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.

Homologous recombination (HR) repairs DNA double-strand breaks using intact homologous sequences as template DNA. Broken DNA and intact homologous sequences form joint molecules (JMs), including Holliday junctions (HJs), as HR intermediates. HJs are resolved to form crossover and noncrossover products. A mismatch repair factor, MLH3 endonuclease, produces the majority of crossovers during meiotic HR, but it remains elusive whether mismatch repair factors promote HR in nonmeiotic cells. We disrupted genes encoding the MLH3 and PMS2 endonucleases in the human B cell line, TK6, generating null MLH3−/− and PMS2−/− mutant cells. We also inserted point mutations into the endonuclease motif of MLH3 and PMS2 genes, generating endonuclease death MLH3DN/DN and PMS2EK/EK cells. MLH3−/− and MLH3DN/DN cells showed a very similar phenotype, a 2.5-fold decrease in the frequency of heteroallelic HR-dependent repair of restriction enzyme–induced double-strand breaks. PMS2−/− and PMS2EK/EK cells showed a phenotype very similar to that of the MLH3 mutants. These data indicate that MLH3 and PMS2 promote HR as an endonuclease. The MLH3DN/DN and PMS2EK/EK mutations had an additive effect on the heteroallelic HR. MLH3DN/DN/PMS2EK/EK cells showed normal kinetics of γ-irradiation–induced Rad51 foci but a significant delay in the resolution of Rad51 foci and a 3-fold decrease in the number of cisplatin-induced sister chromatid exchanges. The ectopic expression of the Gen1 HJ re-solvase partially reversed the defective heteroallelic HR of MLH3DN/DN/PMS2EK/EK cells. Taken together, we propose that MLH3 and PMS2 promote HR as endonucleases, most likely by processing JMs in mammalian somatic cells.

Aaron Nola established himself as one of the best pitchers in baseball in 2018. The Phillies ensured on Wednesday that he will be the ace in their rotation for possibly the next five seasons.

Phillies president Andy MacPhail opened a 28-minute press conference on Friday afternoon at Spectrum Field with facts and figures about investments the organization made the past few seasons as the team wallowed at the bottom of the National League. Then MacPhail talked a lot about Bryce Harper and Manny Machado as well as manager Gabe Kapler.

The countdown to pitchers and catchers reporting is down to single digits for all 30 MLB clubs, but as exciting as it is to see the return of Major League stars, it's also a time to dream about the next wave of baseball talent.

Leading up to the start of Spring Training, the Around the Horn series will examine each of the Angels' positional groupings heading into the 2019 season. Here's a look at the bullpen.

It's almost time for Spring Training yet again, as Angels pitchers and catchers report to their Spring Training complex in Tempe, Ariz. on Feb. 12.

With less than a week left until Angels pitchers and catchers report to Spring Training, it's time for the final Angels Inbox of the offseason.

Since debuting in 2011, center fielder Mike Trout has been far and away the best player in the Majors, but the Angels have reached the postseason just once in his eight-year career.

Brad Ausmus held his first media session of the spring on the day pitchers and catchers officially reported on Tuesday, giving updates on rehabbing players such as Shohei Ohtani, Albert Pujols and Zack Cozart.

The Angels head to Spring Training with most of their roster set, but there will be competition for a few spots. Here's a look at the projected roster for the Angels, as they begin their first campaign under manager Brad Ausmus.

The Angels added a veteran lefty reliever, as Dan Jennings officially signed a Minor League deal on Saturday and joined the club for workouts at the club's Spring Training complex. Jennings will earn $1 million, plus incentives, if he makes the club.

Who do the Angels have in the pipeline? Get scouting reports, video, stats, projected ETAs and more for the Halos' Top 30 Prospects on MLB Pipeline's Prospect Watch.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

The Angels believe they can help newly acquired catcher Jonathan Lucroy improve both offensively and defensively.

Business Development in Madagascar: How to Enable Entrepreneurialism 15 November 2017 — 12:00PM TO 1:00PM Anonymous (not verified) 9 November 2017 Chatham House, London

Zimbabwe Ahead of the Elections: Political and Economic Challenges 8 May 2018 — 10:00AM TO 11:00AM Anonymous (not verified) 3 May 2018 Chatham House, London

The upcoming elections in Zimbabwe will be the first since 2000 in which former president Robert Mugabe and long-time opposition leader Morgan Tsvangirai are not on the ballot paper. A key electoral issue for many voters will be the economy: recent years have been marked by high unemployment rates, chronic cash shortages and mounting public debt. Although this has traditionally been a strong campaigning issue for the opposition, President Emmerson Mnangagwa has fast-tracked comprehensive economic reforms.

At this event, Nelson Chamisa, MDC Alliance presidential candidate, will discuss his efforts to build a united opposition coalition with a strong message, the steps needed to ensure a free and fair election can take place, and the role that international partners can play in Zimbabwe’s democratic process.

Zimbabwe's Elections Were Meant to Start a New Era Expert comment sysadmin 14 August 2018

Emmerson Mnangagwa has been declared president of Zimbabwe amid protests and violence but Zimbabweans are now in a post-political, economy-first mood, writes Knox Chitiyo.

Before Zimbabwe’s general election on 30 July, there was a lot of talk about there being ‘landmark change’ and ‘credibility.’ But in many ways it was déjà vu. President Emmerson Mnangagwa’s ruling ZANU-PF party won the parliamentary vote, taking a majority 144 seats out of 210. The opposition MDC Alliance, a seven-party coalition led by Nelson Chamisa, won 64 seats—an improvement on their 2013 showing of 44 seats, but still falling far short of expectations.

The presidential results were much closer. After clashes on Wednesday, the incumbent Mnangagwa was declared winner early Friday morning, taking 50.8 per cent of the vote against Chamisa’s 44.3 per cent. The 21 other independent presidential candidates polled less than 5 per cent between them.

The polls didn’t quite live up to the hype. There was much that was positive: the prelude and election day were peaceful, with a minimal military presence. Opposition candidates were able to hold nationwide rallies (including in ZANU-PF’s rural heartland) without interference—an electoral first. ZANU-PF leaders and the military called for a peaceful process. Four women candidates contested the presidential vote, another first. More than 5 million Zimbabweans registered out of an eligible voting population of 7.2 million, and there was a near record 75 per cent turnout on voting day. Zimbabwe invited official observers from 46 countries and 15 international organizations, and, for the first time since 2002, observers from the EU, the Commonwealth and the US were present.

But shortcomings included late public access to the imperfect biometric voters roll and controversies about the ballot papers. There were also misogynistic social media attacks and threats against female candidates and the Zimbabwe Electoral Commission (ZEC) chair Justice Priscilla Chigumba.

The three-day wait for presidential results saw a further decline in public trust in the ZEC, and the opposition’s premature announcement of a Chamisa victory only fanned the political flames.

On Wednesday, six unarmed civilians were shot dead by soldiers in Harare, with dozens more assaulted. A Joint International Observer Mission statement promptly condemned the violence and called for restraint.

The election process was a boon for democracy, but ironically the result has entrenched the two-party parliamentary system and marginalized alternative voices. Mnangagwa has been conciliatory in his post-election statements, saying that Nelson Chamisa has a ‘crucial role to play’ and calling for unity to ‘build a new Zimbabwe for all.’

But Chamisa’s MDC Alliance has refused to accept the results, calling them ‘fake’ and a ‘scandal.’ The MDC has raised genuine transparency concerns and will likely challenge the results in court, but much of this may be cosmetic—with little chance of a 2017 Kenya-style presidential re-run. There is no critical mass of opposition parties to sustain a challenge, nor is there a popular appetite for a protracted political feud.

Zimbabwe’s democracy agenda may be heading into the slow lane, and Chamisa may be pressured by his coalition partners to make a political accommodation with Mnangagwa. Nevertheless, despite setbacks, Zimbabwe’s opposition and civil society has a long history of resilience under pressure and the struggle for democracy will continue.

Mnangagwa has a full in-tray. He has to unite a fractious ZANU-PF and manage internal civil-military and generational faultlines. Beyond that, he may need a public reconciliation with Chamisa—similar to how in Kenya and Mozambique, similar incumbent-opposition quarrels were mended by public rapprochements.

But Zimbabweans are now in a post-political, economy-first mood. Resolving the cash crisis is crucial. Few Zimbabweans can withdraw more than $50 a day from banks or ATMs—and much of this is paid out in unpopular ‘bond coins.’ The formal sector has contracted to only 20 per cent of the economy, and the informal sector lacks the capacity to push an economic renewal.

Zimbabwe’s new internationalism is premised upon the 2015 Lima process economic reform pathway for debt arrears clearance. (The country has a $10 billion foreign debt.) There has been a modest increase in foreign and diaspora investment, but the big-money Chinese, Russian and other pledges are long-horizon projects. What Zimbabwe needs is a short-term economic stimulus—to support small and medium-sized businesses.

For this to happen, Mnangagwa has to stay the course on economic reform, ease of doing business and the anti-corruption agenda. The pivot from reform to transformation in Zimbabwe will require all hands on deck, including civil society, the opposition, Zimbabwe diaspora and foreign investors, in a partnership for development.

A positive global verdict on the elections could supercharge investment, but time will tell whether these polls have been a deal-maker or a deal-breaker.

Zimbabwe’s elections often split the global south and the global north, and this could be the case again. The EU will have to decide whether to continue their incremental rapprochement with Zimbabwe, or accelerate to the reciprocity-based, ‘Re-Engagement 2.0’ approach currently favoured by the UK although the US is unlikely to lift statutory sanctions anytime soon.

Zimbabwe’s possible return to the Commonwealth could also be divisive, given the broader global context of the perceived existential clash between beleaguered liberal democracy and the rise of populist—and popular—autocracies across the globe.

President Mnangagwa—along with South Africa’s President Cyril Ramaphosa, Mozambique’s Filipe Nyusi and others—belong to a pragmatic new wave of regional economic reformers nudging liberationism away from ideology. He now has an electoral mandate to lead a divided country. For sisters Chipo and Tendai, both businesswomen based in Harare who voted for Mnangagwa and Chamisa respectively, the future needs to come now. ‘There is too much talk,’ they said, ‘we live every day between hope and despair. We need cash and jobs. We are tired of being tired.’

This was originally published in TIME.

Public Service, Accountability and Delivery in Malawi 17 October 2018 — 12:00PM TO 1:00PM Anonymous (not verified) 11 October 2018 Chatham House, London

Political Reform in Angola: Challenges and Priorities for Elected Officials 31 October 2018 — 4:00PM TO 5:00PM Anonymous (not verified) 26 October 2018 Chatham House, London

Angola’s reformulated National Assembly has passed a series of legislative reforms since elections in August 2017, in which the ruling MPLA won a majority of 150 seats to the 51 held by the UNITA leading opposition party.

Many of the changes have targeted the revitalization of an underperforming economy and improved governance: in June 2018 parliament approved a new private investment law aimed at diversifying Angola’s fiscal base beyond oil revenues while new legislation in May mandated the return of illicitly exported capital of over $100,000.

As the appetite for measurable progress across all sectors of society remains high, and with newly constituted municipal elections scheduled for 2020, inclusive and accountable political debate will remain critical to Angola’s future.

At the event, a cross-party delegation discuss the role of the National Assembly in affecting political change and the importance of maintaining open dialogue among opposing voices to address the challenges facing Angola.

Water, Energy and Development in Angola: From Ambition to Actuality 13 December 2018 — 5:00PM TO 6:00PM Anonymous (not verified) 28 November 2018 Chatham House, London

South Africa’s 2019 Election: Polling Data and Party Prospects 13 March 2019 — 12:30PM TO 1:30PM Anonymous (not verified) 7 March 2019 Chatham House, London

On 8 May 2019, South Africans will vote in their sixth national election. Incumbent President Cyril Ramaphosa is leading his ANC party campaign, which promises inclusive economic growth and social transformation, including through a sustainable land reform programme. However, public frustrations with the party’s record of service delivery and government corruption after 25 years in power could threaten the ANC’s electoral dominance especially in urban areas.

At this meeting, Professor David Everatt, head of the Wits School of Governance and political pollster, will present polling data and discuss the prospects and strategies of the main parties and their leaders ahead of the May election.

Attendance at this event is by invitation only.

South Africa After the Elections: Balancing Domestic and International Policy Priorities 16 May 2019 — 1:30PM TO 2:30PM Anonymous (not verified) 9 May 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

The government that emerges from the 8 May election in South Africa faces immediate domestic and international foreign policy demands. Attracting Foreign Direct Investment to stimulate job growth, accelerating anti-corruption and good governance efforts are at the forefront of the new government’s agenda.

International ambitions will be upgraded such as UN security council reform, maximizing South Africa’s G20, BRICS and IBSA membership and preparing for South Africa’s chairmanship of the African Union (AU) in 2020.

At this meeting, the speakers – Moeletsi Mbeki, deputy chairman of SAIIA and author with Nobantu Mbeki of A Manifesto for Social Change: How to Save South Africa, and Elizabeth Sidiropoulos, chief executive of SAIIA and currently co-editing a volume on A South African Foreign Policy for the 2020s which will be published in 2019 – will reflect on the election and discuss the new government’s domestic and international policy agenda. The meeting will be chaired by Ann Grant, former British High Commissioner to South Africa (2000-05) with past experience working for Oxfam, Standard Chartered Bank and Tullow Oil.

Webinar: Finding Solutions to Insecurity in Cabo Delgado 16 June 2020 — 3:00PM TO 4:30PM Anonymous (not verified) 9 June 2020

A new transatlantic relationship? 4 October 2022 — 6:30PM TO 7:30PM Anonymous (not verified) 22 September 2022 Chatham House and Online

US senator Jeanne Shaheen examines the implications of new UK leadership, the war in Ukraine, and NATO expansion for the US–UK relationship.

In recent weeks, the UK has ushered in a new prime minister and a new monarch. The US will hold potentially power-shifting mid-term elections in November after nearly two years of the Biden presidency that promised to bring the US ‘back’ as a global leader in international affairs.

These leadership changes come at a time when Europe is at war, NATO is expanding and US–China competition is re-ordering long-held alliances. Old assumptions about foreign policy are in flux in the midst of huge international challenges.

Democratic senator Shaheen, a senior member of the Senate Foreign Relations Committee, explores how these changes might influence the US–UK ‘special’ relationship.

• How will the trajectory of Russia’s war on Ukraine influence the bilateral relationship? What leadership is needed now?

• What does Russia’s war on Ukraine mean for NATO in responding to other pressing security challenges?

• What domestic constraints might limit the US’s power to reinsert itself as a global leader?

As with all Chatham House member events, questions from the members drive the conversation.

Read the transcript. 

Black perspectives on international relations 27 October 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 4 October 2022 Chatham House and Online

How can black perspectives help the world tackle global challenges and expand our understanding of international relations?

As social boundaries change, the viewpoints of black academics, thought leaders and policymakers have grown in both influence and strength worldwide, challenging western and institutional norms. 

However, many institutions and organizations, long established with the exclusion of black voices, have to adapt if there is to be greater inclusion and diversity of thought when tackling major global issues.

Growing reflection on the legacy of colonialism and the importance of the power of diversity may be needed for today’s problems.

The search for global racial equality has seen a growing commitment to ensuring the black experience is at the heart of geopolitical discussions.

This panel discussion looks at what changes are occurring now and how is the conversation shifting. It also examines the challenges posed by the increasing politicization of race and culture issues in the current political environment.

Key questions discussed by the panel include:

• What is the importance of black voices in international relations and where are the main challenges to greater incorporation?

• What are some of the leading perspectives, approaches and beliefs within Africa and across the black diaspora regarding international relations?

• To what extent are governments, businesses and leading global institutions making efforts to include more black voices in decision-making?

• How are black academics changing wider geopolitical conversations and to what extent can deeper conversations lead to change?

• Will an ‘African Century’ bring black perspectives on international relations to the fore of the geopolitical agenda?

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

Read the transcript. 

American democracy in 2022: Trump, insurrection, and midterm elections 31 October 2022 — 2:00PM TO 3:00PM Anonymous (not verified) 7 October 2022 Online

How much has Donald Trump changed US politics and democracy, and will Trump and ‘Trumpism’ be more or less significant in the years ahead?

America’s democracy is divided, polarized and fragmenting. Inequality and internal division have a long history. But Trump’s lasting influence on the Republican party, and politics more broadly, continues to leave a mark. Repeated denials of President Joe Biden’s 2020 election win, wrapped in claims of electoral fraud, have eroded faith in the democratic institutions.

The memories of 6 January are still fresh, reminding all of the dangers posed by such actions. All told, America’s democracy has taken a beating in recent years.

To help make sense of the events over recent years and consequences for the coming mid-terms, Peter Baker and Susan Glasser (authors of The Divider: Trump in the White House 2017–2021) walk through in detail how the American politics of today has been arrived at.

Key questions discussed include:

• What has been learned from the January 6 Committee?

• Is there a likelihood of a similar event in the future?

• When and how will Trump lose his influence over the Republican party? 

• What are the broader ramifications of the Trump era?

• What did the events of 6 January mean for America’s relationships globally?

 As with all Chatham House member events, questions from members drive the conversation.

Read the transcript. 

Nigeria's 2023 elections: Security, economic and foreign policy imperatives 5 December 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 23 November 2022 Chatham House and Online

Bola Ahmed Tinubu, presidential candidate for the All-Progressives Congress, discusses his vision and recently-unveiled manifesto for ‘renewing hope’ in Nigeria.

Nigeria is scheduled to hold presidential and national assembly elections on 25 February 2023 as well as governorship and other subnational elections on 11 March 2023.

The elections will end President Muhammadu Buhari’s two terms in office since his election in 2015 and will mark the first time that he is not engaging in a presidential poll since Nigeria’s transition to civilian rule in 1999 – an important marker in Nigeria’s trajectory of democratic consolidation.

Nigeria’s recently enacted Electoral Act has contributed to improved hope around the election process, reflected in the addition of 12.29 million new voters in Nigeria’s voter registration exercise across the federation’s 36 states and 1,491 constituencies.

Yet Nigeria stands at a critical juncture, having suffered from two recessions in the past six years, unprecedented levels of food insecurity, persistent fuel scarcity and high levels of crude oil theft.

Civic fatigue also remains an important challenge and President Muhammadu Buhari’s three main policy pillars of security, economy and corruption continue to be defining issues for citizens.

At this event, Bola Ahmed Tinubu, presidential candidate for the All-Progressives Congress, discusses his vision and recently unveiled manifesto for ‘renewing hope’ in Nigeria including his policy proposals for economic reform and revival and how to deliver secure and inclusive job opportunities for Nigerian citizens.

Download a transcript

This event is a members and Africa programme event and is part of a series of events and outputs examining Nigeria’s 2023 elections and political developments.

As with all Chatham House member events, questions from members drive the conversation.

The future of the Russia-China relationship 9 February 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 26 January 2023 Chatham House and Online

What lies ahead for the ‘unlimited friendship’ between Moscow and Beijing?

Russia’s invasion of Ukraine has raised new questions about the nature of the relationship between Russia and China, with the war seen as having the potential to shift Russia from a close ally to a liability in the eyes of the Chinese government.

This event explores the latest developments in extent of the relationship and interactions between the two: new convergences and divergences, energy links and limitations, declared alliances and private disagreements.

Experts on the panel explore:

• How has the relationship changed since Russia’s 2022 invasion of Ukraine?
• What do the Russian and Chinese people make of the relationship?
• How could a war-weakened Russia be viewed by China?

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

Read the transcript.

Who gains from artificial intelligence? 27 February 2023 — 5:30PM TO 6:30PM Anonymous (not verified) 6 February 2023 Chatham House and Online

What implications will AI have on fundamental rights and how can societies benefit from this technology revolution?

In recent months, the latest developments in artificial intelligence (AI) have attracted much media attention. These technologies hold a wealth of potential for a wide range of applications, for example, the recent release of OpenAI’s ChatGPT, a text generation model, has shed light on the opportunities these applications hold including to advance scientific research and discovery, enhance search engines and improve key commercial applications.

Yet, instead of generating an evidence-based public debate, this increased interest has also led to discussions on AI technologies which are often alarmist in nature, and in a lot of cases, misleading. They carry the risk of shifting public and policymakers’ attention away from critical societal and legal risks as well as concrete solutions.

This discussion, held in partnership with Microsoft and Sidley Austin LLP, provides an expert-led overview of where the technology stands in 2023. Panellists also reflect on the implications of implementing AI on fundamental rights, the enforcement of current and upcoming legislation and multi-stakeholder pathways to address relevant issues in the AI space.

More specifically, the panel explores:

• What is the current state of the art in the AI field?
• What are the opportunities and challenges presented by generative AI and other innovations?
• What are some of the key, and potentially most disruptive, AI applications to monitor in the near- and mid-term? 
• Which applications would benefit from greater public policy/governance discussions?
• How can current and future policy frameworks ensure the protection of fundamental rights in this new era of AI?
• What is the role of multi-stakeholder collaboration?
• What are the pathways to achieving inclusive and responsible governance of AI?

• How can countries around the world work together to develop frameworks for responsible AI that upholds democratic values and advance AI collaboration across borders?

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

Read the transcript.