Lipoprotein (a) [Lp(a)] is characterized by an LDL-like composition in terms of lipids and apoB100, and by one copy of a unique glycoprotein, apo(a). The apo(a) structure is mainly based on the repetition of tandem kringle domains with high homology to plasminogen kringles 4 and 5. Among them, kringle IV type 2 (KIV-2) is present in a highly variable number of genetically encoded repeats, whose length is inversely related to Lp(a) plasma concentration and cardiovascular risk. Despite it being the major component of apo(a), the actual function of KIV-2 is still unclear. Here, we describe the first high-resolution crystallographic structure of this domain. It shows a general fold very similar to other KIV domains with high and intermediate affinity for the lysine analog, -aminocaproic acid. Interestingly, KIV-2 presents a lysine binding site (LBS) with a unique shape and charge distribution. KIV-2 affinity for predicted small molecule binders was found to be negligible in surface plasmon resonance experiments; and with the LBS being nonfunctional, we propose to rename it "pseudo-LBS". Further investigation of the protein by computational small-molecule docking allowed us to identify a possible heparin-binding site away from the LBS, which was confirmed by specific reverse charge mutations abolishing heparin binding. This study opens new possibilities to define the pathogenesis of Lp(a)-related diseases and to facilitate the design of specific therapeutic drugs.

Despite the continued analysis of HDAC inhibitors in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The presence of two Sin3 paralogs in humans, SIN3A and SIN3B, may result in a heterogeneous population of Sin3 complexes and contributes to our poor understanding of the functional attributes of these complexes. Here, we profile the interaction networks of SIN3A and SIN3B to gain insight into complex composition and organization. In accordance with existing data, we show that Sin3 paralog identity influences complex composition. Additionally, chemical cross-linking MS identifies domains that mediate interactions between Sin3 proteins and binding partners. The characterization of rare SIN3B proteoforms provides additional evidence for the existence of conserved and divergent elements within human Sin3 proteins. Together, these findings shed light on both the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.

After successful completion of the Human Genome Project (HGP), HUPO has recently officially launched a global Human Proteome Project (HPP) which is designed to map the entire human protein set. Given the presence of about 30% undisclosed proteins out of 20,300 protein gene products, a systematic global effort is necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP groups employ the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge base. The HPP participants will take advantage of the output and cross-analyses from the ongoing HUPO initiatives and a chromosome-based protein mapping strategy, termed C-HPP with many national teams currently engaged. In addition, numerous biologically-driven projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents and tools for protein studies and analyses, and a stronger basis for personalized medicine. HUPO urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.

Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.

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.

Alpha-1-acid glycoprotein (AGP) is an acute phase glycoprotein in blood, which is primarily synthetized in the liver and whose biological role is not completely understood. It consists of 45% carbohydrates that are present in the form of five N-linked complex glycans. AGP N-glycosylation was shown to be changed in many different diseases and some changes appear to be disease-specific, thus it has a great diagnostic and prognostic potential. However, AGP glycosylation was mainly analyzed in small cohorts and without detailed site-specific glycan information. Here, we developed a cost-effective method for a high-throughput and site-specific N-glycosylation LC-MS analysis of AGP which can be applied on large cohorts, aid in search for novel disease biomarkers and enable better understanding of AGP’s role and function in health and disease. The method does not require isolation of AGP with antibodies and affinity chromatography, but AGP is enriched by acid precipitation from 5 μl of bloodplasma in a 96 well format. After trypsinization, AGP glycopeptides are purified using a hydrophilic interaction chromatography based solid-phase extraction and analyzed by RP-LC-ESI-MS. We used our method to show for the first time that AGP N-glycan profile is stable in healthy individuals (14 individuals in 3 time points), which is a requirement for evaluation of its diagnostic potential. Furthermore, we tested our method on a population including individuals with registered hyperglycemia in critical illness (59 cases and 49 controls), which represents a significantly increased risk of developing type 2 diabetes. Individuals at higher risk of diabetes presented increased N-glycan branching on AGP’s second glycosylation site and lower sialylation of N-glycans on AGP’s third and AGP1’s fourth glycosylation site. Although this should be confirmed on a larger prospective cohort, it indicates that site-specific AGP N-glycan profile could help distinguish individuals who are at risk of type 2 diabetes.

The Costs of Fuelling Humanitarian Aid Research paper sysadmin 7 December 2018

As humanitarian crises become more protracted and aid budgets face unprecedented scrutiny, agencies could save millions by switching from diesel and oil fuels to cleaner energy sources.

Download the accompanying toolkit

Most refugee and internal displacement camps are in remote locations, so humanitarian agencies consume large amounts of fuel on the transport of staff, equipment, and goods such as food and water.

Operations tend to rely on on-site electricity generation to power reception centres, clinics, schools, food storage, water-pumping and street lighting. Despite the essential role of energy in humanitarian action, and the UN’s stated commitment to carbon neutrality by 2020, there is no concerted effort to move away from fossil fuel to date.

Summary points

• Agencies are paying too much for the energy they consume. They are overwhelmingly dependent on oil fuel for electricity generation, even though renewable energy solutions are reducing costs for those deploying them in similar conditions. Well-below-optimum standards of efficiency in buildings, generator use and fleet management are also the norm.
• Agencies typically have few incentives to do things better. There is rarely motivation to conserve fuel, nor performance indicators for energy or fuel use. In addition, energy spending and use lacks transparency.
• Few agencies collect and report on energy use. Where numbers are available, they are usually partial and unverified. Energy costs are rarely transparent in budgets; and donors do not know how much is being spent.
• We estimate that around 5 per cent of humanitarian agencies’ expenditure goes on diesel, petrol and associated costs such as fixing generators. That would mean that the sector spent some $1.2 billion on polluting fuel in 2017.
• Based on current best-practice, the sector could save at least 10 per cent of fuel costs on ground transport, 37 per cent through behaviour change and more efficient technologies, and 60 per cent on generation – all using currently available, affordable and proven practice and technology changes.
• At current prices, this could mean operational savings of over $517 million a year for the humanitarian sector, roughly equal to 5 per cent of UNHCR’s funding gap for 2017.
• In Kenya, annual spending on diesel and petrol for the seven agencies surveyed was $6.7 million in 2017. Replacing gensets with solar systems could create significant savings due the costs of diesel, the likelihood of protracted camp situations, and the opportunities that off-grid solar would offer for extending electricity access to refugees and local populations in Garissa and Turkana counties.
• In Jordan, solar energy now powers the majority of camp facilities and many households. However, the use of grid electricity by humanitarian agencies’ large head offices in Amman remains high and expensive. Improving the energy efficiency of buildings is a priority for savings.
• In Burkina Faso’s Goudoubo camp, NGO offices are desperately short of power – they have no computers or air-conditioning. Investment in renewable forms of energy for this and other camp services such as street lighting and water pumping would enable better service provision, and could drive increased rural energy access among host populations across this area of the Sahel.

Toolkit

An accompanying toolkit, Powering Ahead: Improving How We Use and Account for Energy in Humanitarian Operations, provides practical guidance for humanitarian agencies that want to make energy cost savings and reduce their carbon and emissions footprint.

Innovative Financing for Humanitarian Energy Interventions Research paper sysadmin 28 February 2019

This paper explores the increase in resources and funding needed to improve the access of displaced people to modern and sustainable energy services.

Summary

• In settings that host displaced and refugee communities, energy can act as an enabler for improved healthcare, education and access to clean water. More efficient sources of energy can also save money that can be reinvested in life-saving interventions. A range of challenges exist that inhibit the uptake and effective management of cleaner energy solutions in displacement settings. These are magnified by a lack of available and appropriate funding.
• The current funding gap is significant. In many cases, involving the private sector (both enterprises and investors) is viewed as a way to accelerate delivery of sustainable energy solutions, leverage additional capital, efficiency and expertise, and adopt more sustainable and market-based approaches.
• Displacement settings are an extreme example of complex and unpredictable operating environments. Traditional approaches to the financing of energy access will not be supported by the risk/return characteristics of this market opportunity, so alternative structures are needed.
• Such structures can include mechanisms such as grants, guarantees, ‘results-based financing’ and ‘impact bonds’. These blended financial instruments should aim to leverage first losses – whereby, in the case of default, the first loss is taken by the ‘impact-first’ investors, or guarantors, thereby fully or partially protecting ‘finance-first’ investors.
• Given the specific constraints of displacement settings, any financing mechanisms at present are likely to fall between the categories of providing ‘more efficient aid’ and ‘more efficient aid through markets’. They are likely to constitute a transitional step from grant-making towards the use of commercial investment vehicles.
• While a number of financial mechanisms could be applied to attract private-sector engagement, most remain theoretical, with few being implemented extensively or at scale. Where such financial mechanisms have already been used, access to relevant data is poor, especially in circumstances where the desired outcomes were not achieved.
• The Moving Energy Initiative (MEI) completed feasibility work into the concept of an energy humanitarian fund and found that, while a need for this type of facility has emerged, it sits in a difficult position between energy access, climate and humanitarian funding sources. Key donors are needed to drive forward innovative financing vehicles and further testing of these mechanisms, in order to generate market data and evidence for further iterations and additional investments.

Infrastructure Management Contracts: Improving Energy Asset Management in Displacement Settings Research paper sysadmin 17 April 2019

This paper highlights a number of options for managing electricity infrastructure in refugee camps and outlines the challenges, opportunities and operational implications associated with them. It takes the Kalobeyei settlement in Kenya as a case study.

• Building and maintaining electricity infrastructure to power offices, businesses, households and other operations in displacement settings is difficult. It is especially challenging for the Office of the United Nations High Commissioner for Refugees (UNHCR) and its partner agencies, because supplying electricity is not their core business.
• Private-sector companies exist that are willing and able to develop infrastructure management contracts to provide energy as a service in displacement settings. However, institutional barriers within humanitarian agencies persist, with short budgeting cycles in particular preventing humanitarian agencies from entering into the sorts of long-term service agreements required by the private sector.
• A number of options exist to leverage the expertise of the private sector through ‘public–private partnership’ (P3) structures. Such mechanisms can promote more efficient management of infrastructure by drawing on private-sector experience and expertise, incentivizing appropriate risk-sharing and providing options to leverage private capital in project development.
• Field work from the Kalobeyei settlement in Kenya suggests that a solar/diesel hybrid mini-grid solution was the most economical option to power camp services and infrastructure there. Compared to distributed diesel generation, the annual savings in operating costs were estimated at $49,880, with the additional investment paid back within 3.6 years.
• Humanitarian agencies need to be willing to change their policies to enable long-term service agreements. Alternatively (or, more likely, in conjunction with this option), financial mechanisms such as partial risk guarantees need to be developed to offset some of the risks. This change will need high-level support from donors and humanitarian agencies.
• Once the first infrastructure management contracts can be signed and tested in displacement locations (through the use of donor funding or otherwise) and associated data collected, it will ease the way for future investments in these types of projects.

Online Disinformation and Political Discourse: Applying a Human Rights Framework Research paper sysadmin 5 November 2019

Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law.

This paper examines how human rights frameworks should guide digital technology.

Summary

• Online political campaigning techniques are distorting our democratic political processes. These techniques include the creation of disinformation and divisive content; exploiting digital platforms’ algorithms, and using bots, cyborgs and fake accounts to distribute this content; maximizing influence through harnessing emotional responses such as anger and disgust; and micro-targeting on the basis of collated personal data and sophisticated psychological profiling techniques. Some state authorities distort political debate by restricting, filtering, shutting down or censoring online networks.
• Such techniques have outpaced regulatory initiatives and, save in egregious cases such as shutdown of networks, there is no international consensus on how they should be tackled. Digital platforms, driven by their commercial impetus to encourage users to spend as long as possible on them and to attract advertisers, may provide an environment conducive to manipulative techniques.
• International human rights law, with its careful calibrations designed to protect individuals from abuse of power by authority, provides a normative framework that should underpin responses to online disinformation and distortion of political debate. Contrary to popular view, it does not entail that there should be no control of the online environment; rather, controls should balance the interests at stake appropriately.
• The rights to freedom of thought and opinion are critical to delimiting the appropriate boundary between legitimate influence and illegitimate manipulation. When digital platforms exploit decision-making biases in prioritizing bad news and divisive, emotion-arousing information, they may be breaching these rights. States and digital platforms should consider structural changes to digital platforms to ensure that methods of online political discourse respect personal agency and prevent the use of sophisticated manipulative techniques.
• The right to privacy includes a right to choose not to divulge your personal information, and a right to opt out of trading in and profiling on the basis of your personal data. Current practices in collecting, trading and using extensive personal data to ‘micro-target’ voters without their knowledge are not consistent with this right. Significant changes are needed.
• Data protection laws should be implemented robustly, and should not legitimate extensive harvesting of personal data on the basis of either notional ‘consent’ or the data handler’s commercial interests. The right to privacy should be embedded in technological design (such as by allowing the user to access all information held on them at the click of a button); and political parties should be transparent in their collection and use of personal data, and in their targeting of messages. Arguably, the value of personal data should be shared with the individuals from whom it derives.
• The rules on the boundaries of permissible content online should be set by states, and should be consistent with the right to freedom of expression. Digital platforms have had to rapidly develop policies on retention or removal of content, but those policies do not necessarily reflect the right to freedom of expression, and platforms are currently not well placed to take account of the public interest. Platforms should be far more transparent in their content regulation policies and decision-making, and should develop frameworks enabling efficient, fair, consistent internal complaints and content monitoring processes. Expertise on international human rights law should be integral to their systems.
• The right to participate in public affairs and to vote includes the right to engage in public debate. States and digital platforms should ensure an environment in which all can participate in debate online and are not discouraged from standing for election, from participating or from voting by online threats or abuse.

In eukaryotic DNA replication, DNA polymerase ε (Polε) is responsible for leading strand synthesis, whereas DNA polymerases α and δ synthesize the lagging strand. The human Polε (hPolε) holoenzyme is comprised of the catalytic p261 subunit and the noncatalytic p59, p17, and p12 small subunits. So far, the contribution of the noncatalytic subunits to hPolε function is not well understood. Using pre-steady-state kinetic methods, we established a minimal kinetic mechanism for DNA polymerization and editing catalyzed by the hPolε holoenzyme. Compared with the 140-kDa N-terminal catalytic fragment of p261 (p261N), which we kinetically characterized in our earlier studies, the presence of the p261 C-terminal domain (p261C) and the three small subunits increased the DNA binding affinity and the base substitution fidelity. Although the small subunits enhanced correct nucleotide incorporation efficiency, there was a wide range of rate constants when incorporating a correct nucleotide over a single-base mismatch. Surprisingly, the 3'→5' exonuclease activity of the hPolε holoenzyme was significantly slower than that of p261N when editing both matched and mismatched DNA substrates. This suggests that the presence of p261C and the three small subunits regulates the 3'→5' exonuclease activity of the hPolε holoenzyme. Together, the 3'→5' exonuclease activity and the variable mismatch extension activity modulate the overall fidelity of the hPolε holoenzyme by up to 3 orders of magnitude. Thus, the presence of p261C and the three noncatalytic subunits optimizes the dual enzymatic activities of the catalytic p261 subunit and makes the hPolε holoenzyme an efficient and faithful replicative DNA polymerase.

The origin recognition complex (ORC), composed of six subunits, ORC1–6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2–7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9–mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Even if an internal methionine is used to produce an undetectable, N terminally deleted ORC5, the protein would lack 80% of the AAA+ ATPase domain, including the Walker A motif. The ORC5-depleted cells show normal chromatin binding of MCM2–7 and initiate replication from a similar number of origins as WT cells. In addition, we introduced a second mutation in ORC2 in the ORC5 mutant cells, rendering both ORC5 and ORC2 proteins undetectable in the same cells and destabilizing the ORC1, ORC3, and ORC4 proteins. Yet the double mutant cells grow, recruit MCM2–7 normally to chromatin, and initiate DNA replication with normal number of origins. Thus, in these selected cancer cells, either a crippled ORC lacking ORC2 and ORC5 and present at minimal levels on the chromatin can recruit and load enough MCM2–7 to initiate DNA replication, or human cell lines can sometimes recruit MCM2–7 to origins independent of ORC.

Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we identified a specific G-quadruplex–forming sequence at the heavy-strand promoter (HSP1) that has the potential to cause significant stalling of mtDNA replication. Furthermore, this structured region of DNA corresponds to the break site for a large (3,895 bp) deletion observed in mitochondrial disease patients. The presence of this deletion in humans correlates with UV exposure, and we have found that efficiency of polymerase γ DNA synthesis is reduced after this quadruplex is exposed to UV in vitro.

General Manager Matt Klentak discussed the Phillies' offseason in a press conference on Thursday in Clearwater, Fla. The Phillies remain in contact with the agents for Bryce Harper and Manny Machado. The belief is that the front office still prefers Machado over Harper because of Machado's combination of offense and defense.

Bryce Harper is the final superstar standing for the Phillies.

Improving Economic Management for Sustainable Growth in Zambia 13 July 2018 — 9:00AM TO 10:00AM Anonymous (not verified) 19 June 2018 Chatham House, London

THIS EVENT IS POSTPONED.

High levels of infrastructure investment funded by commercial loans, against a backdrop of subdued economic growth, resulted in an increase in Zambia’s public external debt from $8.7 billion in 2017 to $9.3 billion in March 2018.

In June 2018 Zambia’s Ministry of Finance announced new austerity measures aimed at reducing the country’s debt burden, as part of an ongoing reform agenda that is hoped to stabilise the economy.

In the meantime Zambia grapples with severe social and development challenges. Decreased spending in health, education and social protection, and poor access in rural areas, have already left Zambia ranked 139th out of 188 countries in the UNDP’s 2016 human development index.

At this meeting Margaret Mwanakatwe, minister of finance, discusses the government’s financial reform agenda, its engagement with creditors and IFIs, and plans for generating sustainable growth and job creation.

Higher Education in South Africa: Demands for Inclusion and the Challenges of Reform 17 October 2018 — 5:00PM TO 6:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

Ramaphosa Must Act Fast With New Mandate in South Africa Expert comment sysadmin 23 May 2019

In the wake of South Africa’s election, political constraints will ebb momentarily. The president should seize the opportunity to deliver meaningful change.

On 25 May, Cyril Ramaphosa will be inaugurated as president of South Africa, having dragged the African National Congress (ANC) over the line in the 8 May election. The ANC gained a 57 per cent majority, its lowest vote since 1994, its status as national liberator deeply eroded by successive corruption scandals. Only Ramaphosa’s personal popularity stopped it haemorrhaging more support.

His sustained action against corrupt public servants and promises of job-creating economic growth has attracted support from beyond the ANC’s base, including a significant minority of white voters, and generated significant international goodwill. Ramaphosa now has a short window of opportunity to reset social democracy in South Africa before the political cycle of municipal, party and national elections from 2021 to 2024 forces his attention back to party politics.

Defining ‘Ramaphosa-ism’

But personal popularity is fickle, and goodwill alone will not turn around the ailing economy. To attract investment and keep the electorate on side, Ramaphosa’s government needs to move beyond pragmatic crisis responses and articulate a clear, shared vision for how market intervention can allow the economy to grow while simultaneously delivering social transformation.

Growth will be hard to achieve in the short term. The economy is expected to grow 1.2% in 2019 and 1.5% in 2020, according to the IMF. Consumer confidence remains subdued, and a decade of declining GDP per capita and increasing inequality has put a strain on households. A ‘fiscal stimulus’ in 2018 delivered very little new government spending, and over the past 10 years, the government wage bill has increased three times higher than the rate of inflation.

Eskom, the state electricity provider, has debts equating to the GDP of Latvia and is not the only state-owned enterprise (SOE) that has required bailing out by the government. There are plans to break up Eskom into three separate entities but calls for deeper reform – or even privatization – are growing.

The president’s responses to these challenges will go a long way to defining ‘Ramaphosa-ism’ and the role of government in pursuing equitable economy growth.

Economic expectations under Ramaphosa

Ramaphosa was a champion of the introduction of a minimum wage and a proponent of the National Development Plan, which relies on growth to drive job creation. His support for land reform is an individual conviction as much as it is a party line, although his views are softer than many in the party, with state-owned land being the initial target.

Investor uncertainty on land tenure and regulations in mining will need to be addressed through passing key pieces of legislation on land reform and the revised Mining and Petroleum Resources Development Act.

Where Ramaphosa differs from his predecessors is his links with business. Thabo Mbeki enjoyed a relationship of mutual respect with business; this disintegrated under Jacob Zuma. Ramaphosa, however, is part of South Africa’s business community, having founded the Shanduka Group, with investments in multiple sectors including retail, telecoms and extractives, and served as chairman of MTN and Bidvest. As president, he has surrounded himself with close economic advisers from business and banking.

In the short term, anti-corruption measures and competent appointments will ease investor woes. In the long term, there is a need to improve the ease of doing business, including labour market reforms, and to make South Africa a more competitive business environment by reducing the hold of large conglomerates on the economy. Ramaphosa may also make greater use of public-private partnerships for large projects.

Political constraints

Ramaphosa faces few immediate political challenges. The ANC is still deeply divided, but although Ramaphosa does not enjoy the ideological support of the entire party, his opponents are leaderless post-Zuma, and have been unable to offer a coherent alternative. ANC Secretary General Ace Magashule has fallen into the role of interim figurehead of this faction, and allegations of corruption would make it difficult for him to aspire to national leadership.

The need to avoid splits before the election meant Ramaphosa had to make concessions, and his first cabinet in February 2018 included opponents and those accused of corruption or incompetence, such as Malusi Gigaba and Bathabile Dlamini. Such concessions to political opponents are unlikely to continue after the election.

Meanwhile, opposition parties made some advances in the election, but where Zuma was an easy target, they are still grappling with how to confront Ramaphosa. The party with the biggest gains was the Economic Freedom Fighters, whose increase of just over 4 points from the last election gave it 11 per cent of the vote this time. They will likely continue to be an effective disruptor. Ramaphosa may also be challenged by trade unions on his reforms, notably over any break-up of SOEs.

But the biggest and most immediate external political challenge for Ramaphosa will be rebuilding trust between government and society, in a context where social protest has become an alternative form of political participation. A turnout of 65 per cent may be considered normal in Western democracies but is a notable drop for a country as politicized as South Africa, driven by frustration and a sense of exclusion as much as apathy. Turnout by young people was even lower.

Achieving the vision

South Africa has all the platforms it needs to project its renewal and attract vital external investment – it is a non-permanent member of the UN Security Council, it will take over as chair of the African Union in 2020, it is a member of BRICS and it is the only African member of the G20. But in the recent past, it has struggled to tell a coherent story about its vision for the future and offer to the world.

In the immediate wake of the election, internal and external political constraints will ebb. Ramaphosa must act fast to deliver results before the election cycle starts again. To attract much needed investment stimulus, he will not only need to articulate and market his vision for South Africa, but also outline how he plans to achieve it.

Can diplomacy advance human rights? 25 April 2023 — 4:00PM TO 5:00PM Anonymous (not verified) 7 March 2023 Chatham House and Online

How is diplomacy contributing to advancing human rights through the multilateral system?

The international human rights system has come under significant pressure in recent years. Russia’s invasion of Ukraine and the US-China rivalry have created difficult political pressures, while major global challenges including climate change and global inequality demand answers. Effective diplomacy on human rights has become increasingly difficult, with incentives stacked against bold action.

The relationship between diplomacy and human rights is an uneasy one. Diplomacy is an art of negotiation, persuasion and compromise. Human rights are tightly defined and universal. The relationship between the two may seem paradoxical, but in the context of an unstable world order, it has never been more important.

In the 75th anniversary year of the Universal Declaration of Human Rights, this discussion will explore the critical role of diplomacy in advancing human rights in the future.

• What are the critical human rights challenges today? What is the role of diplomacy in addressing them?

• What is the impact of intensifying competition between the US and China on the human rights system?

• Is there an opening for more leadership emerging from the Global South?

• What is the future of the human rights system in the context of this polarized world?

As with all member events, questions from the audience drive the conversation.

War on Ukraine: Exploring the humanitarian response to the conflict 12 April 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 6 April 2022 Online

This event explores the implications of the humanitarian realities from Russia’s invasion of Ukraine, the largest ground campaign in Europe since World War Two.

Reports from humanitarian organizations working in Ukraine are dire and reveal that a humanitarian disaster on an epic scale is unfolding.

The United Nations (UN) and other organizations estimate 12 million of Ukraine’s population are in need of assistance, 4.1 million have been displaced to neighbouring countries, and 6.4 million have become internally displaced.

Gillian Triggs, the assistant secretary-general and assistant high commissioner for protection at the UNHCR, joins other experts to discuss the humanitarian situation in Ukraine.

The panel considers:

• What are the greatest needs in Ukraine now?
• How can aid agencies meet those needs?
• What are the short and long-term implications of the crisis for Ukraine and Europe?
• How do international organizations work with local NGOs to provide food, medical aid and shelter?

This event is part of a regular series of events offering insight and analysis from experts and policymakers on how the war is affecting Ukraine, the region and the world.

This event is part of Chatham House’s ongoing work on the future of conflict.

Read the transcript

Review: One-man bandwagons The World Today rsoppelsa.drupal 25 May 2022

The ills of strongman politics are diagnosed sharply in this accessible overview – but a cure is nowhere to be found, says Natasha Lindstaedt

The Age of the Strongman: How the Cult of the Leader Threatens Democracy around the World
Gideon Rachman, Bodley Head, £20.00

For anyone reading the headlines, it should come as no surprise that democracy has regressed to where it was in 1989. The profound geopolitical and technological changes in the post-Cold World era have led to chaos, polarization, nationalist backlash and nostalgia for strong leadership in democracies. 

Countries such as Russia and China have provided a new model for leadership that has become frighteningly infectious – the strongman. 

Gideon Rachman charts this new era, offering an accessible overview of 14 examples, including Britain’s Boris Johnson, Donald Trump of the United States, Narendra Modi of India, Jair Bolsonaro of Brazil, Viktor Orbán of Hungary, Xi Jinping of China and – the archetype – Vladmir Putin of Russia.

The idea that we are living in the age of strongman politics is not particularly novel. Scholars of authoritarian politics have noted for years that there has been a steady rise in ‘personalist’ dictatorship and personalism in democracy in general. Nearly 40 per cent of all dictatorships are personalist, meaning domination by a single person, compared with 23 per cent in 1988. Autocracies have become increasingly aggressive, using sharp power to undermine democracy, which signals a shift. 

Autocracies used to focus on their own stability and didn’t interfere with democracies.

Rachman focuses on this threat that the strongman poses to democracy while macho one-man rule spreads across the globe. He provides a well-written, clear overview of why each leader fits the strongman label, what explains their appeal and what informs their worldview. 

Where Rachman is effective is in weaving together the commonalities of these strongmen – and they are all men – and their relationship to each other. Despite their ultra-nationalism, they have created an unofficial, multilateral network of mutual support. This includes leaders whose religious convictions may appear to be in conflict – such as Benjamin Netanyahu of Israel and Muhammed bin Salman of Saudi Arabia. 

This is not just a network of dictators – autocratic-style leaders of democratic countries have been welcomed to the club. In this system, strongmen openly admire each other, revel in their disdain for liberalism and human rights, and share advice and inspiration. 

This contrasts with western European leaders who fail to build such iron-clad bonds.

Each chapter is peppered with anecdotes about Rachman’s first-hand impressions of some of these leaders and other notables in positions of power gained from his decades as a foreign correspondent and analyst. His colourful commentary complements his understanding of how they operate. 

A common theme throughout is that the strongman’s appeal appears as a breath of fresh air for democracy, liberalism or peace. They are often labelled as anti-elitist and men of the people. This honeymoon period ends when each leader shows their true colours: attacking political opponents, sometimes in ruthless purges, disregarding the rule of law, weakening the courts and vilifying or controlling the media. 

A well-placed quote from Recep Erdogan sums this up: ‘Democracy is like a tram you ride until you arrive at your destination.’

Genuine public support exists for these manoeuvres. Dislocation from unmanaged globalization and economic crises has created an audience for political entrepreneurs. Strongman leaders have earned the distinction of being relatable and telling it like it is, despite many being considered to be liars and often filthy rich. 

Their ability to tap into people’s fears of the West, crime, immigrants or other ethnic and religious groups has helped gain them a fiercely loyal following. According to Rachman, strongman politics is linked to fear that a majority group that was once dominant is being threatened – something leaders such as Donald Trump have astutely tapped into.

Unlike some of the kleptocratic regimes of the 1970s and 1980s that were the embodiment of venal opportunists – think of Ferdinand Marcos of the Philippines, Mobutu of the Democratic Republic of the Congo and Jean-Claude Duvalier of Haiti – the strongmen of today have been inspired by the ideology of hyper-nationalism and anti-liberalism. 

Rachman links strongmen to the work of Carl Schmitt, a Nazi Party member, who was a vociferous critic of parliamentary democracy and cosmopolitanism, while touting the importance of illiberal norms to exercise power. Rachman argues that we are in a war of ideas, with liberalism under attack. He hones in on the perennial target George Soros, and how his support for liberal democracy has garnered the unwanted attention from the world’s right-wing ideologues and strongmen.

Social media has been usurped by these leaders and their regimes to forge closer, direct relationships with their supporters, to churn out fake news and create dangerous echo chambers. They are snake oil salesmen, making huge promises but offering very little in practice. They are never as they initially appear, and their images are carefully crafted.

Another theme emerges on the career pathway. Many served as a mayor of a cosmopolitan city. An interesting chapter on Johnson explains how he comes across like a relatable ‘good chap’, being able to handle embarrassing photo-ops. He was also a devoted Europhile, attended Eton and Oxford, and championed multi-culturalism as Mayor of London. Always the opportunist, Johnson had few qualms about campaigning for Brexit, and then later breaking the law to make it happen.

Yet there are some gaps in Rachman’s analysis.

It is never made clear why leaders such as Abdel Fattah el-Sisi of Egypt, Nicolás Maduro of Venezuela and Kim Jong-un of North Korea are largely missing, or a number of other strongman dictators in sub-Saharan Africa. 

Though there is a chapter devoted to Abiy Ahmed of Ethiopia, along with a few paragraphs devoted to Paul Kagame of Rwanda, Meles Zenawi also of Ethiopia, Emmerson Mnangagwa of Zimbabwe and Jacob Zuma of South Africa, the chapter on African strongmen does not acknowledge that this is the only continent where the regional trend is not as depressing. 

Rachman only occasionally engages with data on dictatorships to verify some of the patterns that he explores in the book. And his work would benefit from an examination of the institutional factors that may explain the rise of strongman politics, such as the pre-existing weakness of parties, parliaments and courts. 

Nor does he go in depth into how strongmen interact with their institutions and what the implications of this brand of politics are for conflict and development. The failures of strongmen to address Covid-19 are mentioned, but it is never explained why they may be so poorly equipped to govern. 

So, is democracy dead? Though Rachman is largely pessimistic, he acknowledges that politics tends to go in waves. There is little advice about how the West can expedite the end of this particular wave. 

The one positive Rachman offers is that strongman rule cannot deal with succession. This is largely true, though handovers have taken place, such as with the Kim dynasty. 

But there are definitely more questions raised than answers provided. What is left after strongmen are no longer in power? What must democracies do to undermine strongmen or prevent their rise? Where will the next strongman appear? 

Rachman’s book doesn’t provide these answers, but he does offer an interesting overview of the leaders dominating the headlines.
 

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope ¹⁷⁷Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [¹⁷⁷Lu]Lu-Gemini was prepared with no-carrier-added ¹⁷⁷LuCl₃ to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-¹⁷⁷Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [¹⁷⁷Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [¹⁷⁷Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([¹⁷⁷Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [¹⁷⁷Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [¹⁷⁷Lu]Lu-Gemini behaved similarly to [¹⁷⁷Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [¹⁷⁷Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [¹⁷⁷Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [¹⁷⁷Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [¹⁷⁷Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [¹⁷⁷Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered ¹⁷⁷Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [⁶⁸Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [⁶⁸Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [⁶⁸Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV_max of these lesions was 19.6 (range, 2.7–95.3), and the mean SUV_mean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV_mean, <1.6), with a continuous decline to 4 h after administration (mean SUV_mean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV_max of 31.3) and decreased gradually afterward. Conclusion: [⁶⁸Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [⁶⁸Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret ¹⁸F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus–positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 ¹⁸F-FDG PET/CT and 134 ¹⁸F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no ¹⁸F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of ¹⁸F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if ¹⁸F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUV_max was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement ( = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement ( = 0.86). Quantitative assessment with an estimated best SUV_max ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement ( = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement ( = 0.86). Conclusion: Nuclear medicine physicians without ¹⁸F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

Private prison stocks soared Monday after President-elect Donald Trump announced immigration hardliner Tom Homan as the nation's next "border czar." GeoGroup jumped 4.5%, while CoreCivic increased 6.3%.

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CHANDLER, Ariz., Oct. 23, 2024 — The global edge computing market is expected to grow by more than 30 percent in the next five years, serving mission-critical applications in the […]

The post Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing appeared first on HPCwire.

An American woman who was traveling in Hungary was killed in Budapest last week allegedly by a man she met on vacation.

The Miami Marlins officially hired former Los Angeles Dodgers first base coach Clayton McCullough as their new manager, the franchise announced Monday.

About This Webinar Oracle’s next generation HPC architecture with Intel compute instance based on 3rd Generation Intel® Xeon® Scalable processors, code named “Ice Lake”, changes the game for HPC in […]

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A Maryland Lottery player said following a friend's advice led to her winning a $30,000 prize from a Fast Play game.

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SAN ANTONIO, Nov. 5, 2024 — Rackspace Technology has announced the expansion of Rackspace Spot with a new geographic location and an on-demand GPU-as-a-Service powered by NVIDIA. The expansion comes […]

The post Rackspace Expands Spot Platform with On-Demand NVIDIA GPU-as-a-Service for AI Workloads appeared first on HPCwire.

LONDON, Nov. 1, 2024 — Quantum Motion, a UK-based quantum computing scale-up founded by Professor John Morton, University College London (UCL), and Professor Simon Benjamin, University of Oxford, has worked […]

The post Quantum Motion and Goldman Sachs Identify Quantum Applications in Financial Services Project appeared first on HPCwire.

After a decade of forward deployment in Japan, the USS Germantown departed U.S. Fleet Activities Sasebo on Wednesday.

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When storage is mentioned in an AI or Big Data analytics context, it is assumed to be a high-performance system. In practice, it may not be, and the user eventually […]

The post High-Performance Storage for AI and Analytics Panel appeared first on HPCwire.

Divergent Technologies developed a digital production system that can revolutionize automotive and industrial scale manufacturing. Divergent uses new manufacturing solutions and their Divergent Adaptive Production System (DAPS™) software to make […]

The post Transforming Industrial and Automotive Manufacturing appeared first on HPCwire.

The surge in digital transformation across industries has led to exponential data growth, driving a heightened demand for computing power. However, this growth also intensifies concerns about energy consumption and […]

The post Renewable Power Unlock New Efficiencies for High-Performance Computing appeared first on HPCwire.

A Maryland man found some loose cash in his back pocket and ended up using it to buy a lottery ticket worth more than $45,000.

REDWOOD CITY, Calif., Nov. 4, 2024 — MinIO has announced compelling new optimizations and benchmarks for Arm-based chipsets powering on its object store. These optimizations underscore the relevance of low-power, […]

The post MinIO Optimizes Arm-Based Chipsets for High-Performance AI appeared first on HPCwire.

SAN JOSE, Calif., Nov. 12, 2024 — VDURA, a leader in data infrastructure for AI and HPC, today has announced a groundbreaking release of its VDURA Data Platform software, designed to […]

The post VDURA Unveils Next-Gen Data Platform with Enhanced AI and HPC Performance appeared first on HPCwire.