Reggae artiste Jah Kettle says he was pleased with his recently concluded Canada tour and is now excited to release a new single, titled Nothing Gonna Take Your Love Away, done with fellow reggae act Ras Penco. "The fans were riveting and showed...

Earlier this month when Alicea Samaru-Brown walked across the stage at The University of the West Indies (UWI) graduation, she beamed with pride. Her husband, Dennis Brown, and her son, Orlando Brown, cheered the loudest from the audience and this...

Health Minister Dr Christopher Tufton is warning about the possible dangers to the health of students caused by vaping. "We have seen cases where students have been rushed to the A...

PORT-AU-PRINCE, Haiti (AP) — Haiti's main airport remained closed on Tuesday, a day after violence erupted as the country swore in its new prime minister in a politically tumultuous transition.

The Clarendon police have arrested and charged 25-year-old landscaper Anthony Marshall, of Lamparth district, Trout Hall in the parish for allegedly stealing oranges from a property in his community on Sunday.

When using the distinct count function in SAS Visual Analytics reports, you might find that a negative value is displayed instead of the actual distinct count: imgalt="distinct_count" src="{fusion_66562_1_disti

Knockout mouse models have been extensively used to study the antiviral activity of IFIT (interferon-induced protein with tetratricopeptide repeats). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of “self” in higher eukaryotes, whereas unmodified cap0-RNA is recognized as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess “nonself” cap0-mRNAs. However, in mice and other rodents, the IFIT1 orthologue has been lost, and the closely related Ifit1b has been duplicated twice, yielding three paralogues: Ifit1, Ifit1b, and Ifit1c. Although murine Ifit1 is similar to human IFIT1 in its cap0-RNA–binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, whereas binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict WT mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families to facilitate better design and interpretation of mouse models of human infection and sheds light on the evolutionary plasticity of the IFIT family.

RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuclease activity aided by two metal cofactors at the active site. RNase J2, on the other hand, has endonuclease activity and one metal ion at the active site and is predominantly a monomer. We note that the expression levels of these enzymes vary across Staphylococcal strains. Together, these observations suggest that multiple interacting RNase J paralogs could provide a strategy for functional improvisation utilizing differences in intracellular concentration, quaternary structure, and distinct active site architecture despite overall structural similarity.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Members of the B-cell lymphoma (BCL-2) protein family regulate mitochondrial outer membrane permeabilization (MOMP), a phenomenon in which mitochondria become porous and release death-propagating complexes during the early stages of apoptosis. Pro-apoptotic BCL-2 proteins oligomerize at the mitochondrial outer membrane during MOMP, inducing pore formation. Of current interest are endogenous factors that can inhibit pro-apoptotic BCL-2 mitochondrial outer membrane translocation and oligomerization. A mitochondrial-derived peptide, Humanin (HN), was reported being expressed from an alternate ORF in the mitochondrial genome and inhibiting apoptosis through interactions with the pro-apoptotic BCL-2 proteins. Specifically, it is known to complex with BAX and BID. We recently reported the fibrillation of HN and BAX into β-sheets. Here, we detail the fibrillation between HN and BID. These fibers were characterized using several spectroscopic techniques, protease fragmentation with mass analysis, and EM. Enhanced fibrillation rates were detected with rising temperatures or pH values and the presence of a detergent. BID fibers are similar to those produced using BAX; however, the structures differ in final conformations of the BCL-2 proteins. BID fibers display both types of secondary structure in the fiber, whereas BAX was converted entirely to β-sheets. The data show that two distinct segments of BID are incorporated into the fiber structure, whereas other portions of BID remain solvent-exposed and retain helical structure. Similar analyses show that anti-apoptotic BCL-xL does not form fibers with humanin. These results support a general mechanism of sequestration of pro-apoptotic BCL-2 proteins into fibers by HN to inhibit MOMP.

Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation.

27 July 2020

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. 

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.

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.

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.

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.

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.

Youth innovation can help shape the future of African cities Expert comment LToremark 16 August 2022

To meet the challenges of rapid urbanization, African governments must harness the potential of young innovators to help shape the future of African cities.

It is projected that 1.3 billion people will be living in Africa’s cities by 2050, an increase of almost 1 billion from today, and largely driven by young people migrating to urban centres in search of work. As the continent’s urban population grows, cities will need to adapt by nurturing new economic ecosystems to create jobs, while managing the environmental, social and political pressures that urbanization brings.

The evolution of Africa’s cities is critical for meeting the demands of its youth population and must be co-created with them. Africa’s young innovators are already proving to be an asset in shaping the future of African cities and, if they are allowed to flourish, they could be at the forefront of finding much-needed solutions to the continent’s vast urban challenges.

Growing tech hubs

African countries are increasingly benefitting from growth in technology ecosystems, which are often clustered within cities. There are currently more than 600 tech hubs helping to incubate innovative solutions across cities in Africa. Between 2015 and 2020, the number of start-ups receiving funding grew six times faster than the global average. In 2021 alone, start-ups raised over $4billion in funding – twice as much as in 2020.

But significant challenges remain. While the number of new start-ups is an encouraging indication of the entrepreneurialism and creativity of Africa’s youth, job creation on the level required will demand that they grow and scale up to generate more and higher quality jobs. Research on scaling up in Africa is sparse but research by Endeavor suggests that in Nairobi – one of Africa’s top tech ecosystems – only 5 per cent of companies are able to sustain growth of 20 per cent or more each year, yet they created 72 per cent of new jobs in the previous three years. For Africa to fully harness the potential of digital innovation, making cities the best place for young people to launch ideas and grow them into thriving businesses must become a priority policy for African governments. 

Barriers to scale

On the most basic level, business growth needs access to the services that make cities more liveable and help both urban residents and firms become more productive, such as healthcare, transport, water and sanitation. African cities already struggle to provide their residents – in particular the poorest and most vulnerable – with equitable, reliable, affordable and quality access to these services, in a sustainable manner. And these challenges will only get more acute as urban populations rise rapidly, often without any kind of integrated planning.

For example, an estimated 70-80 per cent of municipal solid waste in Africa is recyclable, yet only about 4 per cent is currently recycled, with more than 90 per cent of waste ending up in uncontrolled dumpsites and landfills. As Africa’s urban population grows, these conditions are likely to worsen – unless there is urgent action. New technology has the potential to help by creating a positive feedback loop between innovation, service delivery and growth. For example, to bridge the waste management gap, innovators are exploring various tech-enabled circular economy models. These solutions are often ground-breaking and have the potential to leapfrog traditional waste management infrastructure. Crucially, they are also formalizing a largely informal sector and creating new jobs.

Across the continent, start-ups like Kaltani, Mr Green Africa and Freetown Waste Transformers build processing facilities to turn waste into energy or reusable products, such as construction materials. Others, like Scrapays, Regenize and Soso Care, are helping households and businesses sell off their recycled materials for cash and virtual currencies or exchange them for critical services, such as micro health insurance premiums. Such start-ups help empower informal waste pickers or agents with tech-enabled tools and target low-income urban communities that would not normally prioritize recycling.

Help or hindrance from the top?

But Africa’s young people cannot do this alone – government decision-makers must become catalysts for entrepreneurial leadership. This requires nurturing a mindset that sees young innovators as Africa’s biggest resource, not a threat. While the importance of young people to Africa’s development is acknowledged in various high-level regional treaties, patterns of inhibition and outright hostility from political ‘elites’ suggest that the disruptive nature of technology start-ups and their access to significant capital through venture capital funding models – unlike existing rent-seeking business models with government control – threatens the political establishment.

The growing use of tech solutions also leads to increased transparency and efficiency of service delivery, which in turn leads to increased demand for government accountability and pressure to adopt more liberal policies. Until there is a shift towards catalysing entrepreneurial leadership, there is a stronger incentive for political elites to leverage their powers to co-opt successful technology businesses, or otherwise try to control them for political gain, than let them flourish. This shift in mindset will be critical to unlocking the full potential of Africa’s young innovators.

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.

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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On October 24 and 25, SophosAI presents ideas on how to use models large and small—and defend against malignant ones.

Alba Simats
Dec 1, 2020; 19:1921-1935
Research

Ji Eun Kim
Dec 20, 2020; 0:RA120.002159v1-mcp.RA120.002159
Research

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

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

Peter Lasch
Dec 1, 2020; 19:2125-2138
Technological Innovation and Resources

Sylwia Struk
Dec 28, 2020; 0:RA119.001766v1-mcp.RA119.001766
Research

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

Nadine Prust
Dec 17, 2020; 0:RA120.002232v1-mcp.RA120.002232
Research

R. Greg Stacey
Nov 4, 2020; 0:RA120.002275v1-mcp.RA120.002275
Research

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

Alison B. Ross
Nov 30, 2020; 0:R120.002190v1-mcp.R120.002190
Review

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review

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

Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1.

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Alice Santonastaso
Dec 1, 2020; 61:1687-1696
Research Articles

Hideaki Kuge
Dec 1, 2020; 61:1747-1763
Research Articles

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles