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Why Ethiopia must close its political gender gap

By www.chathamhouse.org
Published On :: Fri, 29 Jul 2022 18:40:47 +0000

Why Ethiopia must close its political gender gap The World Today mhiggins.drupal 29 July 2022

Women urgently need to gain access to high office if the country hopes to survive, say Hilina Berhanu Degefa and Emebet Getachew.

At the end of 2021, Prime Minister Abiy Ahmed’s government announced the formation of a three-year national dialogue to address Ethiopia’s political crisis, looking at the ongoing civil war and conflict, inflation, unemployment, drought and other urgent domestic issues. 

But, while efforts have been made to ensure the participation of women in this dialogue, it must be more than symbolic otherwise gaps in meaningful gender inclusion could have significant implications on the very survival of the country.
 
One of the challenges for meaningful inclusion is that Ethiopia is a highly patriarchal society. Patriarchal norms and practices permeate all aspects of the country’s social, economic and political life. Women constitute over half of the Ethiopian population and represent 41 per cent of the national parliament.

Nevertheless, most political parties, including those with liberal credentials, are exclusively governed by men, with women taking almost no part in key decision-making processes. As a result, women are relegated to the margins of political and economic activities. 

Prime Minister Abiy Ahmed won praise for appointing a gender-balanced cabinet in 2018. By 2021, women accounted for just 36 per cent of positions


Though there has been little systematic study of the structural challenges faced by Ethiopian women in politics, women members of political parties encounter many barriers, including political violence, male-coded norms and sexist discourses across Ethiopian society.
 
The nature and scale of political violence perpetrated against women is particularly disempowering and affects their ability to participate in political spaces.

While attitudes to gender equality, sexual violence and gender discrimination are often trivialized, they remain ever-present threats in women’s lives. As late as 2016, a significant minority of men still believed wife-beating to be justified in certain situations. Even when women overcome social pressure to pursue their political ambitions, patriarchal views and practices within political party structures about the role of women significantly undermine their active participation and engagement. 

The political space is even more inaccessible to women with disabilities and in conflict and climate-related crises such as among internally displaced people and in pastoral communities. Male-coded norms ingrained at both party and community levels remain a significant concern. Specifically, sex in exchange for candidacy, inconsiderate working schedules affecting women with children and denial of access to equal information and financial resources are frequently reported as major internal hurdles among political parties.

Closing the gender gap could offer Ethiopia a new beginning

Many political initiatives designed to tackle these gender imbalances often have been driven by short-term political considerations without proper gender-gap assessment and policy analysis. In most cases, the authorities have viewed gender-targeted reforms as acts of benevolence, dispensed by the government, without adopting the legal and financial measures necessary to ensure sustainability and impact.
 
Take, for example, Abiy’s appointment of a 50:50 gender-balanced cabinet in 2018. At the time, much was made about its transformative potential, with the prime minister attracting widespread global approval. Yet, a cabinet reshuffle in 2021 reduced female representation to 36.3 per cent, with far less scrutiny or accountability.

The proposed national dialogue presents an ideal opportunity for Ethiopian women to begin reshaping attitudes


This indicates that gender equality in Ethiopia is not considered a priority but rather an endeavour for more opportune, ‘stable’ times. Without thorough measures that create the conditions for real change, the aspiration of having a gender-balanced cabinet will always be challenging to translate into lasting equal representation.
 
The proposed national dialogue presents an ideal opportunity for Ethiopian women to begin reshaping attitudes and closing the gender gap through their inclusion and participation in the political process. To do so, three issues must be addressed.
 
First, the varying rights of women need to be consolidated, including on identity, constitutional reform and economic issues .

Second, gender equality considerations must be absorbed into mainstream political discourse at all levels.

Third, the experiences of women in the recent war, other ongoing conflicts and past and lingering legacies of political violence targeting women from specific communities, must be acknowledged and remedied. 

If Ethiopia is indeed serious about addressing its asymmetric gender power dynamics, this national dialogue provides an excellent opportunity to begin the process. Genuine participation of women as independent actors, with their own agency, could offer Ethiopia a new beginning.


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Climbing out of the Chinese debt trap

By www.chathamhouse.org
Published On :: Mon, 01 Aug 2022 07:21:45 +0000

Climbing out of the Chinese debt trap The World Today mhiggins.drupal 1 August 2022

Beijing must play a pivotal role in soothing African economic distress, says Alex Vines.

Poorer countries across the world – including many in Africa – are facing $35 billion in debt-service payments in 2022. According to the World Bank, around 40 per cent of this total is owed to China.

Across the African continent, the economic impacts of the coronavirus pandemic have increased rates of extreme poverty and inequality. Since early 2022 the situation has worsened even further, due to the knock-on effects of spiking inflation and interest rates following the Russian invasion of Ukraine. Shortages of fuel and foodstuffs have caused prices to leap upwards. Urban unrest is on the rise, and African governments are having to make tough economic choices as their budgets are squeezed ever more tightly.

Across the continent, progress on the UN’s Sustainable Development Goals is being jeopardized, and non-energy-producing lower and lower-middle income African governments are struggling to repay their loans.

During the Covid pandemic, the G20 assisted 31 out of 36 eligible African countries with its Debt Service Suspension Initiative (DSSI). Established in May 2020, the DSSI helped countries concentrate their resources on fighting the pandemic and safeguarding the lives and livelihoods of millions of the most vulnerable people before it expired at the end of 2021. From 2022, it has been replaced by the G20’s Common Framework for Debt Treatments.

As the second-largest economy in the world after the United States, and the dominant lender for many African states, China has an important role to play in such initiatives. Beijing still tries to keep a low profile and renegotiate its terms on a bilateral basis – although it did support Angola’s early call for G20 action on an initiative that would fulfil what the DSSI delivered. The challenge is to encourage more consistency and trust in such initiatives, as Chinese officials consider them to be too western-oriented. 
 

China’s lending to Africa peaked in 2016

Contemporary views of Chinese lending in Africa remain coloured by the rapid expansion of Chinese finance from the early 2000s to resource-rich African states, and oil producers in particular. The reality is that much of China’s lending has evolved, and is neither intrinsically predatory nor problematic for African partners – and China increasingly prefers to do business with states it considers to be better run.

In fact, as commodity prices and growth rates declined from 2015, Chinese lending to Africa fell significantly, from a peak of $29.5 billion in 2016 to $7.6 billion in 2019. The socio-economic impact of the pandemic has made this situation worse.

Over the past two decades, Chinese finance has contributed to an infrastructure boom in many African countries

That China has attracted criticism is often due to a lack of transparency in its investments, especially those in Kenya and Zambia. This reputation has not been helped by opaque lending arrangements imposed by Chinese state-owned banks, requiring borrowers to prioritize them for repayment. This could lead to cutbacks in key areas of social spending, with direct impacts on African communities.

Over the past two decades, Chinese finance has contributed to an infrastructure boom in many African countries. Angola, for example, was able to undertake a rapid post-conflict reconstruction of its infrastructure, with new roads and bridges being built across the country. New models of financing are being developed: in Kenya, the new Nairobi expressway was constructed under a $600 million Build-Operate-Transfer model that provides for ownership to revert to the national government after a 30-year concession period.

Chinese companies have helped African countries build and upgrade over 10,000km of railway, around 100,000km of highway, 1,000 bridges and 100 ports, as well as power plants, hospitals and schools.

China’s involvement in African debt has varied considerably between countries and over time. Although in recent years this involvement has been framed in the context of the Belt and Road Initiative, it has for the most part been uncoordinated and unplanned, with credit being offered by competing lenders with links to different elements of the Chinese state.

In recent years, as reports have emerged around the poor quality of some of China’s past lending, the authorities in Beijing have sought greater control over new development lending and have imposed new sustainability requirements. At the same time, African countries have sought to diversify sources of supply for infrastructure contracts beyond China. Loans are generally now on a smaller, more manageable scale.

With the introduction of its Global Development Initiative in September 2021, there are indications that China is moving to a ‘new development paradigm’, with the emphasis on providing flows of foreign direct investment rather than loans and a focus on supporting small and medium-sized enterprises, human capital investments and green development.
 

African debt distress

A paper drawing on expertise from Chatham House’s Africa, Asia and Global Economy and Finance experts will be published before the G20 summit in Bali in November 2022. It examines seven African countries that the World Bank deemed in 2020 to be in most debt distress or at risk of debt distress because of their Chinese stock – Angola, Cameroon, Republic of Congo, Djibouti, Ethiopia, Kenya and Zambia. Two countries – Côte d’Ivoire and South Africa – have received new loans from China and are not in any distress.

The paper observes that a lack of transparency over the nature of the terms agreed by these African governments has led to intense domestic criticism and international accusations that China is seeking control over strategic assets.

China may have fallen into its own debt trap through profligate and uncoordinated lending to Angola and Zambia


In fact, in Angola and Zambia, China may have accidently fallen into its own debt trap through profligate and uncoordinated lending.

Zambia became the first pandemic-era default in 2020 and is seeking relief on $17 billion of external debt. After holding general elections in August 2022, Angola and Kenya will also seek additional debt relief, but both may also seek more funds from the private commercial market because of the slow progress of the G20’s Common Framework – something flagged as a concern by China.

All seven of the countries that are most indebted to China are actively seeking to reduce this financial reliance on Beijing in the future.

China has a pivotal role to play in finding effective solutions to these and other African countries’ debt distress. Improved coordination and cooperation between creditors in China and in other parts the world could enhance the positive impact of multilateral initiatives, such as the Common Framework, which has aimed to bring China and India to the negotiating table along with the IMF, the Paris Club group of creditor nations and private creditors.

So far, Chad, Ethiopia and Zambia are the only African countries to have signed up to the framework since its launch in 2020. Although China is suspicious of the IMF, if African states collectively encouraged Beijing to engage with the Common Framework, it could be improved so as to provide debt relief to those African countries finding it difficult to repay their loans.


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Independent Thinking: War in Tigray, Zaporizhzhia under fire

By www.chathamhouse.org
Published On :: Thu, 24 Nov 2022 15:37:56 +0000

Independent Thinking: War in Tigray, Zaporizhzhia under fire Audio NCapeling 24 November 2022

Episode six of our new weekly podcast examines the ongoing conflict in Ethiopia and the international response to further attacks on Europe’s largest nuclear plant in Ukraine.

In Tigray, the world’s largest armed conflict rages between Ethiopian federal government troops and the Tigray Defence Forces. With estimates placing those killed in the fighting at 600,000, how did Ethiopia, one of Africa’s great success stories, descend into civil war, and what hopes are there for recent peace initiatives?

Meanwhile in Ukraine, all eyes are on Zaporizhzhia, as Europe’s largest nuclear plant continues to be occupied by Russian forces. With fresh reports of explosions near the reactors, how is the international community responding?

Finally, what role does Turkey, a middle power country with great power ambitions, play in both conflicts?

Joining guest host John Kampfner on the podcast this week are Dr Patricia Lewis, director of the International Security programme at Chatham House, Ahmed Soliman, senior research fellow with our Africa programme, and Galip Dalay, associate fellow with our Middle East and North Africa programme.


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Independent Thinking: China in Africa, conflicts in 2023

By www.chathamhouse.org
Published On :: Fri, 13 Jan 2023 09:40:24 +0000

Independent Thinking: China in Africa, conflicts in 2023 Audio NCapeling 13 January 2023

Episode ten discusses Africa and the complex role China plays on the continent, and how the world should be responding to the major conflicts of 2023.

The first episode of 2023 examines Africa and the complex role China plays on the continent as a new Chatham House report highlights 22 African countries suffering from debt distress with Beijing a key creditor to many of them.

China’s new foreign minister Qin Gang is also touring several African states this week and next, with visits planned to Ethiopia, Angola, Gabon, and the headquarters of the African Union (AU).

This week Chatham House also hosted Dr Comfort Ero, president of the International Crisis Group, to discuss ten conflicts to watch in 2023. The panel examines some of the key conflicts mentioned and how the world is responding to them.

Joining Bronwen Maddox on the podcast this week from Chatham House are Dr Alex Vines, director of the Africa programme, Creon Butler, director of the Global Economy and Finance programme, Dr Yu Jie, senior fellow on the Asia-Pacific programme, and Armida van Rij, research fellow with the International Security programme.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.


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China-Africa relations

By www.chathamhouse.org
Published On :: Wed, 18 Jan 2023 11:04:20 +0000

China-Africa relations Explainer jon.wallace 18 January 2023

What are China’s objectives in Africa, how valid is the concept of ‘debt trap’ diplomacy, and what are China’s military ambitions in the region?

A brief history of China-Africa relations

Africa has been crucial to China’s foreign policy since the end of the Chinese civil war in 1947. China supported several African liberation movements during the Cold War, and for every year since 1950 bar one, the foreign minister of the People’s Republic of China (PRC) has first visited an African country.

China’s new foreign minister Qin Gang visited five African countries and the African Union in January 2023. Wang Yi, the former foreign minister, visited 48 African countries and premier Xi Jinping undertook 10 visits to Africa between 2014 and 2020.

China-Africa relations are the bedrock of China’s foreign policy.
 

Chinese foreign minister Qin Gang, speaking in December 2022

In 1971, the votes of African countries were instrumental in winning the PRC control of China’s seat in the UN General Assembly and Security Council – displacing representatives from Chinese nationalist forces, who had been defeated in the civil war and now governed Taiwan.

In the following decades, China’s focus in Africa switched to eliminating all remaining recognition for Taiwan’s government. Burkina Faso, Malawi, Liberia, Senegal and others all switched their recognition from Taiwan to the PRC. Eswatini is the only African nation still to recognize Taiwan’s government in 2023.

In 1999 China created its ‘Going Out’ strategy, which encouraged Chinese companies to invest beyond China.

The strategy was a statement of China’s growing economic might and created a new wave of Chinese engagement in Africa. It was also an important source of employment for Chinese citizens working on new infrastructure projects.

In November 2003 the first tri-annual Forum for China-Africa Cooperation (FOCAC) summit was held in Beijing. FOCAC was created to improve cooperation between China and African states and signalled China’s growing strategic initiative in Africa.

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Chinese president Xi Jinping delivers his speech during the November 2021 China-Africa Cooperation (FOCAC) meeting in Dakar, Senegal, pledging to offer one billion COVID-19 vaccine doses to Africa. Photo by SEYLLOU/AFP via Getty Images.

In 2013, China’s Belt and Road Initiative (BRI) was launched by Xi Jinping, featuring an ambition to reinvigorate the old silk trading route along the East African coast. This should theoretically have seen Chinese investment concentrated in East Africa, but many other African states also sought opportunities through the BRI, making the initiative quickly expand in scope and ambition.

The BRI saw a huge number of signature infrastructure projects built across Asia and Africa, funded by Chinese loans whose size, nature and origin were often opaque. Some African countries became badly exposed to Chinese lending during this period. 

Chinese investment peaked around 2016. Since then, Chinese loans to African governments declined significantly, falling from $28.4 billion in 2016 to $1.9 billion in 2020 – partly due to changing priorities in domestic Chinese politics, and partly due to the apparent difficulty African countries had repaying loans.

China’s investment in Africa

China has taken a position contrary to Western governments in its African investment. It characterizes its loans as mutually beneficial cooperation between developing countries, promising not to interfere in the internal politics of those it loans to.

In this respect it presents itself in contrast to Western countries, who are accused by China and some African governments of arrogant, democratic posturing – often by former colonial powers that looted African resources during the 18th and 19th centuries.

China has learned by doing, and the reality of large-scale investments taught Chinese investors the limits of their approach. For instance, during the South Sudanese civil war, China had to deal with representatives of various forces opposed to the government to maintain the Greater Nile Oil Pipeline, operated by the China National Petroleum Corporation.

China has not made significant efforts to export communist ideology in Africa since the Cold War ended.

China has not made significant efforts to export communist ideology in Africa since the Cold War ended, claiming that Chinese communism could not be replicated outside of China.

However, ideological links exist between the Chinese Communist Party (CCP) and the rulers of a state like Ethiopia, whose Prosperity Party has origins in ‘revolutionary democracy’ and Marxist-Leninism.

China’s National People’s Congress has formal relations with 35 African parliaments and the CCP International Liaison Department (ILD) has relations with 110 political parties in 51 African countries.

Western politicians have increasingly voiced fears that China’s intentions in Africa are predatory, intended to create a network of African states that are obliged to service their debts by offering China access to resources, trade opportunities and locations for military bases.

Debt trap diplomacy

US commentators often describe Chinese policy in Africa as a ‘debt trap’, part of a deliberate strategy to loan unmanageable sums to African countries, draw them into China’s sphere of influence, and force unfair commitments upon them.

Some African nations do have extensive Chinese loans and are suffering from out-of-control debt, exacerbated by the COVID-19 pandemic, the invasion of Ukraine, and high interest rates. But their situations cannot be entirely blamed on Chinese loans. States including Kenya and Zambia have poorly managed their debt to all creditors, not only China.

Meanwhile, other African countries have created realistic, manageable debt arrangements with China without the tremendous risk and uncertainties that characterized some major BRI projects.

China also faces significant problems due to its extensive loans made during the BRI boom period, as it will struggle to force repayment while maintaining its image as a friend of developing nations.

BRI projects were largely uncoordinated and unplanned, with credit offered by competing Chinese lenders. This contradicts the idea of a coherent ‘debt trap’ policy by China.

However, the idea that China may use debt strategically, to expand its influence in the African content and secure access to resources, cannot be completely dismissed. China is an emerging superpower in strategic competition with the US. Building stronger economic relationships in Africa would be a logical step in its aspirations to be a global power.


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Fighting over ‘white gold’: Sesame in Ethiopia and Sudan

By www.chathamhouse.org
Published On :: Mon, 03 Apr 2023 17:57:35 +0000

Fighting over ‘white gold’: Sesame in Ethiopia and Sudan Expert comment LJefferson 3 April 2023

The supply chain of a seemingly innocuous cash crop – sesame – has intersected with transnational conflict dynamics, exacerbating tensions between Ethiopia and Sudan.

Late 2020 saw the beginning of the devastating war in Tigray and the occupation of a disputed region on the Ethiopia–Sudan border – Al Fashaga – by the Sudanese army. These shocks disrupted settled patterns of land ownership and control in both Ethiopia’s volatile north and Sudan’s borderlands, historically the heart of the sesame and oilseed production that is economically vital to both countries.

These seemingly harmless cash crops are now embedded in local, subnational and national political contestations in both countries. Sesame value chains are being reshaped, with power and profits being used to entrench the grip of political and armed actors who are reinforcing new patterns of land control and driving informal and illicit trade – impacting the coping mechanisms of local communities and threatening to fuel further conflict.

Regional rivalries drive contestation over the Ethiopia supply chain

Internal borders between most of Ethiopia’s regions are marked by boundary disputes, which often degenerate into violent conflict. The most important is between the Tigray and Amhara regions. Since the war began in 2020, the Amhara region has annexed vast areas of western and southern Tigray, which the Amhara region claims were taken from them by Tigray 30 years ago, after the Tigray People’s Liberation Front (TPLF) dominated ethnic coalition came to power.

Conflict has exacerbated a steady decline in formal revenues from sesame exports, dropping over $115 million from 2016 to 2021.

Ethiopia’s exports of spices, oilseeds and pulses brought in over half a billion dollars in 2021, roughly a quarter of the country’s total export revenues and second only to coffee. The sector has been rocked by the war in the north, which accounted for much of Ethiopia’s sesame production, with an estimated 500,000 hectares of sesame fields taken out of cultivation during the 2021 growing season. Conflict has exacerbated a steady decline in formal revenues from sesame exports, dropping over $115 million from 2016 to 2021.

Alongside falling production, the previously integrated value chain has been disrupted and decentralized by political fragmentation and land competition between Amharas and Tigrayans. Before the war, the agricultural sector in Western Tigray/Welkait was dominated by Tigrayan business interests, through the TPLF’s regional endowment fund EFFORT, a business conglomerate including subsidiaries such as Guna Trading House, and Hiwot Agricultural Mechanization.

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Two-minute video explainer: Supply chains, land contestation and conflict in the Horn of Africa

The taking of the area by Amhara forces in late 2020 saw the control over agricultural supply chains shift to actors from the Amhara region, amid contestation between regional officials, businessmen and security actors, backed by political elites. Thousands of displaced ethnic Tigrayan inhabitants of the area have been replaced by ethnic Amharas, enticed to settle there by the Amhara regional government’s offer of grants and leases for land which promise better livelihoods. The sesame they farm is now largely exported through informal and illicit channels, with profits used to reinforce de facto regional control.    

But there is also contestation within the Amhara region over the land and sesame supply chain between sub-regional elites from Gojjam, Gondar and indigenous Welkaites. Welkaites, who were marginalized under TPLF rule, believed that by aligning themselves with powerful Amharas they would reclaim land and influence. But this has not been fully realized, with the local administration reliant on Amhara region subsidies, rather than the federal budget. With little support from the federal government, local Welkait officials are strengthening their ties with Eritrea.

The Ethiopian government’s pursuit of peace with Tigray may lead it to turn away from the Amhara region, which could result in a renewed showdown between Amhara and Tigrayan forces.

At the national level, regional contestation over the control over Western Tigray/Welkait feeds into shifting political alliances between the Amhara, Tigrayans and Oromo which threaten the sustainability of the peace agreement struck between the federal government and TPLF in November 2022 – despite efforts by the government to defer the thorny issue.

While the constitutional return of the land to Tigray remains unlikely anytime soon, there is a feeling that Amhara control over Western Tigray/Welkait is no longer certain. The Ethiopian government’s pursuit of peace with Tigray may lead it to turn away from the Amhara region, despite their alliance during and before the war, which could result in a renewed showdown between Amhara and Tigrayan forces.

The prospect of losing territory could also heighten Amhara nationalist claims on Al Fashaga – the loss of which was partly offset by gaining Western Tigray/Welkait – leading to renewed conflagration with Sudan, outside of federal direction. Eritrea’s presence and alliance with Amhara militias remains a concern, given Asmara’s demonstrable ability to inflame tensions.  

Sudan’s securocrats battle over resources to entrench political power

The war in northern Ethiopia was also used opportunistically by the Sudanese Armed Forces (SAF) to take control of the fertile Al Fashaga borderland. This roughly 250 sq km area had been awarded to Sudan when the boundary was initially demarcated by the British in 1903, a ruling that remained contested by Ethiopia. An uneasy truce had seen Ethiopian farmers cultivate the land under nominal Sudanese administration; a settlement that collapsed in 2020 when thousands of predominantly Amhara farmers were evicted.

Local Sudanese farmers have also lost out – with some not compensated for the loss of lands to their own military, with land given to people from other parts of the country, and through lost relationships with Ethiopian farmers, labourers and investors.

The Sudanese military now allegedly controls more than 90 per cent of the disputed areas and security-linked companies and investors have moved into the lucrative sesame sector, re-routing the supply chain, which used to flow largely through Ethiopian markets. These companies are connected to Sudan’s Military Industrial Corporation, a vast conglomerate of business subsidiaries controlled by SAF – which is headed by General Abdel Fattah al-Burhan.

Competition between Sudanese security actors fuels volatile political rivalries, and further entrenches military control of economic resources.

The commander of the paramilitary Rapid Support Forces, General Mohamed Hamdan Dagolo (or Hemedti), also has interests in agriculture, through his family business Al-Junaid. Both sit at the top of Sudan’s Sovereign Council. Hemedti’s competition with Burhan has seen him develop relations with Ethiopia’s prime minister – counter-balanced by recent rapprochement between Abiy and Burhan – as well as senior Amhara leaders, including over business activities.

Moreover, competition between Sudanese security actors fuels volatile political rivalries, and further entrenches military control of economic resources, undermining civilians at a time when pro-democracy forces are seeking to restore a reform-minded government. One of the key challenges for a new civilian government will be to quickly build up a domestic revenue base to compete with the economic heft of the country’s prominent security institutions, which will demand taking on military-controlled holdings in civic sectors such as agriculture, including sesame.

Informal and illicit trade reinforces conflict dynamics

This context has driven the informalization of trade, with cash crops such as sesame increasingly exported outside of formal channels and connected to other illicit cross-border activities between Ethiopia and Sudan. Indications are that sesame production in Western Tigray/Welkait has recovered significantly during the current 2022/23 harvest season. However, rather than contributing much needed currency to soften Ethiopia’s forex crisis, the Amhara elite-controlled supply chain is primarily being used to secure a variety of regional interests.


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FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:15-07:00

Visual Abstract


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Oncologist, Business Leader, and Investor Arie S. Belldegrun Discusses a Career in Innovative Medical Entrepreneurship: A Conversation with Ken Herrmann and Johannes Czernin

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:15-07:00


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[18F]FDG and [68Ga]Ga-FAPI-04-Directed Imaging for Outcome Prediction in Patients with High-Grade Neuroendocrine Neoplasms

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:15-07:00

Visual Abstract


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Addressing Climate Catastrophe Concerns in Asthma Medication Delivery: Rethinking Inhaler Use for Environmental and Clinical Efficacy

By www.bmj.com
Published On :: Tuesday, November 12, 2024 - 13:24


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Greenwashing assisted dying

By www.bmj.com
Published On :: Tuesday, November 12, 2024 - 14:03


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Citrus Vascular Proteomics Highlights the Role of Peroxidases and Serine Proteases during Huanglongbing Disease Progression

By www.mcponline.org
Published On :: 2020-12-01

Jessica Y. Franco
Dec 1, 2020; 19:1936-1951
Research


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High-throughput and site-specific N-glycosylation analysis of human alpha-1-acid glycoprotein offers a great potential for new biomarker discovery

By www.mcponline.org
Published On :: 2020-12-29

Toma Keser
Dec 29, 2020; 0:RA120.002433v1-mcp.RA120.002433
Research


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Stoichiometry of Nucleotide Binding to Proteasome AAA+ ATPase Hexamer Established by Native Mass Spectrometry

By www.mcponline.org
Published On :: 2020-12-01

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research


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Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target

By www.mcponline.org
Published On :: 2020-12-01

Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research


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Proteome analysis reveals a significant host-specific response in Rhizobium leguminosarum bv viciae endosymbiotic cells

By www.mcponline.org
Published On :: 2020-11-19

David Durán
Nov 19, 2020; 0:RA120.002276v1-mcp.RA120.002276
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A potential role for the Gsdf-eEF1{alpha} complex in inhibiting germ cell proliferation: A protein-interaction analysis in medaka (Oryzias latipes) from a proteomics perspective

By www.mcponline.org
Published On :: 2020-12-08

Xinting Zhang
Dec 8, 2020; 0:RA120.002306v1-mcp.RA120.002306
Research


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Quantitative proteomics reveal neuron projection development genes ARF4, KIF5B and RAB8A associated with Hirschsprung disease

By www.mcponline.org
Published On :: 2020-11-17

Qin Zhang
Nov 17, 2020; 0:RA120.002325v1-mcp.RA120.002325
Research


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Proteomic analyses identify differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage lung adenocarcinoma and their prognostic impacts

By www.mcponline.org
Published On :: 2020-11-30

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research


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Accelerating the field of epigenetic histone modification through mass spectrometry-based approaches

By www.mcponline.org
Published On :: 2020-11-17

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
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Human pancreatic cancer cells under nutrient deprivation are vulnerable to redox system inhibition [Cell Biology]

By www.jbc.org
Published On :: 2020-12-04T00:06:05-08:00

Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.


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The amphipathic helices of Arfrp1 and Arl14 are sufficient to determine subcellular localizations [Cell Biology]

By www.jbc.org
Published On :: 2020-12-04T00:06:05-08:00

The subcellular localization of Arf family proteins is generally thought to be determined by their corresponding guanine nucleotide exchange factors. By promoting GTP binding, guanine nucleotide exchange factors induce conformational changes of Arf proteins exposing their N-terminal amphipathic helices, which then insert into the membranes to stabilize the membrane association process. Here, we found that the N-terminal amphipathic motifs of the Golgi-localized Arf family protein, Arfrp1, and the endosome- and plasma membrane–localized Arf family protein, Arl14, play critical roles in spatial determination. Exchanging the amphipathic helix motifs between these two Arf proteins causes the switch of their localizations. Moreover, the amphipathic helices of Arfrp1 and Arl14 are sufficient for cytosolic proteins to be localized into a specific cellular compartment. The spatial determination mediated by the Arfrp1 helix requires its binding partner Sys1. In addition, the residues that are required for the acetylation of the Arfrp1 helix and the myristoylation of the Arl14 helix are important for the specific subcellular localization. Interestingly, Arfrp1 and Arl14 are recruited to their specific cellular compartments independent of GTP binding. Our results demonstrate that the amphipathic motifs of Arfrp1 and Arl14 are sufficient for determining specific subcellular localizations in a GTP-independent manner, suggesting that the membrane association and activation of some Arf proteins are uncoupled.


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NETosis occurs independently of neutrophil serine proteases [Enzymology]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.


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PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression [Bioenergetics]

By www.jbc.org
Published On :: 2020-12-25T00:06:30-08:00

Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential, and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis, showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that, sildenafil, a phosphodiesterase 5 inhibitor, induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content, and voltage-dependent anion channel protein expression. Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil depends upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.


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HIV-1 Gag release from yeast reveals ESCRT interaction with the Gag N-terminal protein region [Molecular Bases of Disease]

By www.jbc.org
Published On :: 2020-12-25T00:06:30-08:00

The HIV-1 protein Gag assembles at the plasma membrane and drives virion budding, assisted by the cellular endosomal complex required for transport (ESCRT) proteins. Two ESCRT proteins, TSG101 and ALIX, bind to the Gag C-terminal p6 peptide. TSG101 binding is important for efficient HIV-1 release, but how ESCRTs contribute to the budding process and how their activity is coordinated with Gag assembly is poorly understood. Yeast, allowing genetic manipulation that is not easily available in human cells, has been used to characterize the cellular ESCRT function. Previous work reported Gag budding from yeast spheroplasts, but Gag release was ESCRT-independent. We developed a yeast model for ESCRT-dependent Gag release. We combined yeast genetics and Gag mutational analysis with Gag-ESCRT binding studies and the characterization of Gag-plasma membrane binding and Gag release. With our system, we identified a previously unknown interaction between ESCRT proteins and the Gag N-terminal protein region. Mutations in the Gag-plasma membrane–binding matrix domain that reduced Gag-ESCRT binding increased Gag-plasma membrane binding and Gag release. ESCRT knockout mutants showed that the release enhancement was an ESCRT-dependent effect. Similarly, matrix mutation enhanced Gag release from human HEK293 cells. Release enhancement partly depended on ALIX binding to p6, although binding site mutation did not impair WT Gag release. Accordingly, the relative affinity for matrix compared with p6 in GST-pulldown experiments was higher for ALIX than for TSG101. We suggest that a transient matrix-ESCRT interaction is replaced when Gag binds to the plasma membrane. This step may activate ESCRT proteins and thereby coordinate ESCRT function with virion assembly.


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High resolution structure of human apolipoprotein (a) kringle IV type 2: beyond the lysine binding site

By www.jlr.org
Published On :: 2020-12-01

Alice Santonastaso
Dec 1, 2020; 61:1687-1696
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Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

By www.jlr.org
Published On :: 2020-12-01

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles


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Deletion of lysophosphatidylcholine acyltransferase3 in myeloid cells worsens hepatic steatosis after a high fat diet

By www.jlr.org
Published On :: 2020-12-11

Thibaut Bourgeois
Dec 11, 2020; 0:jlr.RA120000737v1-jlr.RA120000737
Research Articles


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SCD1 promotes lipid mobilization in subcutaneous white adipose tissue

By www.jlr.org
Published On :: 2020-12-01

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles


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Adiponectin forms a complex with atherogenic LDL and inhibits its downstream effects

By www.jlr.org
Published On :: 2020-11-03

Akemi Kakino
Nov 3, 2020; 0:jlr.RA120000767v1-jlr.RA120000767
Research Articles


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Problem Notes for SAS®9 - 58465: SAS Life Science Analytics Framework 4.6 - Group membership removal fails with an exception for Process Flows that exist in the Recycle Bin

By
Published On :: Wed, 26 Aug 2020 16:27:10 EST

In SAS Life Science Analytics Framework 4.6, group membership removal fails with an exception if a user is set as assignee, a candidate, or a notification recipient in a user task for a Process Flow . The Process


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Problem Notes for SAS®9 - 48028: Custom Time Frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels

By
Published On :: Wed, 26 Aug 2020 16:17:42 EST

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l


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Problem Notes for SAS®9 - 66095: The message "ERROR: Could not move and link one or more files to..." occurs while running a job-flow instance

By
Published On :: Fri, 21 Aug 2020 15:33:44 EST

In SAS Infrastructure for Risk Management, the message "ERROR: Could not move and link one or more files to..." occurs while running a job-flow instance if an orphaned folder exists in the persistent area.


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WITHDRAWN: Structural and mechanistic studies of hydroperoxide conversions catalyzed by a CYP74 clan epoxy alcohol synthase from amphioxus (Branchiostoma floridae) [Research Articles]

By www.jlr.org
Published On :: 2014-03-04T09:59:12-08:00

This manuscript has been withdrawn by the Author.


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Bisretinoid phospholipid and vitamin A aldehyde: Shining a light [Thematic Reviews]

By www.jlr.org
Published On :: 2020-05-05T13:30:26-07:00

Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids.


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Dietary sphinganine is selectively assimilated by members of the mammalian gut microbiome [Research Articles]

By www.jlr.org
Published On :: 2020-07-09T14:33:39-07:00

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remains largely unknown. Sphingolipids are bioactive components of most foods and are also produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet–microbiome interactions. Here, we used a click chemistry–based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine (sphinganine alkyne [SAA]) into the murine gut microbial community (Bioorthogonal labeling). We identified microbial and SAA-specific metabolic products through fluorescence-based sorting of SAA-containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together, this approach, termed Bioorthogonal labeling-Sort-Seq-Spec (BOSSS), revealed that SAA assimilation is nearly exclusively performed by gut Bacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice revealed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activities of Bacteroides and Bifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability of Bacteroides and Bifidobacterium to metabolize dietary sphingolipids. We conclude that BOSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet–microbiome interactions.


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Docosanoid signaling modulates corneal nerve regeneration: effect on tear secretion, wound healing, and neuropathic pain [Thematic Reviews]

By www.jlr.org
Published On :: 2020-08-11T12:36:10-07:00

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves  are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as  prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer  RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A).  RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.


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Sphingolipids as Critical Players in Retinal Physiology and Pathology [Thematic Reviews]

By www.jlr.org
Published On :: 2020-09-18T07:36:30-07:00

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.


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High-density lipoprotein-associated miRNA is increased following Roux-en-Y gastric bypass surgery for severe obesity [Research Articles]

By www.jlr.org
Published On :: 2020-10-22T06:30:32-07:00

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affects circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDL were isolated from patients with severe obesity (n=53) before, 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDL were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222 and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222 and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222 and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase (PON1) activity were increased and intracellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with increase in cholesterol efflux capacity (r=0.326, P=0.027 and r=0.349, P=0.017 respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction, and may lead to the development of novel treatment strategies for obesity and related metabolic disorders.


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Adiponectin forms a complex with atherogenic LDL and inhibits its downstream effects [Research Articles]

By www.jlr.org
Published On :: 2020-11-03T06:36:28-08:00

Adiponectin, an adipocyte-derived protein, has anti-atherogenic and anti-diabetic effects, but how it confers the anti-atherogenic effects is not well understood. To study the anti-atherogenic mechanisms of adiponectin, we examined whether it interacts with atherogenic low-density lipoprotein (LDL) to attenuate LDL’s atherogenicity. L5, the most electronegative subfraction of LDL, induces atherogenic responses similarly to copper-oxidized LDL (oxLDL). Unlike native LDL endocytosed via the LDL receptor, L5 and oxLDL are internalized by cells via the lectin-like oxidized LDL receptor-1 (LOX-1). Using enzyme-linked immunosorbent assays (ELISAs), we showed that adiponectin preferentially bound oxLDL but not native LDL. In Chinese hamster ovary (CHO) cells transfected with LOX-1 or LDL receptor, adiponectin selectively inhibited the uptake of oxLDL but not of native LDL, respectively. Furthermore, adiponectin suppressed the internalization of oxLDL in human coronary artery endothelial cells (HCAECs) and THP-1–derived macrophages. Western blot analysis of human plasma showed that adiponectin was abundant in L5 but not in L1, the least electronegative subfraction of LDL. Sandwich ELISAs with anti-adiponectin and anti–apolipoprotein B antibodies confirmed the binding of adiponectin to L5 and oxLDL. In LOX-1–expressing CHO cells, adiponectin inhibited cellular responses to oxLDL and L5, including nuclear factor-B activation and ERK phosphorylation. In HCAECs, adiponectin inhibited oxLDL-induced endothelin-1 secretion and ERK phosphorylation. Conversely, oxLDL suppressed the adiponectin-induced activation of adenosine monophosphate–activated protein kinase in COS-7 cells expressing adiponectin receptor AdipoR1. Our findings suggest that adiponectin binds and inactivates atherogenic LDL, providing novel insight into the anti-atherogenic mechanisms of adiponectin.


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Deletion of lysophosphatidylcholine acyltransferase3 in myeloid cells worsens hepatic steatosis after a high fat diet [Research Articles]

By www.jlr.org
Published On :: 2020-12-11T09:30:19-08:00

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.


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How changes to drug prohibition could be good for the UK—an essay by Molly Meacher and Nick Clegg

By www.bmj.com
Published On :: Monday, November 14, 2016 - 23:30


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Thiazide diuretics seem to protect against fracture

By www.bmj.com
Published On :: Tuesday, November 22, 2016 - 11:26


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Different rates of flux through the biosynthetic pathway for long-chain versus very-long-chain sphingolipids [Research Articles]

By www.jlr.org
Published On :: 2020-10-01T00:05:17-07:00

The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate, of ceramides containing diverse N-acyl chains is different. By means of a pulse-labeling protocol using stable-isotope, deuterated free fatty acids, and following their incorporation into ceramide and downstream SLs, we show that very-long-chain (VLC) ceramides containing C24:0 or C24:1 fatty acids turn over much more rapidly than long-chain (LC) ceramides containing C16:0 or C18:0 fatty acids due to the more rapid metabolism of the former into VLC sphingomyelin and VLC hexosylceramide. In contrast, d16:1 and d18:1 ceramides show similar rates of turnover, indicating that the length of the sphingoid LCB does not influence the flux of ceramides through the biosynthetic pathway. Together, these data demonstrate that the N-acyl chain length of SLs may not only affect membrane biophysical properties but also influence the rate of metabolism of SLs so as to regulate their levels and perhaps their biological functions.


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Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease [Research Articles]

By www.jlr.org
Published On :: 2020-10-01T00:05:17-07:00

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.


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Serum lipoprotein (a) associates with a higher risk of reduced renal function: a prospective investigation [Research Articles]

By www.jlr.org
Published On :: 2020-10-01T00:05:17-07:00

Lipoprotein (a) [Lp(a)] is a well-known risk factor for cardiovascular disease, but analysis on Lp(a) and renal dysfunction is scarce. We aimed to investigate prospectively the association of serum Lp(a) with the risk of reduced renal function, and further investigated whether diabetic or hypertensive status modified such association. Six thousand two hundred and fifty-seven Chinese adults aged ≤40 years and free of reduced renal function at baseline were included in the study. Reduced renal function was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2. During a mean follow-up of 4.4 years, 158 participants developed reduced renal function. Each one-unit increase in log10-Lp(a) (milligrams per deciliter) was associated with a 1.99-fold (95% CI 1.15–3.43) increased risk of incident reduced renal function; the multivariable-adjusted odds ratio (OR) for the highest tertile of Lp(a) was 1.61 (95% CI 1.03–2.52) compared with the lowest tertile (P for trend = 0.03). The stratified analysis showed the association of serum Lp(a) and incident reduced renal function was more prominent in participants with prevalent diabetes [OR 4.04, 95% CI (1.42–11.54)] or hypertension [OR 2.18, 95% CI (1.22–3.89)]. A stronger association was observed in the group with diabetes and high Lp(a) (>25 mg/dl), indicating a combined effect of diabetes and high Lp(a) on the reduced renal function risk. An elevated Lp(a) level was independently associated with risk of incident reduced renal function, especially in diabetic or hypertensive patients.


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Genetic susceptibility, dietary cholesterol intake, and plasma cholesterol levels in a Chinese population [Patient-Oriented and Epidemiological Research]

By www.jlr.org
Published On :: 2020-11-01T00:05:43-07:00

Accompanied with nutrition transition, non-HDL-C levels of individuals in Asian countries has increased rapidly, which has caused the global epicenter of nonoptimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRSTC, 57 SNPs), LDL-C (GRSLDL-C, 45 SNPs), and HDL-C (GRSHDL-C, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food-frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRSTC (effect sizes: –0.29, 0.34, 2.45, and 6.47; Pinteraction = 0.002) and GRSLDL-C (effect sizes: –1.35, 0.17, 5.45, and 6.07; Pinteraction = 0.001), respectively. Similar interactions with non-HDL-C were observed between dietary cholesterol and GRSTC (Pinteraction = 0.001) and GRSLDL-C (Pinteraction = 0.004). The adverse effects of GRSTC on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21, and 1.31; Pinteraction = 0.023) and GRSLDL-C on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12, and 1.56; Pinteraction = 0.020) were more profound in those having higher cholesterol intake compared with those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.


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Distinctive sphingolipid patterns in chronic multiple sclerosis lesions [Research Articles]

By www.jlr.org
Published On :: 2020-11-01T00:05:43-07:00

Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.


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Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model [Research Articles]

By www.jlr.org
Published On :: 2020-11-01T00:05:43-07:00

Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.


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