Recent advances in MS-based proteomics have vastly increased the quality and scope of biological information that can be derived from human samples. These advances have rendered current workflows increasingly applicable in biomedical and clinical contexts. As proteomics is poised to take an important role in the clinic, associated ethical responsibilities increase in tandem with the impact on the health, privacy, and well-being of individuals. Here we conducted and report a systematic literature review of ethical issues in clinical proteomics. We add our perspectives from a background of bioethics, the results of our accompanying paper extracting individual-sensitive results from patient samples, and the literature addressing similar issues in genomics. The spectrum of potential issues ranges from patient re-identification to incidental findings of clinical significance. The latter can be divided into actionable and unactionable findings. Some of these have the potential to be employed in discriminatory or privacy-infringing ways. However, incidental findings may also have great positive potential. A plasma proteome profile, for instance, could inform on the general health or disease status of an individual regardless of the narrow diagnostic question that prompted it. We suggest that early discussion of ethical issues in clinical proteomics is important to ensure that eventual regulations reflect the considered judgment of the community as well as to anticipate opportunities and problems that may arise as the technology matures further.

Nuclear Disarmament and the Protection of Cultural Heritage Research paper sysadmin 6 October 2017

States possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear-weapons doctrines and policies.

Summary

• Renewed risk assessments for nuclear weapons and policies are taking place around the world in light of nuclear modernization and the changing geostrategic environment that is making the use of nuclear weapons more likely. As such the humanitarian impacts of nuclear weapons and tests have received increased attention. However, the effect on cultural heritage has so far been neglected.
• The potential for armed conflict to destroy cultural heritage has been recognized in international law since 1954. There is significant evidence on the impact of nuclear weapons on cultural heritage including the consequences of their use in Hiroshima and Nagasaki and the effect of nuclear-testing programmes in places of cultural significance since 1945. States that possess nuclear weapons have increased liabilities and responsibilities to protect cultural heritage and cultural rights. The need to protect cultural heritage should strengthen the case for reducing and eliminating nuclear weapons.
• Failure to take into account the protection of heritage in the development of nuclear weapons policies – including disarmament, non-proliferation and arms-control negotiations – significantly undermines states’ existing commitments to protecting heritage threatened by conflict.
• Risk assessments of the impact of nuclear weapons on cultural heritage and important cultural artefacts – and methods of preventing such catastrophic damage – should be part of protecting cultural heritage in every country and the subject of informed public debate. A new body of knowledge on the full range of nuclear weapons impacts would introduce a fresh perspective to inform decision-makers, international organizations and the public in thinking about nuclear weapons policies and practices.
• Risk and resilience frameworks, which provide sets of solutions for risk assessments, would allow assessments of nuclear weapons threats to heritage and highlight vulnerabilities that need to be addressed. Such frameworks would provide a basis for policymakers to identify the world’s cultural heritage most at risk and help develop mitigation strategies to ensure that it is protected. In particular, states possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear weapons doctrines and policies, as a contribution to transparency and confidence-building, and as a responsibility to the world’s shared heritage. International organizations, such as the UN Educational, Scientific, and Cultural Organization (UNESCO), have a role to play in bridging security perspectives with protecting cultural heritage.

There is nothing quite like the excitement of discovery in science—of finding something no one else knew and seeing a story unfold. One has to be part of an emerging picture to feel the elation. These moments in a lifetime are few and far between, but they fuel enthusiasm and keep one going. They are embedded in struggles and joys of everyday life, years of establishing what Louis Pasteur called “the prepared mind,” working with mentors, trainees, and colleagues, failures and successes. This article recalls 1) how I got to be a biochemist; 2) my contributions as an educator and researcher, especially regarding meprin metalloproteases; and 3) my participation in communities of science. Perhaps my reflections will help an aspiring scientist see how fulfilling a career in science can be.

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.

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.

The 30 prospects below all are getting very long looks this spring with an eye toward breaking camp with the parent club. Even if they start the year in the Minors, they all should get the chance to contribute at some point in the very near future.

The 30 prospects below all are getting very long looks this spring with an eye toward breaking camp with the parent club. Even if they start the year in the Minors, they all should get the chance to contribute at some point in the very near future.

After Ohtani's nearly unprecedented two-way success during his American League Rookie of the Year campaign last year, more clubs are looking into the possibility of having players who can both pitch and play a position. Walsh fits that bill, as he has been a power-hitting first baseman and outfielder in the Minors, but he's made 10 pitching appearances over the past three seasons as well. The Angels are experimenting with him doing both this spring and this upcoming season.

VOLUME 279 (2004) PAGES 33438–33446For Fig. 1B, the second, third, and fifth panels were mistakenly duplicated during article preparation as no yeast colonies were observed in these conditions. The corrected images are presented in the revised Fig. 1B. This correction does not affect the results or conclusions of the work. The authors apologize for the error.jbc;295/50/17382/F1F1F1Figure 1B.

Mine Action in Angola: Clearing the Legacies of Conflict to Harness the Potential of Peace Other resource sysadmin 14 June 2019

This publication draws on and updates the briefing note published following a meeting of the All- Party Parliamentary Group (APPG) on Angola on 26 April 2017. It also incorporates insights from a Chatham House Africa Programme conference session on the legacies of the Angolan Civil War, held on 23 March 2018; and draws on the Africa Programme’s research into conservation-driven development models in Southern Africa.

Almost two decades after the end of its civil war, Angola remains one of the most heavily landmine-contaminated countries in the world. The Angolan government has committed to clearing its landmines by 2025, and there is constructive collaboration between the government and mine clearing agencies in this endeavour, but the target will be achievable only if a decline in funding from international donors is reversed. International funding for mine clearance in Angola fell by more than 80 per cent between 2005 and 2017, and this sharp drop in external support has compounded the impact on domestic funding for national clearance efforts as a result of the downturn in prices for Angola’s main export commodities.

The national mine action agency, the Comissão Nacional Intersectorial de Desminagem e Assistência Humanitária (CNIDAH), is supported by the Mines Advisory Group (MAG), Norwegian People’s Aid (NPA) and the HALO Trust. By 2017, 15 years after the end of the civil war, these organizations had collectively helped clear 56 per cent of known landmine-contaminated land. State-led demining has focused principally on clearing areas designated for infrastructure projects. Now, it is critical that humanitarian demining in largely agricultural and conservation areas is prioritized to bring to an end the daily threat to Angola’s rural poor – as well as to the country’s livestock and wildlife – of injury or death as a result of landmine accidents.

Angola has some of the world’s most important remaining wilderness, including the tributary system for the unique Okavango Delta, and the country has the potential to host one of the most diverse wildlife populations on the continent. However, the presence of landmines and other remnants of the civil war render large areas of the country unsafe both for wildlife and for the local people, whose ability to derive a sustainable livelihood from their natural environment is fundamental to its protection.

Wildlife and tourism provide important economic opportunities for diversification beyond an oil-dominated economy. Critically, Angola’s economic diversification and development objectives can only be achieved if the landmines that prohibit access to land for agriculture, mining, tourism and wildlife are cleared.

There are economic opportunities for released land in the most heavily mined provinces of Cuando Cubango and Moxico. Already, some new funding for mine action in Angola, if upscaled or matched by international donors, could be transformative for its people, and for the conservation of the region’s vital biodiversity.

Angola's Business Promise: Evaluating the Progress of Privatization and Other Economic Reforms 21 January 2020 — 2:30PM TO 3:30PM Anonymous (not verified) 16 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

Minister Nunes Júnior will discuss the progress of the Angolan government’s economic stabilization plans and business reform agenda including the privatization of some state-owned enterprises. These reforms could expand Angola’s exports beyond oil and stimulate new industries and more inclusive economic growth.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Iran: Protests, politics and power 16 November 2022 — 6:00PM TO 7:00PM Anonymous (not verified) 18 October 2022 Online

Join Robert Macaire, UK ambassador to Iran (2018-21), and others to discuss what the protests mean for Iran’s domestic, regional and global power.

Protests in Iran, spurred after Masha Amini died in police custody, have drawn focus on how Iranians feel about state repression, a struggling economy and global isolation. Iran is facing the most adamant challenge to its power structure since the ‘green movement’ in 2009 with protests taking place in more than 50 cities and towns across the country. There is no sign that the government will back down but what will that decision mean for the power it can wield at home and abroad?

This conversation examines how the protests impact Iran’s domestic power, its regional relationships and its relations with the US.

• What do the protests demonstrate about Iran’s power domestically and regionally?

• How do the protests influence the JCPOA?

• What will the government gain if they hold a hard line on protesters?

• How do the protests impact Iran’s regional activities?

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

Read the transcript. 

I’m often asked if I miss working in the House of Commons. Of course I do; it’s one of the most amazing places in the world and remains the cockpit of our nation.There are obviously days I miss it more than others, usually around the big national moments. Whatever your view of Kim Leadbeater’s private member’s bill—the Terminally Ill Adults (End of Life) Bill—its second reading this month will be one of those big moments.Kim is a friend of mine, and we spoke before she decided to put her bill forward after it topped the private members’ ballot at the start of the new parliament. My advice was to proceed with great care, to remember that this will take over your career in many ways, and to read the report produced earlier this year by the Health and Social Care Committee, which I chaired, on the subject of assisted dying/assisted...

Russia and 9/11: Roads not taken Expert comment NCapeling 9 September 2021

Many Russia watchers recall the fleeting moment 20 years ago when the country could have moved away from a path of confrontation with the US.

On 12 September 2001, Russian president Vladimir Putin was the first foreign leader to call George W. Bush to express his condolences – and to offer him support.

Just the previous year, Putin had said Russia joining NATO was a possibility and it suited Russia to draw parallels between the terrorist attacks on the US and its own ‘anti-terrorist’ campaign in Chechnya at the time.

Even though much of the Russian commentary about 9/11 professed empathy rather than sympathy, in their eyes the US was both a victim – as Russia likes to see itself – and ‘had it coming’ while Russia was blameless.

At that time, many in the West were still tempted by the idea Putin’s Russia might develop in a liberal direction, and Putin himself wanted to be seen as constructive especially after Chechnya. He may also have also assumed that, if Russia joined the international alliance, it would be as a co-leader with the US.

An offer which was never stated

Whether he was sincere in his condolences or not, Putin was of course not offering something for nothing – but then few countries ever do. Although less than one-tenth into his time in control of Russia (so far), Putin was still feeling his way but was not a naive president having already been through the controversial sinking of the Kursk submarine.

His first move was to facilitate access to bases in Central Asia for the US campaign in Afghanistan – vital initially but less so later. Apparently, this offer was against the wishes of many of his senior military commanders – although the extent to which it was in his gift to grant such access is questionable.

The quid pro quo, unstated and only dawning on Washington much later, was for the US to keep out of what Russia saw – and still sees – as its backyard. Putin probably misjudged that the US would have neither the inclination nor the capacity to be in that region for anything other than supply chain purposes. And he hoped America now needed Russia after the humiliations of the 1990s.

Common interests could once have been the basis of a partnership with Russia; but to Moscow that meant a partnership of equals which recognized the Kremlin’s self-declared right to conduct out-of-area operations. But the US took a different view and, with nothing written down and no memorandum ever signed, the ensuing disappointment for Russia was gradual but inexorable.

A purely practical reason for declining the ‘offer’ was that, despite its own illusions, Russia had little to bring to the table which was useful and could be offered on acceptable terms. Subsequent initiatives – from specific joint terrorism initiatives to a ‘grand reset’ – could not narrow differences to the point where the character of the relationship changed.

The Northern Distribution Network for supplying US forces in Afghanistan – Russia’s most practical contribution to the notional common cause – took almost a decade to be established and was plagued by problems which often come with a dependence on Russian goodwill.

The Kremlin also had the pleasure of watching US hubris lead to failure in Iraq. And, although knowing the US intervention in Afghanistan would never end well, even Russia could not have foreseen the scale of the defeat and humiliation of chaotic withdrawal.

US achievements with Russia’s neighbours

When it comes to Russia’s post 9/11 ‘offer’ and subsequent expectations, many of the other newly independent countries might never have achieved what they have over the past 20 years if the US had agreed – tacitly or otherwise – to sit back and accept Moscow’s droit de regard over them.

From the Kremlin’s perspective, these states were Russia’s ‘kith and kin’ but it underestimated US willingness to support smaller states over a ‘great power’ – especially as George H.W. Bush pleaded to those states not to go too far too fast. Albeit uneven, most have benefitted from US support for their own independence as well as practical assistance to strengthen their institutions and diversify external relationships.

The three Baltic states consolidated their democracies while their economies, which severed many ties with Russia early, are flourishing and prosperous in contrast to those still in the Russian orbit. They are not only members of NATO and the European Union (EU) but have on occasion been moral leaders as in the case of Lithuania facing down both Belarus and China.

Ukraine has undergone two revolutions in attempting to follow the paths of the Baltic states that continues today. After many false starts Moldova has undergone a similar change recently but at the ballot box not on the streets, to give itself another shot at the prize of true democracy and international acceptance.

Georgia conducted the most radical governance reforms seen in the region after its own revolution although it has taken a few steps backwards of late. Kazakhstan and Uzbekistan have strengthened their independence since then and adjusted their modus vivendi with Russia to their advantage. Putin would hardly be able to give the same assurances about use of bases there today – and indeed reportedly brushed off a request by Biden to use them in the current withdrawal.

Only a minority of formerly Soviet republics have made no progress whatsoever at the governmental level – Belarus and Turkmenistan for sure, perhaps Azerbaijan and Tajikistan too depending on the criteria.

The roads not taken

America’s failure was not so much rejecting Russia’s offer of partnership but failing to pay sufficient attention to it because Russia was still regarded as weak despite being relatively strong in its immediate neighbourhood.

The question of whether it was worth alienating Russia is a moral one. Refusing to sign the Paris Charter – which recognizes the right of independent states to form their own alliances – would have been a further betrayal of people who have long been subjected to their future being decided by stronger powers around them. But Russia may have chosen a path of confrontation anyway as, for the Kremlin, suzerainty over its former republics is considered an entitlement which comes with being a great power.

Although impossible to conclusively prove, all previous frameworks of Russian assumptions and habits of Russian behaviour indicate Moscow would have pocketed the deal and simply moved on anyway. It certainly seems likely that Russia’s other outrages and offenses over the years – from the murders of Litvinenko and Skripal in the UK to the manipulation of information and elections – would still have occurred even if a shabby deal had been made over the heads of the new states on Russia’s borders.

The atrocity of 9/11 was really an opportunity for Russia, a genuine potential turning point and a chance to create a new relationship with the outside world – but its expectations were unrealistic. Russia blew it with demands at the time that could not be met – and rightly were not met. The US rarely receives credit for withstanding Russian blandishments at a moment when its own aura of strength had been so cruelly and effectively punctured by the most brazen of attacks.

Culture notes: Populists of the world unite The World Today rsoppelsa.drupal 25 May 2022

America’s hard-right has successfully played a long game at home, and now it’s schmoozing Europe. We should be worried, says Catherine Fieschi

The politics of advanced democracies is a rather Janus-faced affair these days. No sooner have we breathed a sigh of relief at the results of the French presidential election than a leaked United States Supreme Court document on Roe v Wade signals American abortion rights are under threat. 

Yes, Europe seems to be maintaining political unity in its support of Ukraine, and the US is lavishing eye-watering sums on it both in military and humanitarian aid. Yet one cannot help but feel that these might be short-lived spells of relief in the face of mounting storm clouds on the political horizon. Both at the domestic and international level, populist politics looks to be gathering pace still. 

On the domestic front, we should be cautious in our relief. In the French elections Emmanuel Macron was indeed re-elected, and comfortably so, but there is no denying the space occupied by populist politicians on the left and the right. In the first round, Marine Le Pen gained 23 per cent of the vote, left populist candidate Jean-Luc Mélenchon 22 per cent, and far-right candidate Éric Zemmour 7 per cent. Add to this a record low turnout, and the picture is one of a system in which mainstream politics has overall been rejected in favour of various populist options. 

The Hungarians weren’t so lucky, and Viktor Orbán’s capture of the media and quashing of the opposition over his years in power delivered solid victory. 

What should be cause for further concern is what is happening in the United States, as well as its potential impact on European politics. A quick flick through American politics today suggests dysfunctionalities of staggering magnitude and depth, and the full extent of the success of the right-wing Republican project, as confirmed by the intention to reverse Roe v Wade. 

Any reversal of Roe v Wade is a further step towards a drastic re-territorialization of American politics: into red states and blue states, into urban v rural, into places where taxes fund public education and public goods and where they won’t. It is also about a re-territorialization of institutional power away from the federal and into state institutions. 

The words of JD Vance, the Ohio Republican senatorial candidate – author of the rather good memoir Hillbilly Elegy – pander to an ‘American heartlands’ view of the United States’ role in the world. Asked about the fate of Ukraine, Vance simply replied that he ‘didn’t really care what happens to Ukraine one way or another’. 

On an even more basic level, we would do well to keep in mind that there were 440 anti-voter bills in 49 states at the end of 2021 and rising, calling into question citizens’ basic rights to vote. Republicans have pursued this agenda relentlessly. They have played a long game and invested in media, education and minor and not so minor projects – all of which have secured them a social and political base that is well-disposed towards the deep reversal of the American liberal global project and that of its allies across the world.

And it is perhaps on this last point that we should be most alarmed. Between May 18-20, the Conservative Political Action Conference, an American conclave of the right, was held in Europe. Viktor Orbán gave the keynote speech, and other speakers included the Brazilian President Jair Bolsonaro’s son, Eduardo, and the president of Spain’s far-right party Vox, Santiago Abascal, as well as some well-known American Trumpian voices, including Trump himself. Marine Le Pen, whose earlier appearance at the conference had met with rapturous applause, chose not to cosy-up too closely to Orbán in the run-up to the French parliamentary elections in June but she sent her deputy. 

The export of the Fox News-driven conference from across the Atlantic is deeply worrying. Up until now populists have failed in their attempts at international alliances. At the European Union level their nationalism has always been in the way of their working together, and their groups tend to be short-lived or ineffective as a result. As for American attempts in Europe, the one led by Steve Bannon, the former White House adviser, in 2020 that aimed to create an Academy for the Judeo-Christian West ended as a damp squib – possibly not helped by his dismissal from the White House amid charges of defrauding donors.

But something may be changing: the conference’s embrace of Orbán and an international smattering of ‘strongmen’ hailing from the hard-right, aligned with Putin and sup-ported by Trump and a media empire, suggests that we are entering a Trumpian-infused second act that in its triumphal revanchism is seeking to create an international right-wing populist, or even authoritarian front. This is about politics, media, but also money – something European populist parties have been short of. As Marine Le Pen explained to French voters, her party is so poor it had to borrow money from a Russian bank.  

As some have pointed out, the Russian aggression against Ukraine has complicated matters when it comes to Russian funding of disinformation to the West. Many routes have been shut down. But a new route between the US and Hungary as a platform to floss Europe with dirty money is a good replacement to the old Russian route. 
 

Culture notes: Will the EU find its voice at last? The World Today mhiggins.drupal 30 January 2023

Russia’s invasion of Ukraine has galvanized the bloc, but doubt remains about how it can capitalize on this moment, writes Catherine Fieschi.

Despite its reticence to believe that Russia would attack Ukraine, once Vladimir Putin’s tanks rolled across the Donbas, the European Union finally grasped the momentous nature of the events unfolding on its eastern flank. The immediate reaction of Europe’s member states was one of unity, resolve and uncharacteristically rapid decision-making, at least on sanctions and energy policy.

That they would need to act in concert across a concatenation of crises that would be either triggered (energy), worsened (inflation) or heightened (geopolitical instability) by Putin’s move was obvious. And so, Europe’s collective narrative of this past year slid into place, and it goes something like this: We gave Russia the benefit of every doubt, including after their invasion of Crimea when we still tried to bring them back to the negotiating table, but Putin has made the fundamental choice of turning away from democracy and the rule of law.

Now, the narrative goes on, we have to treat them as enemies and give ourselves the means to become resilient in the face of aggression as Ukraine is all that stands – both symbolically and geographically – between us and the chaos of a Europe-wide war.

Like any good narrative, it is anchored in previous trials and exploits. Having learnt from its failure to coordinate action during the eurozone crisis and then the migration crisis, Europe was keen to make the most of its resilience in the face of the Covid pandemic in the form of the joint vaccine purchases and a massive recovery plan.

The Russian invasion of Ukraine is an added – albeit dramatic and costly – opportunity to pursue further collective action and discover the next chapter of its shared purpose, as a political and perhaps even a defence alliance.

Europe had long been in need of an arc to follow. In the aftermath of the Second World War, peace and prosperity seemed enough. But the new multipolar world that emerged from the ashes of the Cold War and then 9/11 were more difficult to navigate for a largely commercial and regulatory alliance.

Could the EU, then, ever find its political voice?

David vs Goliath

While Brexit and Covid created rallying points, the shock and tragedy of the invasion delivered everything the EU needed in narrative terms: a David and Goliath story, with the opportunity to feature on Team David in European terms while allying with the United States, and a ‘band of brothers’ element to shore up a union bruised by the defection of a key but troubled member. Above all, the appearance of an arch-villain in the form of Vladimir Putin put Europe back into the familiar and mythical territory of the 1940s and then the Cold War.

When on May 28, 2016, Putin seated himself on the throne of the Byzantine emperors in Mount Athos’ Protaton Church in Greece in a scene truly worthy of Game of Thrones, the writing should have been on the wall. That day he explicitly laid out his aim to appoint himself as the new Eastern emperor who would fight the decadence of the West.

‘Today,’ Putin told the world, ‘we restore the values of patriotism, historical memory and traditional culture.’ Later, he cited Ukraine as the biggest unfinished mission of his years in power. That Europe – and Germany in particular – had taken so long to decipher Putin’s dark designs only adds to the narrative’s epic quality, positioning Europe as a victim of its own good faith and open heart.

Cracks in the narrative

But the narrative is not free from cracks. The Baltic states would argue that they had long warned of Putin’s nefarious intentions; and Poland has always been convinced of the threat posed by its neighbour.

C-X-C motif chemokine receptor 4 (CXCR4)–directed imaging has gained clinical interest in aiding clinical diagnostics in primary aldosteronism (PA). We retrospectively evaluated the feasibility of CXCR4-directed scintigraphy using the novel CXCR-4 ligand [^99mTc]Tc-pentixatec in patients with PA. Methods: Six patients (mean age ± SD, 49 ± 15 y) underwent CXCR4-directed scintigraphy (including planar imaging and SPECT/CT) 30, 120, and 240 min after injection of 435 ± 50 MBq of [^99mTc]Tc-pentixatec. Adrenal CXCR4 expression was analyzed by calculating lesion-to-contralateral ratios (LCRs). Imaging results were correlated to clinical information. Histopathology and clinical follow-up served as the standard of reference. Results: Three subjects showed lateralization of adrenal tracer accumulation, with a mean maximum lesion-to-contralateral ratio of 1.65 (range, 1.52–1.70), which correlated with morphologic findings on CT. One individual underwent adrenalectomy and presented with complete biochemical and clinical remission at follow-up. Histopathologic workup confirmed unilateral aldosterone-producing adenoma. Conclusion: [^99mTc]Tc-pentixatec scintigraphy with SPECT in patients with PA is feasible and might offer a valuable alternative to CXCR4-directed imaging with [⁶⁸Ga]Ga-pentixafor PET.

Preclinical data have shown that ¹⁶¹Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their ¹⁷⁷Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β^– particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their ¹⁷⁷Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by ¹⁶¹Tb. When activity concentrations were considered, both [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with ¹⁷⁷Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by ¹⁶¹Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

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).

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [¹⁷⁷Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [¹⁷⁷Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (TBS) and changes in normalized peak count (nPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in TBS_second-first, TBS_third-first, and TBS_fourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [¹⁷⁷Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. –0.049, 0.08 vs. –0.116, and 0.109 vs. –0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). nPC_second-first showed significant group differences (mean, –0.107 vs. –0.282; P = 0.033); nPC_third-first and nPC_fourth-first did not reach statistical significance (mean, –0.122 vs. –0.312 and –0.183 vs. –0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, TBS_fourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. TBS_second-first and TBS_third-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. nPC_second-first, nPC_third-first, and nPC_fourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: TBS and nPC can predict [¹⁷⁷Lu]Lu-DOTATATE response by the second treatment session.

Following early acceptance by urologists, the use of surgical robotic platforms is rapidly spreading to other surgical fields. This empowerment of surgical perception via robotic advances occurs in parallel to developments in intraoperative molecular imaging. Convergence of these efforts creates a logical incentive to advance the decades-old image-guided robotics paradigm. This yields new radioguided surgery strategies set to optimally exploit the symbiosis between the growing clinical translation of robotics and molecular imaging. These strategies intend to advance surgical precision by increasing dexterity and optimizing surgical decision-making. In this state-of-the-art review, topic-related developments in chemistry (tracer development) and engineering (medical device development) are discussed, and future scientific robotic growth markets for molecular imaging are presented.

Prognosticators anticipate the Federal Reserve on Thursday will announce a second rate cut after lowering the federal lending rate by 0.5% in September.

The U.S. Food and Drug Administration has determined commonly used oral phenylephrine is "not effective" and has proposed its removal from over-the-counter nasal decongestants.

CAMBRIDGE, England, Oct. 15, 2024 — Nu Quantum has announced a proof-of-principle prototype that advances the development of modular, distributed quantum computers by enabling connections across different qubit modalities and […]

The post Nu Quantum Unveils Qubit-Photon Interface to Enable Distributed Quantum Computing Networks appeared first on HPCwire.

Oregon, Ohio State, Georgia and Miami lead the first edition of the 2024-25 College Football Playoff rankings, the selection committee announced.

Tua Tagovailoa and Daniel Jones are among UPI senior sports writer Alex Butler's five must-start fantasy football quarterbacks for Week 10.

Billy Napier will remain in place as head football coach at Florida, despite the Gators producing another lackluster campaign during his third season, athletic director Scott Stricklin announced Thursday.

Mike Gesicki and Jonnu Smith are among UPI senior sports writer Alex Butler's four must-start fantasy football tight ends for Week 10.

Tyrone Tracy Jr. and Najee Harris are among UPI senior sports writer Alex Butler's four must-start fantasy football running backs for Week 10.

Brian Thomas Jr. and Jameson Williams are among UPI senior sports writer Alex Butler's four must-start wide receivers for Week 10 of the fantasy football campaign.

Premier League reference David Coote is suspended indefinitely after videos surfaced that appeared to show him criticizing former Liverpool coach Jurgen Klopp, officials announced Monday.

Gerry Faust, who won five Ohio high school football state titles before taking over as coach at Notre Dame in the early 1980s, has died, his family announced. He was 89.

Veteran quarterback Dak Prescott will undergo season-ending surgery to repair his injured hamstring, Dallas Cowboys owner Jerry Jones announced Tuesday.

Justin Herbert, Russell Wilson and Quentin Johnston lead UPI senior sports writer Alex Butler's fantasy football waiver wire priority list for Week 11 of the 2024 NFL season.

PITTSBURGH, Sept. 24, 2024 — Ansys and TSMC today announced a successful pilot with Microsoft that significantly speeds-up the simulation and analysis of silicon photonic components. Together, the companies achieved […]

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SANTA CLARA, Calif., Oct. 22, 2024 — Celestial AI today announced the acquisition of silicon photonics intellectual property from Rockley Photonics, including worldwide issued and pending patents. The combination of Celestial […]

The post Celestial AI Acquires Rockley Photonics Patent Portfolio, Strengthening Photonic Fabric IP appeared first on HPCwire.

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

A British daredevil was intentionally dragged behind his motorcycle at a speed of 159.52 mph to break a Guinness World Record.

A North Carolina man's age turned out to be a lucky number when it inspired him to buy a scratch-off lottery ticket worth $200,000.

A North Carolina woman made a stop for orange juice and ended up winning $250,000 from a scratch-off lottery ticket.