Japan’s G7 leadership: Defending the liberal order amid crisis 28 February 2023 — 9:00AM TO 10:00AM Anonymous (not verified) 20 February 2023 Online

How G7 countries should best respond to global economic and security challenges in order to defend the liberal international order.

In May 2023 Japan hosts the G7 summit in Hiroshima, where leaders of the US, UK, Canada, France, Germany and Italy come to discuss the most urgent challenges facing the world.

This year’s summit takes place against a backdrop of continued global economic and political instability from the war in Ukraine to intensifying competition between China and the West.

The speakers discuss Japanese Prime Minister Fumio Kishida’s priorities at the summit and consider how G7 countries should best respond to global economic and security challenges in order to defend the liberal international order.

This event is the third of a three-part series held in partnership with Japan House London.

Watch the first event which looked at Africa-Japan relations here, and the second event, on the UK and Japan’s engagement with Southeast Asia, here.

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.

Following its snap election, Japanese politics has entered uncharted waters Expert comment LToremark 5 November 2024

Prime Minister Ishiba’s election gamble has failed. Japan now faces another period of political uncertainty, which could affect its international standing.

In Japan’s snap election on 27 October, the ruling coalition of the Liberal Democratic Party (LDP) and New Komeito lost the overwhelming majority it had held since the 2012 general election. The ruling coalition now has 215 seats, leaving it 18 seats short of a majority. 

The largest opposition party is the Constitutional Democratic Party of Japan (CDP), which gained 50 seats to 148. The second largest opposition party is the Japan Innovation Party (Ishin), which lost six seats to 38, and the third largest opposition party is the National Democratic Party (NDP), which gained 21 seats to 28.

But the opposition is divided and there is no real appetite to form a coalition government. This will likely result in a hung parliament, which will further destabilize Japan’s government.

The election results reveal three key things  about the state of Japanese politics and what comes next.

First, that Prime Minister Ishiba’s snap election gamble has failed. The aim was for Ishiba, a non-mainstream member of the LDP, to strengthen the party base and stabilize his administration. But with the ruling coalition losing its majority, the party base has been further weakened and the Ishiba administration is now more likely to be short-lived. LDP voters as well as the public in general  had hoped that Ishiba, as the ‘opposition within the party’, would change the LDP’s structure and government policies, eliminate the uncertainty surrounding party funding and increase transparency on how MPs use public funds to finance political activities.

However, when Ishiba became LDP leader and prime minister, he abandoned his previously more critical stance and prioritized carrying on the policies of the mainstream LDP, leaving his supporters feeling betrayed.

Second, while the ruling coalition has been punished, the people of Japan still did not vote for a change of government. The opposition is divided and, despite its gains in this election, the CDP is not fully committed to take the lead and consolidate the opposition to form a coalition. The CDP also suffers from internal division. The left wing of the party would prefer a coalition with the Communist Party, while the right wing of the party does not want to form a coalition with the LDP or the Communist Party, preferring a partner such as the NDP.

Third, the NDP has become the key to future Japanese politics. By becoming the minority ruling party, the NDP is in a position to control the fate of Ishiba administration. While the CDP has no intention of cooperating with the LDP, the NDP is more willing to do so in order to implement its own policies. As the budget cannot be passed without the NDP’s cooperation, the ruling coalition will have no choice but to accept the NDP’s policy of substantial tax cuts through the expansion of tax credits. It will also likely have to accept an option for married couples to decide their family names, which requires a change of civil codes and is something it has been reluctant to do so far. 

If the NDP’s demands are rejected, a no-confidence motion will likely be submitted and passed, leaving the Ishiba cabinet with no choice but to resign or dissolve the House of Representatives (the lower house of Japan’s parliament).

But the NDP has chosen to not form a coalition with the ruling party and enter government. Why? From the NDP’s point of view, forming a coalition with the LDP, would mean getting involved in the LDP’s internal turmoil – something it wishes to avoid. In addition, elections to the House of Councillors (upper house of parliament) will be held in the summer of 2025. The NDP may have judged that it will have a better chance of implementing its policies by cooperating with the government on a case-by-case basis, rather than forming a coalition with a party that is losing public support and risk following suit.

The minority ruling system that has emerged after the election is extremely rare in Japan’s political history and is likely to make its politics even more unstable in the years ahead. The Ishiba administration will probably be able to survive until the budget is passed in March next year by cooperating with the NDP, but beyond that its prospects are unclear.

As the House of Councillors elections get closer, some in the LDP may say that they cannot fight the election with Ishiba as prime minister. If so, they may choose the option of a same-day election for the lower and the upper house. The cost of an election campaign is significant, and the LDP’s financial strength gives it an advantage in the case of a same-day election. There is also a strong possibility that the public will choose the LDP to regain stability in government. However, this election has shown that public distrust of the LDP is high, and if Ishiba continues to be pushed around by the NDP, his party’s chances of winning would be reduced.

Japanese politics has entered uncharted waters, where the patterns and customs of the past do not apply. There are now doubts both at home and abroad as to whether Ishiba, who has a weak party base, will be able to stay on and steer the government. Over the past decade, the Abe and Kishida administrations have provided Japan with political stability, which has in turn enhanced its international presence. An unstable political system, with frequent changes of government, will likely lead to a decline in Japan’s international influence.

There is also a risk that US–Japan relations  could become unstable. Although the NDP does not have a strong agenda to change the course of this relationship, Ishiba may struggle to keep the promise made by his predecessors to increase defence spending. Ishiba’s nationalist posture could also create a confrontational relationship with the United States, while his weak leadership means he may not seek to invest in strengthening the US–Japan alliance. 

Donald Trump’s win in the US presidential election could pose a further risk. Although Trump might be open to Ishiba’s demand for parity with the US, he could become irritated with Ishiba’s weak domestic position. Ishiba may not be able to make decisions – or a deal with Trump – unless the NDP agrees to it.

Lord Hammond Joins Panel of Senior Advisers News Release NCapeling 10 December 2020

Chatham House is pleased to announce that Lord Hammond of Runnymede is joining our Panel of Senior Advisers.

How can companies defend civic space? 2 February 2021 — 4:00PM TO 5:00PM Anonymous (not verified) 19 January 2021 Online

Panellists discuss how companies can go beyond corporate social responsibility and philanthropy initiatives to protect and support civic freedoms around the world.

Please click on the below link to confirm your participation and receive your individual joining details from Zoom for this event. You will receive a confirmation email from Zoom, which contains the option to add the event to your calendar if you so wish.

There is increasing pressure on companies to use their power and profits to engage with social and political causes. In doing so, companies can help to support the ‘shared civic space’ that enables the private sector and civil society organizations to benefit from a society that respects the rule of law and human rights, at a time when many of these rights are under threat around the world.

Many companies have introduced CSR initiatives, due diligence mechanisms and corporate philanthropy. Over 11,000 companies are now signatories to the UN’s Global Compact for sustainable and socially responsible business worldwide.

But as demonstrated by misguided corporate responses to the Black Lives Matter protests this year, there is a danger of corporate activism being perceived as ‘lip service’ rather than genuinely addressing the negative impacts of business operations on civic space.

Recent Chatham House research indicates that meaningful engagement by businesses on such issues must be timely, contextually sensitive and industry-relevant. For example, in 2015, Tiffany & Co. worked with other companies to intervene on behalf of Rafael Marques after he was arrested for reporting on widespread human rights abuses in the Angolan diamond industry. During COVID-19, Microsoft offered free cybersecurity software to healthcare and human rights organizations at increased risk of hacking attacks.

This panel event will draw upon practical examples of private sector support for civic space across different sectors, geographies and political environments.

Why might companies step up to defend freedom of association, expression or political participation even where this comes at a financial or political cost? How can companies resist complicity with governments or regulation that threaten civic space? And what forums exist, or should exist, for developing tactical alliances between companies and civil society actors?

This event is also the launch of a new Chatham House resource, The Role of the Private Sector in Protecting Civic Space.

Expert

Expert

DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases.

A. G. Sergeev, A. Kh. Khachatryan and Kh. A. Khachatryan
Trans. Moscow Math. Soc. 83 (), 55-65.
Abstract, references and article information

Noga Alon, Anurag Bishnoi, Shagnik Das and Alessandro Neri
Trans. Amer. Math. Soc. 377 (), 5389-5410.
Abstract, references and article information

Christian Weiss
Theor. Probability and Math. Statist. 111 (), 199-209.
Abstract, references and article information

Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response.

20 July 2020

Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.

A booming tech sector can unleash pan-African trade The World Today mhiggins.drupal 31 July 2022

The new African Continental Free Trade Area must embrace hyperscale data centres, cross-border digital payments and other innovations to realise its potential.

The Africa Continental Free Trade Area (AfCFTA) not only lays the groundwork for a single market across the continent, it can act as a driving force to unleash the full potential of the technology revolution that is under way across the African continent. 

To help achieve this, the AfCFTA must go beyond simply lowering barriers to the movement of goods and services, to what the World Bank calls an ‘FDI [foreign direct investment] deep scenario’. This requires harmonizing policies on investment, competition, intellectual property rights and e-commerce to encourage FDI at a greater scale. 

The World Bank estimates that the AfCFTA could increase income across the continent by 7 per cent by 2035 (an additional $445 billion), mainly by boosting intra-regional trade in manufactured goods and lifting approximately 40 million people from extreme poverty. Under an FDI deep scenario, the projected income growth jumps to 9 per cent by 2035, supporting 50 million people out of extreme poverty. 

The initial focus of the AfCFTA is on movement of goods and services and the associated financial flows through the establishment of the Pan-African Payment and Settlement System (PAPSS), a technology that enables instant local currency payment across Africa without first converting to a hard currency. In addition, harmonizing policies and easing the movement of data could enable technology to accelerate the anticipated AfCFTA income growth.

Global venture capital is pouring in

There is no doubt the African tech industry is growing. In 2021, 681 African technology companies raised $5.2 billion in equity venture funding, up from $2 billion in 2019, according to Partech Partners’ annual Africa Tech Venture Capital report. 

It is understandable why the industry has attracted global venture capital. While tech businesses are often initially focused on meeting needs in their home markets, most have a strong desire to tap into the pan-African market, with its 1.3 billion consumers across 54 countries and a combined GDP of $3.4 trillion. This in turn should attract global venture capital to invest in Africa. 

The AfCFTA has created a framework for technology-led companies to scale across the continent in a way that will impact digital infrastructure, logistics, energy and much else. For example, Africa’s hyperscale data centre capacity would benefit from the ability to locate centres in the lowest cost jurisdiction with the best energy availability and to use that to power cloud storage across the continent.

Yet various regulatory constraints, including the desire for each state to own its population’s data on local servers, prevent that. As a result, African data centres are less competitive than those in America and China. 

Similarly, logistics and other sectors would be transformed if the information on goods in transit, such as digital customs documentation, could move easily across borders while being tracked across all 54 countries. Financial services would also benefit from the ability to pay across borders in a low-cost, frictionless way.

Fintech companies should be encouraged to build technology solutions linking to PAPSS and other initiatives to accelerate the adoption-of-use cases that PAPSS supports – such as intra-Africa instant payment, embedded finance and remittances services.

AfCFTA may also unlock mergers and acquisitions (M&A) activity among African and international firms. Technology companies are using M&A to enter new markets, as the international payments platform Stripe did when it acquired the Nigerian business Paystack, and the payments business MFS Africa did when it took over the fintech start-up Baxi. 

Governments and regulators must support innovation

Given the difficulty of a country-by-country organic growth strategy across Africa, M&A is likely to increase in various technology sectors over the next few years. With the anticipated ease of doing business that the AfCFTA could facilitate, we are likely to witness further welcome consolidation, creating larger corporates that create more jobs and increase tax revenues. 

To unlock the benefits that technology will bring, governments and regulators need to play a supportive role in encouraging innovation. They will need to ensure the appropriate consumer protections are in place without stifling creativity through regulation, inefficiencies or rent-seeking. 

At the same time, governments and regulators should not permit themselves to be held to ransom by dominant incumbents, such as banks and mobile operators in the fintech space, at the expense of stifling technology companies looking to disrupt their respective industries. 

Only then will the AfCFTA allow Africa to benefit from its tech potential. 

Risana Zitha writes this article in a personal capacity

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.

Visual Abstract

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

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

Colin T. McDowell
Nov 24, 2020; 0:RA120.002256v1-mcp.RA120.002256
Research

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.

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.

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Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies.

The adipocyte-derived hormone leptin increases trafficking of KATP and Kv2.1 channels to the pancreatic β-cell surface, resulting in membrane hyperpolarization and suppression of insulin secretion. We have previously shown that this effect of leptin is mediated by the NMDA subtype of glutamate receptors (NMDARs). It does so by potentiating NMDAR activity, thus enhancing Ca2+ influx and the ensuing downstream signaling events that drive channel trafficking to the cell surface. However, the molecular mechanism by which leptin potentiates NMDARs in β-cells remains unknown. Here, we report that leptin augments NMDAR function via Src kinase–mediated phosphorylation of the GluN2A subunit. Leptin-induced membrane hyperpolarization diminished upon pharmacological inhibition of GluN2A but not GluN2B, indicating involvement of GluN2A-containing NMDARs. GluN2A harbors tyrosine residues that, when phosphorylated by Src family kinases, potentiate NMDAR activity. We found that leptin increases phosphorylation of Tyr-418 in Src, an indicator of kinase activation. Pharmacological inhibition of Src or overexpression of a kinase-dead Src mutant prevented the effect of leptin, whereas a Src kinase activator peptide mimicked it. Using mutant GluN2A overexpression, we show that Tyr-1292 and Tyr-1387 but not Tyr-1325 are responsible for the effect of leptin. Importantly, β-cells from db/db mice, a type 2 diabetes mouse model lacking functional leptin receptors, or from obese diabetic human donors failed to respond to leptin but hyperpolarized in response to NMDA. Our study reveals a signaling pathway wherein leptin modulates NMDARs via Src to regulate β-cell excitability and suggests NMDARs as a potential target to overcome leptin resistance.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.

The early detection of pancreatic ductal adenocarcinoma is a complex clinical obstacle yet is key to improving the overall likelihood of patient survival. Current and prospective carbohydrate biomarkers CA19-9 and sTRA are sufficient for surveilling disease progression yet are not approved for delineating PDAC from other abdominal cancers and non-cancerous pancreatic pathologies. To further understand these glycan epitopes, an imaging mass spectrometry approach was utilized to assess the N-glycome of the human pancreas and pancreatic cancer in a cohort of PDAC patients represented by tissue microarrays and whole tissue sections. Orthogonally, these same tissues were characterized by multi-round immunofluorescence which defined expression of CA19-9 and sTRA as well as other lectins towards carbohydrate epitopes with the potential to improve PDAC diagnosis. These analyses revealed distinct differences not only in N-glycan spatial localization across both healthy and diseased tissues but importantly between different biomarker-categorized tissue samples. Unique sulfated bi-antennary N-glycans were detected specifically in normal pancreatic islets. N-glycans from CA19-9 expressing tissues tended to be bi-, tri- and tetra-antennary structures with both core and terminal fucose residues and bisecting N-acetylglucosamines. These N-glycans were detected in less abundance in sTRA-expressing tumor tissues, which favored tri- and tetra-antennary structures with polylactosamine extensions. Increased sialylation of N-glycans was detected in all tumor tissues. A candidate new biomarker derived from IMS was further explored by fluorescence staining with selected lectins on the same tissues. The lectins confirmed the expression of the epitopes in cancer cells and revealed different tumor-associated staining patterns between glycans with bisecting GlcNAc and those with terminal GlcNAc. Thus, the combination of lectin-IHC and IMS techniques produces more complete information for tumor classification than the individual analyses alone. These findings potentiate the development of early assessment technologies to rapidly and specifically identify PDAC in the clinic that may directly impact patient outcomes.

Deep proteome coverage in bottom-up proteomics requires peptide-level fractionation to simplify the complex peptide mixture before analysis by tandem mass spectrometry. By decreasing the number of co-eluting precursor peptide ions, fractionation effectively reduces the complexity of the sample leading to higher sample coverage and reduced bias towards high abundance precursors that are preferentially identified in data-dependent acquisition strategies. To achieve this goal, we report a bead-based off-line peptide fractionation method termed CIF or Carboxylate modified magnetic bead-based isopropanol gradient peptide fractionation. CIF is an extension of the SP3 (single-pot solid-phase-enhanced sample preparation) strategy and provides an effective but complementary approach to other commonly used fractionation methods including strong cation exchange (SCX) and reversed phase (RP)-based chromatography. We demonstrate that CIF is an effective offline separation strategy capable of increasing the depth of peptide analyte coverage both when used alone or as a second dimension of peptide fractionation in conjunction with high pH RP. These features make it ideally suited for a wide range of proteomic applications including the affinity purification of low abundance bait proteins.

Cells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

POSTPONED: Zimbabwe Futures 2025: Financial Sector Expansion and Policy Priorities 15 November 2017 — 9:00AM TO 11:30AM Anonymous (not verified) 6 November 2017 Harare, Zimbabwe 

This roundtable will draw on current best practice and senior level expertise to identify policy options for financial stability and sector growth. A depoliticized analysis of the development agenda will highlight requisite conditions and prospective policies for a business-driven roadmap to the economic recovery of Zimbabwe, with a specific focus on the financial sector.

Participants will discuss macro-economic policy and stability, retail banking products and services, fintech, mobilizing domestic finance for national infrastructure and balancing consumer price index and inflation.

This event is being held in partnership with the Zimbabwe Business Club.

PLEASE NOTE, THIS EVENT HAS BEEN POSTPONED UNTIL FURTHER NOTICE.

Zimbabwe Futures 2030: Policy Priorities for Economic Expansion 28 February 2019 — 9:00AM TO 1:00PM Anonymous (not verified) 7 February 2019 Harare, Zimbabwe

This roundtable draws on current best practice and senior level expertise to identify policy options for long term economic expansion in Zimbabwe and pathways for inclusive development.

Participants discuss the necessary policies and business strategies to enable and support the effective implementation of the Transitional Stabilization Programme and longer term national development plans.

The discussions highlight requisite conditions for a business-driven and inclusive process towards Zimbabwe’s long-term economic recovery.

This event was held in partnership with the Zimbabwe Business Club and Konrad Adenauer Stiftung.

Zimbabwe's Economy During the Coronavirus Pandemic and Beyond 8 September 2020 — 10:00AM TO 11:30AM Anonymous (not verified) 26 August 2020

COVID-19 has had a devastating effect on Zimbabwe’s already floundering economy. Important foreign currency earning industries have virtually stopped, and across the country livelihoods are at risk and an increasing number of people are reliant on government grants.

Businesses are having to become more flexible but are constrained by a weak policy environment and lack of confidence in the economy. Since 2017, the government has been pursuing an economic reform agenda and Transitional Stabilization Programme (TSP), which was scheduled for completion by the end of 2020. The deepening challenges highlight the need to accelerate economic reform and build confidence in order to achieve sustainable and inclusive growth.

At this webinar, speakers discuss the measures that government, businesses, and individuals are adopting in response to the COVID-19 economic challenge, and the policies required for recovery.

Read a meeting summary

This webinar is held in partnership with the Konrad Adenauer Stiftung.

South Africa's Economic Reform and Employment in the Context of the Coronavirus Pandemic 3 September 2020 — 3:00PM TO 4:00PM Anonymous (not verified) 26 August 2020 Online

President of COSATU, Zingiswa Losi, discusses the organization’s priorities for protecting jobs and workers, and working with other stakeholders to build a sustainable post-pandemic economy.

Employment in South Africa fell by an estimated 18 per cent between February and April 2020. The measures imposed to control the spread of COVID-19 suffocated an already weak economy and unemployment has hit a new high.

The stated aims of the government’s economic reform plans include the support of job creation in labour intensive industries, but the reform of the state and rebalancing of the economy and fiscus could lead to further job losses in state agencies and enterprises.

Protecting jobs while ensuring the health and safety of workers are dual priorities, and require the joint commitment and ‘social compact’ of labour, business and government.