Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.

Methionine, through S-adenosylmethionine, activates a multifaceted growth program in which ribosome biogenesis, carbon metabolism, and amino acid and nucleotide biosynthesis are induced. This growth program requires the activity of the Gcn4 transcription factor (called ATF4 in mammals), which facilitates the supply of metabolic precursors that are essential for anabolism. However, how Gcn4 itself is regulated in the presence of methionine is unknown. Here, we discover that Gcn4 protein levels are increased by methionine, despite conditions of high cell growth and translation (in which the roles of Gcn4 are not well-studied). We demonstrate that this mechanism of Gcn4 induction is independent of transcription, as well as the conventional Gcn2/eIF2α-mediated increased translation of Gcn4. Instead, when methionine is abundant, Gcn4 phosphorylation is decreased, which reduces its ubiquitination and therefore degradation. Gcn4 is dephosphorylated by the protein phosphatase 2A (PP2A); our data show that when methionine is abundant, the conserved methyltransferase Ppm1 methylates and alters the activity of the catalytic subunit of PP2A, shifting the balance of Gcn4 toward a dephosphorylated, stable state. The absence of Ppm1 or the loss of the PP2A methylation destabilizes Gcn4 even when methionine is abundant, leading to collapse of the Gcn4-dependent anabolic program. These findings reveal a novel, methionine-dependent signaling and regulatory axis. Here methionine directs the conserved methyltransferase Ppm1 via its target phosphatase PP2A to selectively stabilize Gcn4. Through this, cells conditionally modify a major phosphatase to stabilize a metabolic master regulator and drive anabolism.

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

Africa Aware: Relations between Ethiopia and Sudan Audio bhorton.drupal 9 April 2022

This episode of Africa Aware examines the relationship between Ethiopia and Sudan.

Ahmed Soliman provides an overview of the Africa Programme’s work on cross-border conflict as part of the XCEPT project.

First, we speak to Kholood Khair on the steady deterioration in relations between Sudan and Ethiopia. Then Abel Abate Demissie discusses how recent political developments in Ethiopia and Sudan have impacted relations between the two countries.

This podcast was produced with support from the Cross-Border Conflict Evidence, Policy and Trends (XCEPT) project, funded by UK Aid from the UK government. The views expressed do not necessarily reflect the UK government’s official policies.

It is also part of a series of outputs on Ethiopia’s political transition.

Now is the moment to launch an African vaccine industry The World Today mhiggins.drupal 31 July 2022

The continent plans to make 60 per cent of its vaccines by 2040. After the failure of the world to help in the pandemic, it’s high time, says Ngozi Erondu.

The lack of an African vaccine industry has been a glaring concern for decades. Before the pandemic, 99 per cent of Africa’s vaccines were manufactured outside the continent. As well as endangering the lives of millions, this situation has inhibited social and economic progress on the continent.

In response, the Africa Centres for Disease Control and Prevention (Africa CDC) has undertaken an ambitious plan, outlined in the Partnerships for African Vaccine Manufacturing (PAVM) Framework for Action, to develop the nascent African vaccine manufacturing sector into an end-to-end industry by 2040. The framework aims to raise the share of African-manufactured vaccines used across the continent to 60 per cent by 2040, or the equivalent to up to 1.7 billion doses annually.

Seven of every 10 vaccines used in Africa are currently donated through Gavi, the Vaccine Alliance. Most are administered within childhood immunization programmes and are largely manufactured either in India, or by  multinational vaccine manufacturers in North America or Japan.

Vaccine donations have inhibited the development in Africa of vaccines and other countermeasures against diseases.

Though the Ebola virus was discovered in Central Africa in 1976, vaccine development was not adequately funded until it emerged in Europe in 2014. Human monkeypox resurfaced in Nigeria in 2017, yet the global Coalition for Epidemic Preparedness Innovations only targeted it for vaccine development in July this year.

The pandemic highlighted Africa’s fatal dependency on imported vaccines. Only 20 per cent of Africans are fully vaccinated against Covid-19, due to the failure of countries in the Global North to ensure the equitable distribution of vaccines via the COVAX facility to 40 per cent of the world’s most vulnerable people. 

The pandemic also confirmed that Africa could not rely on fellow states of the Global South. At the height of the Delta variant outbreak in early 2021, India halted vaccine exports to Africa, where only 1.5 per cent of the population had at that time received any vaccine doses.

After decades of discussions, there are signs that Africa could soon succeed in creating its own vaccine industry. First, the 55-member African Union is in the process of establishing the African Medicines Agency, a regional regulatory body. 
 

‘The new public health order’

Additionally, the African Export-Import Bank and African Development Bank (AfDB) have established a foundation to provide financial and strategic support for the development of the pharmaceutical industry and the consolidation of regional vaccination programmes in Africa (the foundation would potentially negotiate intellectual property rights and licensing issues but that remains to be seen).

Second, studies show there is an emerging middle class in Africa. In a 2011 report by the AfDB, this was estimated at some 56 million households. Potentially, this means many people will be able to buy vaccines and medicines made in Africa.

About a third of African countries currently pay for their vaccine needs. According to PAVM forecasts, the value of the total African market could reach between $3 billion and $17 billion by 2040.

The recent entry into effect of the African Continental Free Trade Area should also prove conducive to African vaccine development. Through economic integration, free movement and harmonized regional standards, countries that invest in their biopharmaceutical and medical technology sectors may attract employees, regional and international businesses, and investment. Further, the pandemic has encouraged people to relocate to countries with, or planning for, universal healthcare.

Building an African pharmaceutical industry from the ground up could take much longer than two decades and cost tens of billions of dollars. Nevertheless, the moment seems ripe, and timely support has been forthcoming from influential regional actors, including Rwandan President Paul Kagame, South Africa’s Cyril Ramaphosa, and private sector business executives, including the Zimbabwean-born billionaire Strive Masiyiwa.

With a pandemic treaty embedding equity in prevention, preparedness and response some way off, and given the limitations surrounding the recent World Trade Organization compromise on the TRIPS waiver – which temporarily waives Covid-19 vaccine patent protections for poorer countries – it is doubly important for Africa to build up its own pharmaceutical industry and emergency systems. 

In 2021, John Nkengasong, then director of Africa CDC, wrote of the necessity of a post-pandemic ‘new public health order’ for Africa. Such a change may threaten the global health organizations, industries and institutes who derive payment from ‘saving Africa’ during emergencies. Additionally, through strengthening Africa CDC, other actors such as the World Health Organization may find that they have a diminished strategic role on the continent.
 
While Africa should not dismiss these valuable and long-standing partnerships, it must take the opportunity to advance its interests and to assume leadership in this important area.

Africa-Japan relations and evolving multilateralism 23 November 2022 — 9:00AM TO 10:30AM Anonymous (not verified) 17 November 2022 Online

This panel discussion reflects on the outcomes of TICAD 8 in 2022 and looks forward to TICAD 9 in 2025.

The eighth edition of the Tokyo International Conference on African Development (TICAD), held in Tunisia from 27–28 August 2022, marked the second time that Japan’s now-triennial summit was hosted in an African country, after TICAD 6 was held in Kenya in 2016.

The summit was attended by 48 representatives of African countries and at least 20 heads of state and government and included a pledge by the Japanese government to commit $30 billion in public and private finance to Africa over the next three years.

In reaffirming the three pillars of TICAD 8 – revolving around the economy, societal resilience, and peace and stability – the newly adopted Tunis Declaration (28 August 2022) also outlined some of the key projects underpinning Japan’s pledge, including a $4 billion fund for a Green Growth Initiative with Africa (GGA).

2023 will mark 30 years since the inception of TICAD in 1993 and ten years since the African Union (AU)’s adoption of its flagship Agenda 2063, on which the Tunis Declaration placed distinct emphasis.

This panel discussion reflects on the outcomes of TICAD 8 in 2022 and looks forward to TICAD 9 in 2025, exploring wider developments in summitry, Africa-Asia relations, and modes of multilateralism.

Questions explored include:

• How has international summitry evolved over the past three decades since the inception of TICAD in 1993, which represented the first periodic high-level summit engagement with Africa by a ‘non-traditional’ partner?
• Looking ahead to TICAD 9 in 2025, what are the priorities for enforcing the stated tenets of TICAD – ‘African ownership, international partnership, inclusivity and openness’ – in cooperation efforts?
• What lessons can be drawn from TICAD’s co-partnership approach (with the African Union Commission and others) – particularly given increasing calls for AU membership of the G20 and Prime Minister Kishida’s pledge at TICAD 8 to support a permanent African UNSC seat during its non-permanent membership in 2023–24? Beyond membership, what are the priorities for furthering agency?
• How are Africa-Asia relations evolving and diverging? How are Japan and other Asian countries perceived by different African countries?

This event is the third in the Chatham House – Japan House London webinar series (2022-2023). The series is held in partnership with Japan House London. You can watch previous webinars from the series here.

Africa in 2023: Continuing political and economic volatility Expert comment NCapeling 6 January 2023

Despite few African trade and financial links with Russia and Ukraine, the war in Ukraine will cause civil strife in Africa due to food and energy inflation.

Africa’s economy was recovering from the COVID-19 pandemic in 2022 when a range of internal and external shocks struck such as adverse weather conditions, a devastating locust invasion, and the Russian invasion of Ukraine – all of which worsened already rapidly-rising rates of inflation and borrowing costs.

Although the direct trade and financial linkages of Africa with Russia and Ukraine are small, the war has damaged the continent’s economies through higher commodity prices, higher food, fuel, and headline inflation.

The main impact is on the increasing likelihood of civil strife because of food and energy-fuelled inflation amid an environment of heightened political instability.

Key African economies such as South Africa and Nigeria were already stuck with low growth and many African governments have seen their debt burdens increase – some such as Ethiopia and Ghana now have dollar debt trading at distressed levels – and more countries will follow in 2023.

On average the public sector debt-to-GDP ratio of African countries stood at above 60 per cent in 2022. The era of Chinese state-backed big loans and mega-projects which started 20 years ago in Angola after the end of its civil war may be coming to an end but Chinese private sector investments on the continent will continue through its Belt and Road Initiative and dual circulation model of development.

Great and middle powers building influence

Geopolitical competition in Africa has intensified in 2022, particularly among great powers such as China, Russia, the US, and the EU but also by middle powers such as Turkey, Japan, and the Gulf states.

The sixth AU-EU summit held in Brussels in February 2022 agreed on the principles for a new partnership, although the Russian invasion of Ukraine which followed disrupted these ambitions. Japan’s pledge of $30 billion in aid for Africa at TICAD 8 in August 2022 was clearly made due to the $40 billion pledged at the China–Africa summit in November 2021.

The US also launched a new strategy to strengthen its partnership and held a second US-Africa Leaders’ summit in Washington in December, the first since 2014. Russia’s ambition has been curtailed by its invasion of Ukraine, postponing its second summit with African states to 2023.

The imposition of international sanctions complicated its trade and investments, and military support such as that provided by Russian paramilitary group Wagner focused on Mali, Libya and the Central African Republic (CAR) has been curtailed.

The strategic importance of Africa has resulted in all the UN P5 members calling on the G20 to make the African Union (AU) its 21st member in 2023 under India’s presidency.

International competition to secure Africa’s critical and strategic minerals and energy products intensified in 2022 and, in the energy sector, European countries are seeking to diversify away from Russian oil and gas with alternative supplies, such as those from Africa.

Western mining companies and commodity traders are also increasingly seeking alternative supplies from Africa. Decarbonization is becoming a driver of resource nationalism and geopolitical competition in certain African mining markets, home to large deposits of critical ‘transition minerals’ such as copper, cobalt, graphite, lithium, or nickel.

COP27 was hosted in Egypt in November and gave African leaders an opportunity to shape climate discussions by pushing priority areas such as loss and damage, stranded assets, access to climate finance, adaptation, and desertification. Climate adaptation in Africa is a key condition to preserving economic growth and maintaining social cohesion.

The Horn of Africa, particularly Somalia, is suffering from one of the worst droughts in memory. The geopolitical and geoeconomic ramifications of the war in Ukraine has directly impacted the African continent by contributing to food and cooking oil inflation and humanitarian aid delivery.

Thoughout 2022 the AU was undergoing intensive reform and it struggled to respond to the growing number of security crises across the continent. Hotspots in 2023 will be in the western Sahel and Lake Chad Basin, eastern DRC, and northern Mozambique, all of them crossing state borders.

In Mozambique, a 2019 peace deal assisted by the United Nations (UN) will see the last ex-guerrillas from Renamo demobilized in 2023 to reintegrate into civilian life – some having been recruited in 1978.

In eastern Congo, M23 – one of around 120 armed groups – resumed its conflict against the central government. After lying dormant for several years, it took up arms again in 2021 and has been leading an offensive in eastern DRC against the Congolese army.

According to the UN, Rwanda has been supporting M23, and Kenya’s parliament approved in November the deployment of about 900 soldiers to the DRC as part of a joint military force from the East African Community (EAC) bloc – DRC joined the EAC in March.

In the Horn of Africa, Ethiopia saw an uneasy ceasefire agreed between the federal government and the Tigray People’s Liberation Front (TPLF).

Islamist militant groups in Africa further expanded their territorial reach in 2022, particularly in the western Sahel where al-Qaeda and Islamic State affiliates are competing for influence and continued to make inroads.

The drawdown and exit of western forces from Mali, both the French Operation Barkane and international contributions for the UN’s MINUSMA mission there, adds new dimensions to regional security challenges.

Mali’s decision in May to withdraw from the G5 Sahel has also eroded the regional security architecture. Jihadist activity may spread further into coastal states which has resulted in international partners such as France and the UK redesigning their security assistance strategies for the region.

Coups on the increase again

Since 2020, there have been successful military coups in Burkina Faso (twice), Chad, Guinea, Mali (twice), and Sudan, and failed ones in the CAR, Djibouti, Guinea-Bissau, Madagascar, Niger, and possibly Gambia and São Tomé and Príncipe.

Three national elections illustrate the state of African democracy in 2022. In Angola’s August elections, the ruling MPLA lost its absolute majority with the opposition UNITA winning the majority in Luanda for the first time.

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.

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.

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, 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.

Africa Aware: Supply chains, land contestation, conflict Audio NCapeling 30 March 2023

This episode examines relations between Ethiopia and Sudan as part of an XCEPT project mini-series.

The war in northern Ethiopia since November 2020, and subsequent conquest of disputed farmlands in Al-Fashaga by the Sudanese army on the Ethiopia-Sudan border, has brought into focus the importance of agricultural commodities such as sesame as a potential driver of land contestation and conflict. 

The panel discusses the interrelation of commodity and conflict supply chains, land contestation, and boundary disputes in the Horn of Africa, with a particular focus on the regions of Wolkait/Western Tigray in northwest Ethiopia and Al Fashaga in eastern Sudan.

This podcast was produced with support from the Cross-Border Conflict Evidence, Policy and Trends (XCEPT) project, funded by UK Aid from the UK government.

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Felicia Grasso
Dec 1, 2020; 19:1986-1996
Research

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

Wenhe Zhu
Dec 29, 2020; 0:RA120.002353v1-mcp.RA120.002353
Research

Tricia Rowlison
Dec 1, 2020; 19:2090-2103
Research

Simone Kurz
Dec 29, 2020; 0:RA120.002266v1-mcp.RA120.002266
Research

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

Kyle Swovick
Dec 28, 2020; 0:RA120.002301v1-mcp.RA120.002301
Research

Yi Liu
Dec 1, 2020; 19:1968-1985
Research

Charlotte A. G. H. van Gelder
Dec 1, 2020; 19:1952-1967
Research

Weixian Deng
Dec 22, 2020; 0:RA120.002411v1-mcp.RA120.002411
Research

Sean A Burnap
Dec 7, 2020; 0:RA120.002305v1-mcp.RA120.002305
Research

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

Mingkun Yang
Nov 24, 2020; 0:RA120.002144v1-mcp.RA120.002144
Research

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

Laura F Fielden
Nov 11, 2020; 0:RA120.002370v1-mcp.RA120.002370
Research

Daniel J. Geiszler
Dec 1, 2020; 0:TIR120.002216v1-mcp.TIR120.002216
Technological Innovation and Resources

Tirsa L. E. van Westering
Dec 1, 2020; 19:2047-2067
Research

Jianhua Wang
Nov 4, 2020; 0:RA120.002375v1-mcp.RA120.002375
Research

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources

Philipp Emanuel Geyer
Dec 17, 2020; 0:RA120.002359v1-mcp.RA120.002359
Research

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.

The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

Gle1 is a conserved, essential regulator of DEAD-box RNA helicases, with critical roles defined in mRNA export, translation initiation, translation termination, and stress granule formation. Mechanisms that specify which, where, and when DDXs are targeted by Gle1 are critical to understand. In addition to roles for stress-induced phosphorylation and inositol hexakisphosphate binding in specifying Gle1 function, Gle1 oligomerizes via its N-terminal domain in a phosphorylation-dependent manner. However, a thorough analysis of the role for Gle1 self-association is lacking. Here, we find that Gle1 self-association is driven by two distinct regions: a coiled-coil domain and a novel 10-amino acid aggregation-prone region, both of which are necessary for proper Gle1 oligomerization. By exogenous expression in HeLa cells, we tested the function of a series of mutations that impact the oligomerization domains of the Gle1A and Gle1B isoforms. Gle1 oligomerization is necessary for many, but not all aspects of Gle1A and Gle1B function, and the requirements for each interaction domain differ. Whereas the coiled-coil domain and aggregation-prone region additively contribute to competent mRNA export and stress granule formation, both self-association domains are independently required for regulation of translation under cellular stress. In contrast, Gle1 self-association is dispensable for phosphorylation and nonstressed translation initiation. Collectively, we reveal self-association functions as an additional mode of Gle1 regulation to ensure proper mRNA export and translation. This work also provides further insight into the mechanisms underlying human gle1 disease mutants found in prenatally lethal forms of arthrogryposis.

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

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.

Transient receptor potential vanilloid 1 (TRPV1) channel is a multimodal receptor that is responsible for nociceptive, thermal, and mechanical sensations. However, which biomolecular partners specifically interact with TRPV1 remains to be elucidated. Here, we used cDNA library screening of genes from mouse dorsal root ganglia combined with patch-clamp electrophysiology to identify the voltage-gated potassium channel auxiliary subunit Kvβ1 physically interacting with TRPV1 channel and regulating its function. The interaction was validated in situ using endogenous dorsal root ganglia neurons, as well as a recombinant expression model in HEK 293T cells. The presence of Kvβ1 enhanced the expression stability of TRPV1 channels on the plasma membrane and the nociceptive current density. Surprisingly, Kvβ1 interaction also shifted the temperature threshold for TRPV1 thermal activation. Using site-specific mapping, we further revealed that Kvβ1 interacted with the membrane-distal domain and membrane-proximal domain of TRPV1 to regulate its membrane expression and temperature-activation threshold, respectively. Our data therefore suggest that Kvβ1 is a key element in the TRPV1 signaling complex and exerts dual regulatory effects in a site-specific manner.

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.