseases. And they know it delivers more nicotine than the cigarettes it's supposed to replace. But the social aspects of vaping drives young people to use Juul and other e-cigarettes, according to nearly two-thirds of teens and young adults in a new study. Less than 5% say the availability of fruity flavors drives use of e-cigarettes by members of their generation, and only 10% say addiction does.




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Ultraviolet light exposes contagion spread from improper PPE use

(Florida Atlantic University) Despite PPE use, reports show that many health care workers contracted COVID-19. A novel training technique reinforces the importance of using proper procedures to put on and take off PPE when caring for patients during the pandemic. Researchers vividly demonstrate how aerosol-generating procedures can lead to exposure of the contagion with improper PPE use. The most common error made by the health care workers was contaminating the face or forearms during PPE removal.




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Celebrating a Cultural Centre star

Mozart once called the pipe organ the “king of instruments” and Hong Kong has musical royalty sitting in the heart of Tsim Sha Tsui.

 

It is hard to miss the pipe organ when you are inside the Cultural Centre Concert Hall. With its four manuals, 93 stops and 8,000 pipes, it can produce an exceptional array of timbre and volume.

 

“The pipe organ is the ‘pearl’ of a concert hall,” explained pipe organist Chiu Siu-ling.

 

“Its enormous range of sounds, coupled with a huge variety of tone colours, creates a remarkable musical experience equivalent to that of an orchestra. It is the king of instruments.”

 

Star performer

The four-storey tall pipe organ was hand-made by famed Austrian manufacturer Rieger Orgelbau and installed when the Cultural Centre was built 30 years ago. It has attracted several world-renowned performers to Hong Kong over the years.

 

“When we built it in 1989, it was the first, huge mechanically operated organ in Asia. I think it is still our biggest organ we have ever built in Asia,” Rieger pipe organ maintenance technician Gerhard Pohl said.

 

He added that the instrument is also remarkably versatile.

“There are many organs they are built just for one musical style. On this organ, you can play everything, even jazz music.”

 

Mr Pohl comes to Hong Kong once a year to give the 30-year-old organ its annual health check. In between visits by the manufacturer’s technicians, William Wen ensures the Cultural Centre’s star performer remains in tip-top condition.

 

Top tuner

Mr Wen is Hong Kong’s only pipe organ maintenance technician. He carries out routine checks on the instrument and tunes it every month.

 

“Keeping it in tune is my responsibility. I take care of it.”

 

Mr Wen was one of the first in Hong Kong to learn the instrument in the 1980s. He became interested in pipe organ maintenance after a visit to an organ manufacturing company in Europe.

 

He recalled that in the ‘80s, organists in Hong Kong were few and far between. He was called upon to test the Cultural Centre organ before the grand opening, making him one of the first organists to play it.

 

“It was dark in the hall, so at first, I only noticed the organ’s keys. When I got closer, I was astounded by just how big the instrument was.”

 

Mr Wen takes up to five hours per maintenance visit to thoroughly check the pipes and tune the organ. He explained that the organ is regularly updated and was fitted with an electrical coupler system, providing greater flexibility in switching between lighter and stronger key actions as desired by the player.

 

“It has been updated a few times. In 2010, the organ was installed with an electrical coupler system. I used to get someone to press the keys for me while I would tune it from inside. But now, I just need a mobile phone on which I can tune it by myself.”

 

Musical legacy

To promote organ music and nurture local organists, the Cultural Centre has been organising the “King of the Instruments” Pipe Organ Education Series annually since 1999. Now the programme’s principal instructor, Ms Chiu has been teaching from the outset.

 

“People are not allowed to touch the instrument in a lot of other concert halls, and they seldom hold pipe organ concerts. This is actually not good for the organ. It has to be played to keep it in good condition or the keys and parts will become hard and old. This inspires me teach and let more and more musicians learn and play the instrument,” Ms Chiu explained.

 

More than 300 organists have so far been trained on the Cultural Centre’s organ. But it has also played something other than music - it has played Cupid too.

 

Like-minded musicians

Pipe organist Simon Chan met his wife, Shirley Cheng, through the programme.

 

“I joined the Pipe Organ Education Series in 2000. After that, I continued learning the organ with Ms Chiu and eventually became one of the course tutors. I met my wife in 2003 on the course.”

 

Ms Cheng was also a student on the course. She switched majors from information technology to music and that fateful decision led to meeting her husband.

 

“He asked me to watch him play. He was playing a big piece which was powerful and loud, and that was when I fell for his charms.”

 

The couple decided to embark on a life journey together and now hope to pass on their love of music and the pipe organ to their children.

 

“I wish for my kids to learn music too and to find out more about the pipe organ. This instrument brought their father and mother together and I want them to know our story,” said Ms Cheng.

 

The organist-music teacher duo also hopes to share the joy of the pipe organ with the rest of the community.




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SAS Notes for SAS®9 - 34114: Creating a detailed SAS Stored Process Server log by default

The SAS Stored Process Server does not create a detailed log file by default. However, you can create a detailed SAS Stored Process Server log file (that will contain information about all of the code that was executed) by using this approach. AUTO




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Germline genomic profiles of children, young adults with solid tumors to inform managementand treatment

(Cleveland Clinic) A new Cleveland Clinic study demonstrates the importance of genetics evaluation and genetic testing for children, adolescents and young adults with solid tumor cancers. The study was published today in Nature Communications.




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Focused ultrasound opening brain to previously impossible treatments

(University of Virginia Health System) Focused ultrasound, the researchers hope, could revolutionize treatment for conditions from Alzheimer's to epilepsy to brain tumors -- and even help repair the devastating damage caused by stroke.




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Cool Met Stuff, rainstorms, Hong Kong, summer, loss of property, casualties, reviews, extreme torrential rain

Every summer, rainstorms occur in Hong Kong occasionally, leading to loss of property or even casualties.




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Public health training in climate change: What are prospective employers thinking?

(Columbia University's Mailman School of Public Health) Researchers found that 92 percent of employers who responded to a survey on climate change and public health reported need for public health professionals with training in climate change will very likely increase in the next 5 to 10 years. While graduates of public health programs who focus on climate change are in demand in the current job market, these positions appear to be just a small proportion of the total number of jobs available in public health.




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Disappearance of animal species takes mental, cultural and material toll on humans

(American Friends of Tel Aviv University) The research reveals that hunter-gatherer societies expressed a deep emotional and psychological connection with the animal species they hunted, especially after their disappearance. The study will help anthropologists and others understand the profound environmental changes taking place in our own lifetimes.




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Deformed skulls in an ancient cemetery reveal a multicultural community in transition

(PLOS) The ancient cemetery of Mözs-Icsei d?l? in present-day Hungary holds clues to a unique community formation during the beginnings of Europe's Migration Period, according to a study published April 29, 2020 in the open-access journal PLOS ONE by Corina Knipper from the Curt-Engelhorn-Center for Archaeometry, Germany, István Koncz, Tivadar Vida from the Eötvös Loránd University, Budapest, Hungary and colleagues.




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Cultivating cooperation through kinship

(University of Chicago Press Journals) Extensive cooperation among biologically unrelated individuals is uniquely human. It would be surprising if this uniqueness were not related to other uniquely human characteristics, yet current theories of human cooperation tend to ignore the human aspects of human behavior. This paper presents a theory of cooperation that draws on social, cultural, and psychological aspects of human uniqueness for which current theories have little or no explanation.




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Demographic expansion of several Amazonian archaeological cultures by computer simulation

(Universitat Pompeu Fabra - Barcelona) Expansions by groups of humans were common during prehistoric times, after the adoption of agriculture. Among other factors, this is due to population growth of farmers which was greater than of that hunter-gatherers. We can find one example of this during the Neolithic period, when farming was introduced to Europe by migrations from the Middle East.




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Alternative resupply plan for RV Polarstern now in place

(Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research) Thanks to the support of additional German research vessels, the MOSAiC expedition will continue, despite the coronavirus pandemic. The new team will start in May.




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First results from NASA's ICESat-2 mission map 16 years of melting ice sheets

(University of Washington) By comparing new measurements from NASA's ICESat-2 mission with the original ICESat mission, which operated from 2003 to 2009, scientists were able to measure precisely how the Greenland and Antarctic ice sheets have changed over 16 years.




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Multiple flooding sources threaten Honolulu's infrastructure

(University of Hawaii at Manoa) In a study published in Scientific Reports, researchers at the University of Hawai'i at Mānoa, found in the next few decades, sea level rise will likely cause large and increasing percentages of land area to be impacted simultaneously by the three flood mechanisms. Further, they found direct marine inundation represents the least extensive--only three percent of the predicted flooding, while groundwater inundation represents the most extensive flood source.




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Citizen-science project measures impact of coronavirus pandemic on mental health

What impact has the lockdown had on our mental health, and what determines how people cope with isolation?




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AGS honors Dr. John B. Murphy for pioneering work to build a better health workforce

(American Geriatrics Society) The American Geriatrics Society (AGS) today announced that John B. Murphy, MD, a clinician, educator, and administrator working to embed geriatrics education in the fabric of medical curricula and clinical operations will be honored with the 2020 Dennis W. Jahnigen Award celebrating work to train health professionals in the care we all need as we age.




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Geriatrics experts award high honor to visionary organization: West Health

(American Geriatrics Society) For only the second time in its near 80-year history, the American Geriatrics Society (AGS) will award one of its highest honors typically reserved for individuals to West Health, a family of nonprofit organizations dedicated to lowering healthcare costs to enable older adults to successfully age in place.




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Position statement addresses difficult issue: allocating scare resources in COVID-19 era

(American Geriatrics Society) The COVID-19 pandemic has placed unprecedented pressure on societies worldwide, given the pandemic's rapid, often deadly spread. In health care, the pandemic has raised the pressing question of how society should allocate scarce resources during a crisis. This is the question experts addressed today in a new position statement published by the American Geriatrics Society (AGS) in the Journal of the American Geriatrics Society (DOI: 10.1111/jgs.16537).




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Addressing Health Literacy and Numeracy to Improve Diabetes Education and Care

Richard O. White
Oct 1, 2010; 23:238-243
Articles




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A High Level of Patient Activation Is Observed But Unrelated to Glycemic Control Among Adults With Type 2 Diabetes

Robert Mayberry
Jul 1, 2010; 23:171-176
Feature Articles




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Management of Type 1 Diabetes in Older Adults

Ruban Dhaliwal
Feb 1, 2014; 27:9-20
Research to Practice




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Diabetes Self-Management Education for Older Adults: General Principles and Practical Application

Emmy Suhl
Oct 1, 2006; 19:234-240
Articles




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Insulin-Related Knowledge Among Health Care Professionals in Internal Medicine

Rachel L. Derr
Jul 1, 2007; 20:177-185
Feature Articles




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Cultural Barriers to Care: Inverting the Problem

Toni Tripp-Reimer
Jan 1, 2001; 14:
Articles




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Self-Management Goal Setting in a Community Health Center: The Impact of Goal Attainment on Diabetes Outcomes

Daren R. Anderson
Apr 1, 2010; 23:97-105
Feature Articles




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Content creators being left out - Online fun and frolic but no royalties

As online parties continue to rise, the question of how artistes and other musicians will get paid from these virtual sessions becomes even more pertinent. During an online forum held by the Jamaica Reggae Industry Association (JaRIA) yesterday...




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J’can healthcare worker dies from COVID-19-related complications

Antoniette Bryden has fond memories of her mother, Arlene Reid, 51, a healthcare worker originally from Yallahs, St Thomas, who died of COVID-19 in Brampton, Ontario, Canada, on April 27. Reid, a personal support worker (PSW) who worked part-time...




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It’s becoming depressing - Mother enduring long wait for newborn’s coronavirus results

A Manchester mother is pleading with the authorities to provide her with the results of COVID-19 tests done on her and her week-old baby. The woman claims that she has been in isolation in hospital since April 27, a day after she gave birth to...




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It felt like prison - Cruise ship worker happy to be home

"It felt like prison." Those are the exact words of Jermaine who returned to the island yesterday after he was stranded on a cruise ship for 56 days in South Hampton, United Kingdom. "Bwoy we are out of prison ... it was rough mentally. They...




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Alumni and Students From Greater China Donate PPE to NY Healthcare Workers Desperate for Gear

As the pandemic ebbed in China, alumni from the region raised more than $2.1 million to send crucial protective gear to New York healthcare workers.




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Alumni Food Entrepreneurs Team Up to Feed NYC Healthcare Workers

Fundraising efforts, along with a generous donation from Beyond Meat, founded by Ethan Brown ’08, helps restaurant P.S. Kitchen, owned by April Tam Smith ’10 and Graham Smith ’21, provide meals to healthcare workers.




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Bolton’s Attack on the International Criminal Court May Backfire

20 September 2018

Dr Max du Plessis SC

Associate Fellow, International Law Programme
The US national security advisor’s recent threats look damaging but they may in fact strengthen support for the ICC from other states.

2018-09-20-Bolton.jpg

John Bolton speaks to the Federalist Society on 10 September. Photo: Getty Images.

On 10 September, US National Security Advisor John Bolton used his first major speech since joining the White House to attack the International Criminal Court’s (ICC) potential investigation of American personnel in Afghanistan. The ‘American patriots’, as Bolton describes them, are being investigated for potential torture and ill-treatment of detainees, mostly in 2003 and 2004, during the United States-led invasion of the country.

Bolton has a long history of opposition to the ICC. Although the US signed the ICC Statute under president Bill Clinton, it was ‘unsigned’ by Bolton, then an under-secretary of state in the George W Bush administration.

And when the court first opened its doors in 2002, Bolton helped secure, in what he described on 10 September as one of his ‘proudest achievements’, around 100 bilateral agreements with other countries to prevent them from delivering US personnel to the ICC. Those agreements were often extracted under pressure, with the US threatening to cut off military and other aid to countries that refused to sign.

In recent years under the Obama administration, relations between the US and the ICC improved, and the US offered help and support to the court. Bolton’s attack is aimed at reversing those gains – with measures aimed directly at the court and its staff.

These include: (i) negotiating ‘even more binding, bilateral agreements to prohibit nations from surrendering US persons to the ICC’; (ii) banning ICC judges and prosecutors from entering the US, sanctioning their funds in the US financial system and prosecuting them in the US criminal courts (and doing the ‘same for any company or state that assists an ICC investigation of Americans’); and (iii) ‘taking note if any countries cooperate with ICC investigations of the United States and its allies, and remember[ing] that cooperation when setting US foreign assistance, military assistance and intelligence sharing levels’.

These are serious threats – they would potentially undermine the work of a court that is designed to prosecute the world’s worst crimes. The ICC prosecutor and its judges would be barred entry from the US to attend to vital work of the court.

Some of that work, ironically, is at the behest of the US. For instance, two of the UN Security Council’s referrals to the ICC, one in relation to atrocities committed in Sudan, the other in respect of the crimes committed by Muammar Gaddafi in Libya, were referred with US support. 

Also, the meetings of the ICC Assembly of States Parties are held each year at UN headquarters in New York. Those meetings may have to be held elsewhere if the ICC judges and staff are under threat of arrest.

In the case of the potential torture linked to operations in Afghanistan, the ICC has not been acting on its own initiative in investigating. For example, the Center for Constitutional Rights submitted ‘victim’s representations’ to the ICC on behalf of two of their clients, Sharqawi Al Hajj and Guled Hassan Duran, emphasizing the importance of an ICC investigation of US officials for serious crimes arising out of post-9/11 detention and interrogations.

According to the center, both Al Hajj and Duran were detained by the CIA in black sites or 'proxy-detention' by other countries, tormented and tortured.

Although the US is not a party to the ICC Statute, Afghanistan is, and therefore the court has jurisdiction over US nationals who allegedly committed atrocities in Afghanistan. And it should be noted that the investigation includes pursuing any atrocities committed by the Taliban and Afghan security forces during the same period.

So the basis for attacking the work of the ICC based on this is shaky, and Bolton’s threats raise a number of important international law questions going forward. 

For one, they may be unlawful retaliatory steps, given that the US has obligations to accord at least some privileges and immunities to judges and other personnel of the ICC under the 1947 UN Headquarters Agreement between the UN and US. Counter-measures might be considered by member states of the ICC, either alone, or collectively. 

In this regard, Bolton’s comments about the EU will not go unnoticed: he suggests Europe is a region where ‘the global governance dogma is strong’. The US may yet come to learn just how strong that ‘dogma’ is.

With US abstention from the ICC, the opening remains for Europe and other regions to position themselves at the heart of the international criminal justice regime, thereby – as in response to the US attitude towards climate change – building a network of partnerships with other like-minded nations to compensate for US disengagement.

Further, while the ICC has many critics, and could be improved as an institution, Bolton’s speech may have the effect of galvanizing support for the world’s first permanent international criminal court. That could be a good thing for the court, which is sorely in need of support for its work.

Whatever concerns states may have about the ICC, they may be outweighed by a mutual desire to stand up to perceived bullying by the Trump administration, in favour of the international rule of law. 




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Engage China to Uphold Multilateralism – But Not at Any Cost

12 June 2019

Harriet Moynihan

Senior Research Fellow, International Law Programme
Where China’s interests align with those of the international community, there are opportunities for the country’s influence and economic power to strengthen the rules-based international order. Where they do not, states that traditionally support that order should join together to push back.

2019-02-01-China.jpg

Students holding Chinese national flags watch the live broadcast of the 40th anniversary celebration of China's reform and opening-up at Huaibei Normal University on 18 December. Photo: Getty Images.

China’s adherence to the rules-based international system is selective, prioritizing certain rules in favour of others. States supportive of that ‘system’ – or, as some argue, systems[1] – should identify areas of mutual strategic interest so that they can draw China further into the global rules-based order and leverage China as a constructive player that potentially also contributes to improvements in such areas. This is particularly apposite at a time when the US is in retreat from multilateralism and Russia seems bent on disrupting the rules-based international order.

Supportive player

There are many reasons for actively engaging with China on mutual areas of interest. China is a committed multilateralist in many areas, recognizing that often international cooperation and frameworks hold the key to its domestic problems, for example in the fields of environmental sustainability and financial regulation.

China’s economic power is valuable in upholding international institutions: China is the UN’s third-largest donor (after the US and Japan) at a time when the UN is facing budgetary shortfalls. China is also the second-highest contributor to the UN peacekeeping budget, and the largest contributor of peacekeeping forces among the five permanent members of the UN Security Council.

China also has a valuable role to play in the settlement of international disputes over trade and investment. China is a big supporter of the World Trade Organization (WTO)’s dispute settlement mechanism, and one of its most active participants;[2] China is currently playing an active role in negotiations to save the WTO’s appellate mechanism from folding in the wake of the US’s refusal to nominate new judges.

The last 15 years have also seen a major shift in Chinese attitudes to investment arbitration, from a general suspicion and limitation of arbitration rights to broad acceptance and incorporation of such rights in China’s trade and investment treaties. China is actively engaged in multilateral negotiations through the UN Commission on International Trade Law (UNCITRAL) on reforms to investor–state dispute settlement.

China has shown leadership on global climate change diplomacy, urging nations to remain committed to the Paris Agreement in the wake of the US decision to pull out, and has been an important interlocutor with the UK and the EU on these issues. As a strong supporter of the Paris Agreement, but also as the world’s top emitter of carbon dioxide, China has a crucial role to play in pushing forward implementation of the Paris targets. Despite its high emissions, China remains one of the few major economies on track to meet its targets,[3] giving it greater leverage to peer review other parties’ efforts.

A recent report by the UK parliament’s Foreign Affairs Committee (FAC), on China and the rules-based international order, noted that where a body of trust and goodwill is developed with China, there is the possibility of discovering interests that coincide and the ability to work together on issues mutually regarded as of global importance. The report refers to a number of success stories from UK partnership with China in multilateral forums, including in counterproliferation and global health.[4]

Developing areas of global governance

As well as working with the current system, China is increasingly involved in the shaping of newer areas of international law – whether it be submissions to the International Tribunal for the Law of the Sea (ITLOS) on procedural rules for the emerging deep-sea mining regime or pitching for a greater role in Arctic governance.[5]

This enthusiasm should be harnessed to promote the international rule of law, but at the same time there needs to be recognition of the strategic goals that drive China’s engagement. China’s interest in the Arctic, while including the desire to protect its ecology and environment, is also about access to marine resources, as well as about the Arctic’s strategic potential for China’s military.

China’s submissions to ITLOS on the rules of procedure for deep-sea mining are constructive, but also reflect an ambition to secure first-mover advantage when commercial mining eventually takes place. Like other major powers working in this policy area, China’s actions are guided by self-interest, but that doesn’t mean its goals can’t be pursued through multilateral rules.

China is also interested in creating new international structures and instruments that further its strategic aims. For example, with Russia (through the Shanghai Cooperation Organisation) it has proposed an International Code of Conduct for Information Security in the UN.[6]

China is also pondering an array of options for dispute-resolution mechanisms for its Belt and Road projects, including the possibility of an Asian version of the international Convention on the Settlement of Investment Disputes, which might sit under the auspices of the Asian Infrastructure Investment Bank (AIIB).[7]

The creation of new instruments and institutions need not be a threat to the rules-based international order in itself. We have already seen a combination of the creation of parallel complementary regimes alongside the reform of existing institutions, for example in development financing through the AIIB or the New Development Bank (often referred to as the ‘BRICS Bank’); these two banks are relatively conventionally structured along the lines of Western-dominated institutions, albeit with greater Chinese control. Based on these examples, selective adaptation seems more likely than a hostile ‘Eastphalian’ takeover.[8]

Risks

There is, however, a real risk that in certain areas China may promote a rival authoritarian model of governance, assisted by an opportunistic convergence with Russia on issues such as human rights, development and internet governance. In areas where China’s core interests clash with those of the rules-based international order, China has shown itself to be unbending, as in its refusal to abide by the July 2016 decision of the Permanent Court of Arbitration in its dispute with the Philippines over the South China Sea.[9]

China is becoming more assertive at the UN, but while it seeks to project itself there as a responsible emerging global leader, it is promoting a vision that weakens international norms of human rights, transparency and accountability,[10] while also carrying out practices domestically that raise serious human rights concerns (not least the detention of hundreds of thousands of Uighurs in re-education camps in Xinjiang).[11]

China’s increased dominance geographically and geopolitically through its Belt and Road infrastructure projects carries with it a number of social and economic risks, including smaller states becoming trapped in unsustainable financial debts to China.

But at a recent Chatham House conference on Asia and international law, participants highlighted the limitations on how far China can shape an alternative governance model.[12] China currently lacks soft power, cultural power and language power, all of which are needed in order to embed an alternative model abroad. China also currently lacks capacity and confidence to build coalitions with other states in the UN.

Where it has tried to get buy-in from the international community for its new institutions, such as the China International Commercial Court (CICC) announced in July 2018, there has been scepticism about the standards to be applied.[13] Unless the court can demonstrate sufficient due process, international parties are likely to prefer other centres with a strong reputation for upholding the rule of law, such as those in London, Dubai and Singapore.

Where China does promote its own governance model at the expense of the rules-based international order, states are starting to push back, often in concert. EU member states so far have adopted a joined-up approach to the Belt and Road Initiative. With the exception of Italy, they have refused to sign a Memorandum of Understanding on participation unless China provides much greater transparency on its compliance with international standards.

The EU also recently presented a coordinated response to China on the situation in Xinjiang.[14] Similarly, members of the so-called ‘Five Eyes’ intelligence-sharing alliance (comprising Australia, Canada, New Zealand, the UK and the US) have acted together in relation to certain incidents of cyber interference attributed to China.[15]

There are also signs of pushback from smaller states closer to home in relation to challenges to national sovereignty, debt diplomacy and financial viability arising from Belt and Road projects. The Sri Lankan government recently reversed the award of a $300 million housing deal to China, instead opting for a joint venture with an Indian company.

China has been downscaling its investments as a way to counter some of the backlash it has received: the most recent Belt and Road summit put forward a more modest set of aspirations. This suggests that there is some scope for states to stand up to China and use leverage to secure better deals.

Many international institutions have been Western-dominated for years;[16] China, together with many emerging and middle powers, has felt for some time that the international architecture does not reflect the world we live in. Given that context, states that champion the rules-based international order should acknowledge China’s desire to update the international order to reflect greater multipolarity, globalization and technological change, while being clear-eyed about their engagement with China. This involves investing in a proper understanding of China and how it works.[17]

Where possible, cooperation with China should lead to outcomes that are backed up by international standards and transparency. The above-mentioned FAC report cites evidence that the UK’s support, and that of other developed countries, had a positive impact in shaping the governance and standards of the AIIB.[18] China has brought in international experts to advise on disputes before the CIIC, which may reassure would-be litigants.

China’s relationship with the rules-based international order needs to be assessed pragmatically and dynamically. China can be a valuable partner in many areas where its objectives are closely aligned with those of the international community – from trade to climate change to peacekeeping.

But where the country’s core interests are at odds with those of the wider international community, an increasingly confident China will strongly resist pressure, including on the South China Sea and human rights. In these areas, states supportive of international law can most powerfully push back through alliances and by ensuring that their own core values are not compromised in the interests of economic benefits.

What needs to happen

  • China’s rising power and selective commitment to multilateralism make it a potentially influential ally in modernizing international governance.
  • China is increasingly involved in shaping newer areas of international law. This enthusiasm could be harnessed in the service of institutional development and reform.
  • Other states should identify areas of mutual strategic interest where China may offer a constructive role, including dispute settlement, health and climate change.
  • However, engagement must not ignore the strategic calculations that drive China’s agenda, or its poor record on civil and political rights, transparency and accountability.
  • Cooperation with China should lead to outcomes that are backed up by international standards and transparency.
  • Where China’s actions undermine the rules-based international order, coordinated action by states supportive of that order is likely to be more effective than acting individually.

Notes

[1] Chalmers, M. (2019), Which Rules? Why There is No Single ‘Rules-Based International System’, RUSI Occasional Paper, April 2019, London: Royal United Services Institute, https://rusi.org/occasional-papers/Which-Rules-Why-There-Is-No-Single-Rules-Based-International-System.

[2] See, for example, Moynihan, H. (2017), China’s Evolving Approach to International Dispute Settlement, Briefing, London: Royal Institute of International Affairs, https://www.chathamhouse.org/publication/chinas-evolving-approach-international-dispute-settlement.

[3] UN Environment (2018), Emissions Gap Report 2018, p. XVII, https://www.unenvironment.org/resources/emissions-gap-report-2018.

[4] House of Commons Foreign Affairs Committee (2019), China and the Rules-Based International System: Sixteenth Report of Session 2017–19, p. 32, https://publications.parliament.uk/pa/cm201719/cmselect/cmfaff/612/612.pdf.

[5] Moynihan, H. (2018), ‘China Expands Its Global Governance Ambitions in the Arctic’, Expert Comment, 15 October 2018, https://www.chathamhouse.org/expert/comment/china-expands-its-global-governance-ambitions-arctic.

[6] Updated version proposed 9 January 2015.

[7] Moynihan, H. (2018), ‘Exploring Public International Law Issues with Chinese Scholars – Part Four’, Meeting Summary, 3 June 2018, https://www.chathamhouse.org/publication/exploring-public-international-law-issues-chinese-scholars-part-four.

[8] Chatham House (2019, forthcoming, ‘Security and Prosperity in the Asia-Pacific: The Role of International Law’, conference summary, https://www.chathamhouse.org/event/security-and-prosperity-asia-pacific-role-international-law.

[9] Permanent Court of Arbitration Case No. 2013-19 (Philippines v China), Award of 12 July 2016, https://pca-cpa.org/wp-content/uploads/sites/6/2016/07/PH-CN-20160712-Award.pdf.

[10] Piccone, T. (2018), China’s Long Game on Human Rights at the United Nations, Washington, DC: Brookings Institution, https://www.brookings.edu/wp-content/uploads/2018/09/FP_20181009_china_human_rights.pdf.

[11] Wye, R. (2018), ‘‘The entire Uyghur population is seemingly being treated as suspect’: China’s persecution of its Muslim minority’, LSE Religion and Global Society blog, 18 September 2018, https://blogs.lse.ac.uk/religionglobalsociety/2018/09/the-entire-uyghur-population-is-seemingly-being-treated-as-suspect-chinas-persecution-of-its-muslim-minority/.

[12] Chatham House (2019, forthcoming, ‘Security and Prosperity in the Asia-Pacific: The Role of International Law’.

[13] Walters, M. (2018), ‘Jury is out over China’s new commercial court, say lawyers’, Law Society Gazette, 1 November 2018, https://www.lawgazette.co.uk/law/jury-is-out-over-chinas-new-commercial-court-say-lawyers/5068125.article.

[14] The Economist (2019), ‘Hope remains for Western solidarity. Look at embassies in Beijing’, 17 April 2019, https://www.economist.com/china/2019/04/20/hope-remains-for-western-solidarity-look-at-embassies-in-beijing.

[15] In December 2018, the Five Eyes attributed the activities of a Chinese cyber espionage group targeting intellectual property and sensitive commercial property to China’s Ministry of State Security.

[16] Roberts, A. (2017), Is International Law International?, Oxford: Oxford University Press.

[17] Parton, C. (2019), China–UK Relations: Where to Draw the Border Between Influence and Interference?, RUSI Occasional Paper, February 2019, London: Royal United Services Institute, p. 30, https://rusi.org/publication/occasional-papers/china-uk-relations-where-draw-border-between-influence-and.

[18] House of Commons Foreign Affairs Committee (2019), China and the Rules-Based International System, p. 15.

This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization.




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MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates [Lipids]

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.




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Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity

Mona Radwan
Apr 1, 2020; 19:640-654
Research




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Cybersecurity in the Commonwealth: Building the Foundations of Effective National Responses in the Caribbean

Invitation Only Research Event

8 March 2019 - 9:00am to 5:30pm

Bridgetown, Barbados

Event participants

Joyce Hakmeh, Cyber Research Fellow, International Security Department, Chatham House

This workshop is the second in a series in the 'Implementing the Commonwealth Cybersecurity Agenda' project. The workshop aims to provide a multi-stakeholder pan-Commonwealth platform to discuss how to take the implementation of the 'Commonwealth Cyber Declaration' forward with a focus on the second pillar of the declaration – building the foundations of an effective national cybersecurity response with eight action points. 

As such, the workshop gathers different project implementers under the UK Foreign and Commonwealth Office’s Cyber Programme, in addition to other key relevant stakeholders from the global level, to explore ongoing initiatives which aim to deliver one or more of pillar two’s action points.

The workshop addresses issues from a global perspective and a Commonwealth perspective and will include presentations from selected partners from different Commonwealth countries.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Cyber Governance in the Commonwealth: Towards Stability and Responsible State Behaviour in Cyberspace

Invitation Only Research Event

7 October 2019 - 10:30am to 5:30pm

Addis Ababa, Ethiopia

This roundtable is part of a series under the project, 'Implementing the Commonwealth Cybersecurity Agenda', funded by the UK Foreign and Commonwealth Office (FCO). The roundtable aims to provide a multi-stakeholder, pan-Commonwealth platform to discuss how to implement the Commonwealth Cyber Declaration with a focus on its third pillar 'To promote stability in cyberspace through international cooperation'.

In particular, the roundtable focuses on points 3 and 4 of the third pillar which revolve around the commitment to promote frameworks for stability in cyberspace including the applicability of international law, agreed voluntary norms of responsible state behaviour and the development and implementation of confidence-building measures consistent with the 2015 report of the UNGGE. 

The workshop also focuses on the commitment to advance discussions on how existing international law, including the Charter of the United Nations and applicable international humanitarian law, applies in cyberspace.

The roundtable addresses the issue of global cyber governance from a Commonwealth perspective and will also include a discussion around the way forward, the needed capacity of the different Commonwealth countries and the cooperation between its members for better cyber governance.

Participants include UNGGE members from Commonwealth countries in addition to representatives to the UN Open-Ended Working Group from African countries as well as members from academia, civil society and industry.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Trump’s Threat to Target Iran’s Cultural Heritage Is Illegal and Wrong

7 January 2020

Héloïse Goodley

Army Chief of General Staff Research Fellow (2018–19), International Security
Targeting cultural property is rightly prohibited under the 1954 Hague Convention.

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Donald Trump at Mar-a-Lago in December. Photo: Getty Images

As tensions escalate in the Middle East, US President Donald Trump has threatened to strike targets in Iran should they seek to retaliate over the killing of Qassem Soleimani. According to the president’s tweet, these sites includes those that are ‘important to Iran and Iranian culture’.

Defense Secretary Mark Esper was quick on Monday to rule out any such action and acknowledged that the US would ‘follow the laws of armed conflict’. But Trump has not since commented further on the matter.

Any move to target Iranian cultural heritage could constitute a breach of the international laws protecting cultural property. Attacks on cultural sites are deemed unlawful under two United Nations conventions; the 1954 Hague Convention for the Protection of Cultural Property during Armed Conflict, and the 1972 UNESCO World Heritage Convention for the Protection of the World Cultural and Natural Heritage.

These have established deliberate attacks on cultural heritage (when not militarily necessary) as a war crime under the Rome Statute of the International Criminal Court in recognition of the irreparable damage that the loss of cultural heritage can have locally, regionally and globally.

These conventions were established in the aftermath of the Second World War, in reaction to the legacy of the massive destruction of cultural property that took place, including the intense bombing of cities, and systematic plunder of artworks across Europe. The conventions recognize that damage to the cultural property of any people means ‘damage to the cultural heritage of all mankind’. The intention of these is to establish a new norm whereby protecting culture and history – that includes cultural and historical property – is as important as safeguarding people.

Such historical sites are important not simply as a matter of buildings and statues, but rather for their symbolic significance in a people’s history and identity. Destroying cultural artefacts is a direct attack on the identity of the population that values them, erasing their memories and historical legacy. Following the heavy bombing of Dresden during the Second World War, one resident summed up the psychological impact of such destruction in observing that ‘you expect people to die, but you don’t expect the buildings to die’.

Targeting sites of cultural significance isn’t just an act of intimidation during conflict. It can also have a lasting effect far beyond the cessation of violence, hampering post-conflict reconciliation and reconstruction, where ruins or the absence of previously significant cultural monuments act as a lasting physical reminder of hostilities.

For example, during the Bosnian War in the 1990s, the Old Bridge in Mostar represented a symbol of centuries of shared cultural heritage and peaceful co-existence between the Serbian and Croat communities. The bridge’s destruction in 1993 at the height of the civil war and the temporary cable bridge which took its place acted as a lasting reminder of the bitter hostilities, prompting its reconstruction a decade later as a mark of the reunification of the ethnically divided town.

More recently, the destruction of cultural property has been a feature of terrorist organizations, such as the Taliban’s demolition of the 1,700-year-old Buddhas of Bamiyan in 2001, eliciting international condemnation. Similarly, in Iraq in 2014 following ISIS’s seizure of the city of Mosul, the terrorist group set about systematically destroying a number of cultural sites, including the Great Mosque of al-Nuri with its leaning minaret, which had stood since 1172. And in Syria, the ancient city of Palmyra was destroyed by ISIS in 2015, who attacked its archaeological sites with bulldozers and explosives.

Such violations go beyond destruction: they include the looting of archaeological sites and trafficking of cultural objects, which are used to finance terrorist activities, which are also prohibited under the 1954 Hague Convention.

As a war crime, the destruction of cultural property has been successfully prosecuted in the International Criminal Court, which sentenced Ahmad Al-Faqi Al-Mahdi to nine years in jail in 2016 for his part in the destruction of the Timbuktu mausoleums in Mali. Mahdi led members of Al-Qaeda in the Islamic Maghreb to destroy mausoleums and monuments of cultural and religious importance in Timbuktu, irreversibly erasing what the chief prosecutor described as ‘the embodiment of Malian history captured in tangible form from an era long gone’.

Targeting cultural property is prohibited under customary international humanitarian law, not only by the Hague Convention. But the Convention sets out detailed regulations for protection of such property, and it has taken some states a lot of time to provide for these.

Although the UK was an original signatory to the 1954 Hague Convention, it did not ratify it until 2017, introducing into law the Cultural Property (Armed Conflicts) Act 2017, and setting up the Cultural Protection Fund to safeguard heritage of international importance threatened by conflict in countries across the Middle East and North Africa.

Ostensibly, the UK’s delay in ratifying the convention lay in concerns over the definition of key terms and adequate criminal sanctions, which were addressed in the Second Protocol in 1999. However, changing social attitudes towards the plunder of antiquities, and an alarming increase in the use of cultural destruction as a weapon of war by extremist groups to eliminate cultures that do not align with their own ideology, eventually compelled the UK to act.

In the US, it is notoriously difficult to get the necessary majority for the approval of any treaty in the Senate; for the Hague Convention, approval was achieved in 2008, following which the US ratified the Convention in 2009.

Destroying the buildings and monuments which form the common heritage of humanity is to wipe out the physical record of who we are. People are people within a place, and they draw meaning about who they are from their surroundings. Religious buildings, historical sites, works of art, monuments and historic artefacts all tell the story of who we are and how we got here. We have a responsibility to protect them.




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The Commonwealth Cyber Declaration: Achievements and Way Forward

Invitation Only Research Event

4 February 2020 - 9:15am to 5:30pm

Chatham House, London

In April 2018, the Commonwealth Heads of Government Meeting (CHOGM), held in London, saw the creation and the adoption of the Commonwealth Cyber Declaration. The declaration outlines the framework for a concerted effort to advance cybersecurity practices to promote a safe and prosperous cyberspace for Commonwealth citizens, businesses and societies. 

The conference will aim to provide an overview on the progress made on cybersecurity in the Commonwealth since the declaration was announced in 2018. In addition, it will examine future challenges and potential solutions going forward.

This conference is part of the International Security Programme's project on Implementing the Commonwealth Cybersecurity Agenda and will convene a range of senior Commonwealth representatives as well as a selection of civil society and industry stakeholders. This project aims to develop a pan-Commonwealth platform to take the Commonwealth Cyber Declaration forward by means of a holistic, inclusive and representative approach.

Please see below meeting summaries from previous events on Cybersecurity in the Commonwealth:  

Attendance at this event is by invitation only. 

Esther Naylor

Research Assistant, International Security Programme
+44 (0)20 7314 3628




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Oman’s New Sultan Needs to Take Bold Economic Steps

16 January 2020

Dr John Sfakianakis

Associate Fellow, Middle East and North Africa Programme
The country is in a good regional position, but the economy is at a crossroads.

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Sultan Haitham bin Tariq speaks during a swearing in ceremony as Oman's new leader. Photo: Getty Images.

The transition of power in Oman from the deceased Sultan Qaboos to his cousin and the country’s new ruler, Sultan Haitham bin Tariq, has been smooth and quick, but the new sultan will soon find that he has a task in shoring up the country’s economic position.

Above all, the fiscal and debt profile of the country requires careful management. Fiscal discipline was rare for Oman even during the oil price spike of the 2000s. Although oil prices only collapsed in 2014, Oman has been registering a fiscal deficit since 2010, reaching a 20.6 per cent high in 2016. As long as fiscal deficits remain elevated, so will Oman’s need to finance those deficits, predominately by borrowing in the local and international market.

Oman’s Debt-to-GDP ratio has been rising at a worrying pace, from 4.9 per cent in 2014 to an IMF-estimated 59.8 per cent in 2019. By 2024, the IMF is forecasting the ratio to reach nearly 77 per cent. A study by the World Bank found that if the debt-to-GDP ratio in emerging markets exceeds 64 per cent for an extended period, it slows economic growth by as much as 2 per cent each year.

Investors are willing to lend to Oman, but the sultanate is paying for it in terms of higher spreads due to the underlying risk markets are placing on the rising debt profile of the country. For instance, Oman has a higher sovereign debt rating than Bahrain yet markets perceive it to be of higher risk, making it costlier to borrow. Failure to address the fiscal and debt situation also risks creating pressure on the country’s pegged currency.

If oil revenues remain low, Sultan Haitham will have to craft a daring strategy of diversification and private sector growth. He is well placed for this: Sultan Haitham headed Oman’s Vision 2040, which set out the country’s future development plans and aspirations, the first Gulf country to embark on such an assessment. However, like all vision documents in the Gulf, Oman’s challenge will be implementation.

In the age of climate change, renewable energy is a serious economic opportunity, which Oman has to keep pursuing. If cheap electricity is generated it could also be exported to other Gulf states and to south Asia. In Oman, the share of renewables in total electricity capacity was around 0.5 per cent in 2018; the ambition is to reach 10 per cent by 2025.

However, in order to reach this target, Oman would have to take additional measures such as enhancing its regulatory framework, introducing a transparent and gradual energy market pricing policy and integrating all stakeholders, including the private sector, into a wider national strategy.

Mining could provide another economic opportunity for Oman’s diversification efforts, with help from a more robust mining law passed last year. The country has large deposits of metals and industrial minerals and its mountains could have gold, palladium, zinc, rare earths and manganese.

Oman’s strategic location connecting the Gulf and Indian Ocean with east Africa and the Red Sea could also boost the country’s economy. The Duqm special economic zone, which is among the largest in the world, could become the commercial thread between Oman, south Asia and China’s ‘Belt and Road Initiative.’

Oman has taken important steps to make its economy more competitive and conducive to foreign direct investment. Incentives include a five-year renewable tax holiday, subsidized plant facilities and utilities, and custom duties relief on equipment and raw materials for the first 10 years of a firm’s operation in Oman.

A private sector economic model that embraces small- and medium-sized enterprises as well as greater competition and entrepreneurship would help increase opportunities in Oman. Like all other Gulf economies, future employment in Oman will have to be driven be the private sector, as there is little space left to grow the public sector.

Privatization needs to continue. Last year’s successful sale of 49 per cent of the electricity transmission company to China’s State Grid is a very positive step. The electricity distribution company as well as Oman Oil are next in line for some form of partial privatization.

The next decade will require Oman to be even more adept in its competitiveness as the region itself tries to find its new bearings. Take tourism for instance; Oman hopes to double its contribution to GDP from around 3 per cent today to 6 per cent by 2040 and the industry is expected to generate half a million jobs by then. Over the next 20 years, Oman will most likely be facing stiff competition in this area not only by the UAE but by Saudi Arabia as well.

The new sultan has an opportunity to embark on deeper economic reforms that could bring higher growth, employment opportunities and a sustainable future. But he has a big task.




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Webinar: Reimagining the Role of State and Non-State Actors in (Re)building National Health Systems in the Arab World

Research Event

22 April 2020 - 1:00pm to 2:00pm

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

As new cases of COVID-19 continue to surge, countries around the world struggle to mitigate the public health and economic effects of the virus. It is becoming increasingly clear that an effective pandemic response requires a whole-of-government, whole-of-society approach. In the Arab world, where health systems are already strained by armed conflicts and displaced populations, a whole-of-society response to the pandemic is particularly critical as countries have become increasingly dependent on non-state actors, notably the private sector, for healthcare provision and any response that includes the state alone may not be sufficient to address the pandemic.

In a recent article, Fadi El-Jardali, argued that while the pandemic will have grave health and economic consequences for years to come, it brings with it a valuable opportunity to re-envision the role of state and non-state actors in strengthening health systems. The article addressed the need for increased collaboration between state and non-state actors, and the rethinking of existing cooperation models to provide quality healthcare services for all.  

In this webinar, part of the Chatham House project on the future of the state in the Middle East and North Africa, Dr El-Jardali will discuss how state and non-state actors can collaborate more effectively to address the shortcomings of national health care systems amidst the pandemic and beyond. The article’s author will share insights on the different capacities available in Arab societies that governments can draw upon to ensure that Universal Health Coverage, equity considerations and social justice are at the core of health systems.

You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Alternatively, you can watch the event live on the MENA Programme Facebook page.

 

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors

Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.




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3-year freedom from progression following 68GaPSMA PET CT triaged management in men with biochemical recurrence post radical prostatectomy. Results of a prospective multi-center trial.

Background: 68Ga PSMA PET CT (PSMA) is increasingly used in men with biochemical recurrence (BCR) post radical prostatectomy (RP), but its longer term prognostic / predictive potential in these men is unknown. The aim of this study was to evaluate the predictive value of PSMA PET for 3 year freedom from progression (FFP) in men with BCR post RP undergoing salvage radiotherapy (sRT). Methods: This prospective multi-center study enrolled 260 men between 2015 and 2017. Eligible patients were referred for PSMA with rising PSA following RP. Management following PSMA was recorded but not mandated. PSMA protocols were standardised across sites and reported prospectively. Clinical, pathological and surgical information, sRT, timing and duration of androgen deprivation (ADT), 3 year PSA results and clinical events were documented. FFP was defined as a PSA rise ≤ 0.2ng/mL above nadir post sRT, with no additional treatment. Results: The median PSA was 0.26ng/mL (IQR 0.15 - 0.59) and follow-up 38 months (IQR 31-43). PSMA was negative in 34.6% (90/260), confined to prostate fossa 21.5% (56/260), pelvic nodes 26.2% (68/260), and distant disease 17.7% (46/260). 71.5% (186/260) received sRT, 38.2% (71/186) to the fossa only, 49.4% (92/186) fossa + pelvic nodes and 12.4% (23/186) nodes alone/SBRT. PSMA was highly predictive of FFP at 3 years following sRT. Overall, FFP was achieved in 64.5% (120/186) of those who received sRT, 81% (81/100) with negative/fossa confined vs. 45% (39/86) for extra fossa disease (p<0.0001). On logistic regression PSMA was more independently predictive of FFP than established clinical predictors, including PSA, T-stage, surgical margin status or Gleason score (P < 0.002). 32% of men with a negative PSMA PET did not receive treatment. Of these, 66% (19/29) progressed, with a mean rise in PSA of 1.59ng/mL over the 3 years. Conclusion: PSMA PET result is highly predictive of FFP at 3 years in men undergoing sRT for BCR following RP. In particular, men with negative PSMA PET or disease identified as still confined to the prostate fossa demonstrate high FFP, despite receiving less extensive radiotherapy and lower rates of additional ADT than those with extra fossa disease.




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Tau PET imaging with 18F-PI-2620 in patients with Alzheimer's disease and healthy controls: a first-in-human study

18F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen’s d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. 18F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R2 > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.




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Pre-treatment 18F-FDG PET/CT Radiomics predict local recurrence in patients treated with stereotactic radiotherapy for early-stage non-small cell lung cancer: a multicentric study

Purpose: The aim of this retrospective multicentric study was to develop and evaluate a prognostic FDG PET/CT radiomics signature in early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic radiotherapy (SBRT). Material and Methods: Patients from 3 different centers (n = 27, 29 and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control (LC). The primary tumour was semi-automatically delineated in the PET images using the Fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. A total of 184 IBSI-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the four institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 (1.7 – 63.4) and 25.5 (7.7 – 57.8) months in training and testing sets respectively. In univariate analysis, none of the clinical variables, 2 PET and 2 CT features were significantly predictive of LC. The best predictive models in the training set were obtained by combining one feature from PET, namely information correlation 2 (IC2) and one from CT (Flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (IC2 and Strength), reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (HR) (p<0.001). The latter model obtained an accuracy of 0.91 (sensitivity 100%, specificity 81%), with a HR undefined (P = 0.023) in the testing set, however other models relying on CT radiomics features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that two radiomic features derived from FDG PET were independently associated with LC in patients with NSCLC undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision-making.