Climate change and sea ice loss leaves polar bears exposed to more diseases, research suggests.

Scientists have revealed that more than a third of tree species are facing extinction.

It is also set to be the world's first breach of 1.5C of warming across an entire calendar year.

Britain's Oliver Bearman, 18, discusses his F1 debut and the prospect of working alongside seven-time world champion Lewis Hamilton at Ferrari.

Oliver Bearman replaces Kevin Magnussen for the entire Sao Paulo Grand Prix weekend after the Dane had to pull out through illness.

Climate change is wreaking havoc on farmers in Nigeria.

Arm wrestling is trying to shed its reputation as a bar sport. Could its inclusion at the African Games could help it enter the mainstream?

Those who died in two world wars and other conflicts are remembered on Armistice Day across the UK and internationally.

Although most states do not require you to securely store your firearms in any particular manner or device, you might want to consider doing so. There are several good reasons to keep any firearms that are not under your direct control locked up securely. It is important to note that some states and cities have […]

The post Do I Need To Have A Safe First To Own Firearms? appeared first on Patriot Outdoor News.

The prime minister was in Paris, while Sophie, the Duchess of Edinburgh led events at the National Memorial Arboretum.

Scotland call up Stuart Armstrong for the games against Croatia and Poland as Che Adams and Lewis Morgan withdraw from the squad.

velocityconf: @da3mon Sorry! We were just doing some followup with past Velocity attendees. Sorry to intrude. No harm intended. :-(

Ducati North America CEO Jason Chinnock enlisted in the US Army out of high school and served with the Third Armored Division in Desert Storm.

My father, the birder, is often excited to share his sightings with me — especially so this summer when he got back from a long-planned trip to South Africa. 153 species! I love how he finds joy and peace by connecting with the world through observing birds, interacting with fellow birders, and telling tales of his birding adventures. In so many wonderful ways, Dad’s daily routines and way of life are linked to nature and the birds he loves.

The latest and greatest iteration of the best farming game out there – Farming Simulator 25 – has just launched… Continue reading Best mods for Farming Simulator 2025

The post Best mods for Farming Simulator 2025 appeared first on ReadWrite.

There's a reason Hitler holds a special place of disgrace in public memory. He combined the ambition and destruction of Attila The Hun with the personal malice of a serial killer.

The post The REAL Harm Done By Calling Everyone You Don’t Like ‘Hitler’ Is BIGGER Than Lefties Think appeared first on Clash Daily.

Without a consequence-free hook-up culture, Planned Parenthood's business model collapses. The left's response to Trump's election is an existential threat... to itself!

The post OOPS: Planned Parenthood Sounds Alarm As Lefties Weaponize Abstinence appeared first on Clash Daily.

Beijing briefing: China bets on warmer EU relations The World Today mhiggins.drupal 30 January 2023

With the Sino-US Xi relationship cooling, Xi Jinping is sending a new diplomatic team to Europe – but his ties to Putin may mean slow progress, writes Yu Jie.

It has been a momentous year for Beijing. Twelve months after Russia’s invasion of Ukraine, its relations with the West have become more strained than ever. And after President Xi Jinping secured an unprecedented third term in office at the 20th Party Congress, the country has embarked on a chaotic exit from the Covid lockdown amid hopes the economy will rebound quickly.

Some are already asking if Beijing will set a course correction in its diplomatic priorities to spare itself some of the setbacks it incurred in 2022. But when it comes to foreign affairs, China’s priorities rarely change. 

The Chinese leadership seeks to create a stable external environment to allow its domestic economic development. This conservative maxim was adopted in the 1980s by Deng Xiaoping, and President Xi is likely to follow it as a time-honoured recipe for diplomatic reconciliation.

China’s awkward position

Beijing’s close relationship with Moscow and its failure to oppose Russia’s invasion of Ukraine have put China in an awkward position. Xi and his colleagues have begun to realize that cooperation with Russia comes with substantial limits to avoid undermining China’s own political priorities and longer-term economic interests.

Interestingly, pundits interpreted the omission of ‘pursuing new types of great power relations’ in the 20th Party Congress report as an acceptance by the party leadership that its fraught relationship with advanced developed nations is likely to remain, with little prospect of improvement in the short term.

Chinese diplomatic literature has always presented Russia as a great power, but the abandonment of such terms signals that Beijing is keen to put clear daylight between itself and Vladimir Putin, although international commentators may argue this is not enough and nothing has changed.

There has been little sign of China using its influence to help resolve the Ukraine conflict. Facing, as it feels it now does, a ‘collective West’ and not the Americans alone, Beijing has concluded there are few reasons not to move closer to Russia.

But a reset would appear necessary if China is to tackle its domestic economic woes. So far, Beijing’s main political tactic has been to reassure European countries that it is willing to use its ties with Russia to restrain Putin from entertaining the deployment of nuclear weapons. That was the message conveyed during the visit of Olaf Scholz, the German Chancellor, and it will be said again when both President Emmanuel Macron of France and Giorgia Meloni, Italy’s prime minister, each visit later this year.

Economically, China has traditionally relied on its relationships with the European Union and the United States to support innovation and growth. So, a perceived isolation from ‘a collective West’ is not an attractive option given Xi’s hopes of achieving a robust economic rebound after dropping the country’s ‘zero-covid’ policy. A precarious bilateral tie with the US has already reduced Beijing’s choice of partners and consumers. Worsening Sino-US relations and a tightening of access to overseas markets for Chinese companies have prompted Beijing not only to reconsider the country’s sources of economic growth but to reconfigure its approach to foreign affairs.

China is making a renewed push to strengthen ties with the Global South, which does not see the war in Ukraine as black and white as the West does. Such a move is only possible because five decades of engagement with the ‘collective West’ has allowed China to emerge from poverty and become a global economic powerhouse.

A new diplomatic team

In an attempt to reset the tone of China’s relations with the EU, its largest trading partner, Xi has formed a new diplomatic team headed by Qin Gang, as Minister of Foreign Affairs, who is returning from his post in Washington as ambassador to the US and who has a background in European affairs. Achieving warmer relations will be easier said than done, however, as China has maintained its ‘neutrality’ at Russia’s aggression since February 2022.

This article is by Toni Šušnjar.

Warfare and military are an integral part of much of ancient and medieval fantasy. This is no surprise: warfare was a key element in development of society and of history, and much of mythology is also about it. As such, it is difficult for fantasy writers and readers alike to avoid war and military matters in general. And if you are going to do something, try to do it well. Army does not spring from the ground like the spartoi of Jason.

Environment and Geography

Environmental conditions include terrain, climate and resources. All three influence how an army will fight and which weapons it will use.

Terrain can be highly varied, but I will divide it into three categories: mountainous, rolling hills and flat. Mountains and forests – and especially forested mountains – are conductive to infantry warfare. Depending on other conditions (such as society, climate etc.), this can mean either light infantry with focus on ambushes, raiding and guerilla warfare; or heavy infantry, with focus on direct confrontation. Both of these were, at different points, in evidence in Spain and Greece.

Continue reading Building a Fantasy Army — Environment & Society at Mythic Scribes.

This article is by Toni Šušnjar.

Strategy and Enemies

The structure of an army will depend on the strategy, as strategy will determine the army’s role and tasks. A state which carries out expansion through outright territorial conquest will have large numbers of heavy infantry, combat engineers and artillery, and possibly some heavy cavalry as well (e.g. Roman Empire, 10th century Byzantine Empire). If conquest is done by slowly destroying an opponent’s economic and social structures through constant raiding (such as chevauchee or razzia / ghazw), then majority of the army will be light cavalry, with some heavy cavalry support (e.g. Seljuk and Ottoman Empires), and light infantry will be used if terrain is unsuitable for cavalry. If a state is defending against cavalry raids, then light cavalry will be dominant (e.g. 15th century Hungary), whereas heavy cavalry will predominate if enemy raiders are primarily infantry. If enemy armies are too powerful to face in the field, light and heavy cavalry will be used to harass the invading army and cut off its supplies and foraging. In terrain unsuitable for cavalry operations, heavy infantry will be used instead.

Raiding — as a strategy — is generally preferred against a peer opponent, especially if a state cannot have a developed logistical support system.

Continue reading Building a Fantasy Army — Strategy & Organization at Mythic Scribes.

This article is by Toni Šušnjar.

Recruitment and Numbers

The most basic style of recruitment is that of a local militia – rural or urban – where a portion or all of the free men take up arms. Militiamen are usually not highly trained, but they make up for lack of training with motivation: fleeing not only carries social stigma, but is also harshly punished. As such, militias were more effective than what would be expected of “civilians in arms”. Militias almost always depended on relatively cheap and easy to use weapons, though urban militias might have access to more expensive weapons – such as hoplite panoply or crossbows. Tribal militias typically used weapons that were also used for hunting and sport. Peasant levy however was only ever used in a support and harassment role, and often had weapons modified from agricultural implements. Only urban militias could have heavy equipment. A common disadvantage of militia armies is the inability to deploy over long distances and time-frames due to soldiers having a day job; thus, focus on long-term warfare (be it conquest or defence) typically brings about the professionalization of the army. This also means that militias are best used in cases with high political fragmentation – such as city-states.

Continue reading Building a Fantasy Army — Recruitment & Logistics at Mythic Scribes.

This article is by Toni Šušnjar.

In Antiquity and early the Middle Ages, the main weapon was the spear. Only a few exceptions appeared: Roman legions, which used javelins instead, and Macedonian pike phalanx with its sarissa. In the later Middle Ages, the main weapon could be a pike or a polearm (such as polehammer, poleaxe, halberd etc.), before the pike made its return in early modernity. Ranged weapons were not used to cause casualties, but rather to inconvenience the enemies and break up their formation.

Weapons and tactics will adapt to each other, as well as to the terrain and the enemies faced – but adaptations will be done within the boundaries of the society. A society without a significant tradition of horse archery will not counter horse archers with their own, but rather with foot archers. Horse archery was important for nomadic societies, because they could not afford the casualties which resulted from the shock and attrition tactics of the settled societies.

Weapons and armour likewise have a relationship, but since armour is the more difficult to produce of the two, it is developments in armour which typically drive the adaptation of weapons, rather than the other way around.

Continue reading Building a Fantasy Army — Weapons & Tactics at Mythic Scribes.

Advice for Fantasy Writers

This article is by Toni Šušnjar.

One of basic elements of fantasy warfare is fantasy army. And one of basic elements of army is its size, which will affect organization and logistics, as well as strategies and tactics it can employ. Thus, prospective fantasy writers should understand factors which limit the size of premodern militaries. But to understand that, it is first to understand differences in what writers mean when they talk of armies.

Army vs Field Army

Basic difference one has to understand is that of military versus army versus field army. Latter distinction is especially important, and often difficult, as both can be described as simply “army” in sources and thus it is necessary to rely on contextual clues.

Military is the overall armed forces of the country. It can include

Army or ground forces is the overall land-based forces that the state can control.

Field army is a formation of land forces, that is, a portion of land forces deployed as a coherent force under single commander with the aim of achieving a goal.

Continue reading Size of Armies at Mythic Scribes.

Advice for Fantasy Writers

This article is by Toni Šušnjar.
Note: This is Part Two of a two-part essay. Here is the link to Part One.

Feudal Army

Feudal army is a complex beast: it may include landed troops, mercenaries, town militias, conscripted peasants, or any combination of these. Thus estimating size of a feudal army will require estimating size of each element of the listed, and the size of field army will never be an exact proportion of the total military force available – or often even able to be estimated.

Landed troops are perhaps easiest to estimate – but even that is not simple. In 15th century Germany, it was generally held that 20 hufen (plots) were required to support a man-at-arms (armored cavalryman) while 10 hufen were required for a lightly armored cavalryman (typically a mounted crossbowman). Hufe was a single peasant’s plot or 121 406 m2. In theory, a state with million men and 85% rural population should have been able to raise 12 750 cavalry, as per the calculation below:

• 1 000 000 men * 0,85 = 850 000 men = 170 000 plots;
• lance (gleve) = 1 man at arms + 2 light cavalrymen (note that historically size of lance varied – this is just an example) = 40 plots
• 170 000 plots = 4 250 lances = 4 250 men-at-arms + 8 500 light cavalrymen

This gives a total of 1,275% of population.

Continue reading Size of Armies Part 2 at Mythic Scribes.

Can the world avoid a new nuclear arms race? 18 November 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 16 October 2024 Chatham House and Online

Leading experts discuss how states are expanding nuclear arsenals amid rising geopolitical challenges.

Leading experts discuss how states are expanding nuclear arsenals amid rising geopolitical challenges.

The Doomsday Clock stands at 90 seconds to midnight – the closest to global catastrophe it has ever been. As geopolitical competition intensifies, nuclear risks are resurging at an alarming rate. The collapse of key arms control agreements, such as the Intermediate-Range Nuclear Forces (INF) Treaty, has removed crucial safeguards against arms races. Efforts to extend or replace existing treaties face significant hurdles in the current geopolitical climate.

Nuclear rhetoric has become more aggressive, as evidenced by Russian and North Korean nuclear threats. Several nuclear-armed states are also engaging in extensive modernization programmes of their nuclear arsenals, potentially fuelling a new arms race.

Despite these pressures, the number of nuclear possessor states has held steady so far. The ongoing Iranian efforts to build nuclear weapons is the closest attempt by a new state to acquire nuclear weapons. As the global security environment becomes more and more tense, existing nuclear possessor states increasingly rely on their nuclear weapons. This might threaten the global consensus against nuclear proliferation.

This session examines these competing pressures and propose strategies to reduce the risks of nuclear weapons use and proliferation. Our expert panel explores diplomatic initiatives, technical measures, and policy innovations to address these critical challenges.

This expert panel discusses key questions including:

• Are we already in the middle of a global nuclear arms race?
• How can international arms control treaties be negotiated in the current geopolitical environment?
• Does a new US president change the nuclear calculus? Is the US still able to reassure allies of its ‘extended deterrence’?
• How can we reduce the risk of additional proliferation? Which states might want to acquire nuclear weapons and what can we do about it?

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.

16 July 2020

COP27: Navigating a difficult road to Sharm El-Sheikh Expert comment NCapeling 6 July 2022

Against a backdrop of rising urgency, COP27 in Egypt will bring all aspects of climate action into the spotlight – but especially the role of the host country.

As COP26 drew to a close in Glasgow, Egyptian officials announced their priorities for COP27, emphasizing climate finance and climate adaptation – a new approach given previous COPs mainly focused on mitigation, reducing emissions to limit climate damage.

This was followed by the COP27 presidency outlining its vision at MENA Climate Week 2022 to achieve ‘substantive and equal progress’ on all aspects of the negotiations, and Egypt emphasizing its intention to focus on implementing existing carbon reduction targets rather than pushing for further carbon cuts.

Egypt argues it is hosting COP27 on behalf of African nations and that, while it is promoting the interests of the developing world, it will be an impartial arbiter. However it is also useful to consider its priorities from the Egyptian government’s perspective.

Agenda drivers

Egypt has long prioritized climate finance and adaptation because it remains in need of technical and financial support to adapt, especially in agriculture and tourism.

It plans to expand its access to climate funding and investment, an area in which Egypt has been relatively successful as it currently receives 27 per cent of all multilateral climate finance in the MENA region and has issued the region’s first sovereign green bonds.

With public debt currently 94 per cent of GDP, Egyptian officials have also called for debt relief for Egypt and other developing countries.

Egypt’s Climate Change Strategy reflects this approach, aiming to enhance Egypt’s rank on the Climate Change Performance Index in order to ‘attract more investments and acquire more climate funding’.

Limiting the mitigation scope and the focus on finance also echoes Egypt’s own reluctance to make carbon reduction commitments. The Egyptian nationally determined contribution (NDC) – its 2030 pledge under the Paris Agreement – does not include any quantifiable emission reduction targets.

Egypt is one of only a few countries which failed to submit an updated NDC in 2021 and its upcoming update will not include an economy-wide carbon reduction target.

Egypt has also never published a long-term strategy and has no decarbonization plans despite independent estimates it should cut rising emissions by one-quarter by 2030, and by two-thirds by 2050 to be aligned with the Paris Agreement. This partly explains why observers rate Egypt’s climate action as highly insufficient.

Furthermore, Egypt’s championing of ‘moving from pledges to implementation’ without having quantifiable carbon reduction pledges of its own effectively exempts it from both pledging and implementation.

As a developing country, Egypt’s negotiating position is supported by UNFCCC provisions which recognize differentiated responsibilities and respective capabilities of nations.

Its proposal to focus COP27 on the implementation of climate action and finance pledges is important in consolidating progress. But not pushing for more emission reductions at this critical moment risks derailing global decarbonization momentum and undermining global climate action.

According to optimistic estimates, if current climate pledges were implemented the world would still remain on track for 2°C of warming by the end of the century, with far worse impacts than if warming was curbed at 1.5°C.

Under a 2°C scenario, 37 per cent of the global population could regularly be exposed to extreme heat waves compared to 14 per cent in a 1.5°C warmer world, with developing countries expected to be worst-affected.

A 2°C trajectory also runs the risk of tipping points such as the melting of ice sheets in Antarctica and Greenland, triggering runaway climate change. Time to change the warming trajectory is running out as the latest IPCC assessment warns the window of opportunity is now ‘brief and rapidly closing’, and the UN Secretary General recently called for faster carbon cuts by the end of 2022 to avoid a ‘climate catastrophe’.

A different energy transition

Egypt opted not to join any of the voluntary sectoral coalitions at COP26 on reducing methane, clean energy transition, transition to zero-emissions vehicles, or moving beyond oil and gas.

This position is explained by its growing role as an exporter and advocate for fossil gas in the energy transition. Egypt is the second-largest producer of natural gas in Africa and is emerging as a fossil gas hub for the eastern Mediterranean, which is shaping its domestic energy policy.

Its 59GW electricity generation capacity is almost double the peak demand and is dominated by gas-powered electricity generation, which currently represents 42 per cent of all Africa’s gas generation.

Egypt’s climate policy is also shaped by fossil gas, and its national Climate Change Strategy encourages the expansion of gas use by promoting a transition to compressed natural gas for vehicles, the expansion of its domestic natural gas network – despite having universal access to electricity – and shifting to a gas-fuelled shipping sector.

Egypt also voiced support for other African countries to extract and deploy fossil gas and oil resources, making it one of the protagonists of the ‘great fossil gas pushback’. These advocates defend the right of developing countries to deploy fossil gas as a ‘transition fuel’ and champion its necessity to solve energy poverty.

But their position is not shared by all African and developing countries, and is rejected by some civil society groups, who argue it risks locking in greenhouse gases and local emissions for decades as well as delaying future development of low carbon energy systems.

Egypt’s huge spare generation capacity has contributed to a slowdown in renewable energy projects over the past two years. With renewables representing just 6GW, Egypt is expected to miss its renewable energy target for 2022, set at 20 per cent of generating capacity.

Engaging Egypt better

But these positions are more malleable than they seem, and Egypt is open to dialogue – not just on refining the COP27 agenda but also on reviewing its own climate priorities and leveraging its energy sector for a more ambitious transition.

Visual Abstract

Visual Abstract

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

Oxylipins are potent lipid mediators involved in a variety of physiological processes. Their profiling has the potential to provide a wealth of information regarding human health and disease and is a promising technology for translation into clinical applications. However, results generated by independent groups are rarely comparable, which increases the need for the implementation of internationally agreed upon protocols. We performed an interlaboratory comparison for the MS-based quantitative analysis of total oxylipins. Five independent laboratories assessed the technical variability and comparability of 133 oxylipins using a harmonized and standardized protocol, common biological materials (i.e., seven quality control plasmas), standard calibration series, and analytical methods. The quantitative analysis was based on a standard calibration series with isotopically labeled internal standards. Using the standardized protocol, the technical variance was within ±15% for 73% of oxylipins; however, most epoxy fatty acids were identified as critical analytes due to high variabilities in concentrations. The comparability of concentrations determined by the laboratories was examined using consensus value estimates and unsupervised/supervised multivariate analysis (i.e., principal component analysis and partial least squares discriminant analysis). Interlaboratory variability was limited and did not interfere with our ability to distinguish the different plasmas. Moreover, all laboratories were able to identify similar differences between plasmas. In summary, we show that by using a standardized protocol for sample preparation, low technical variability can be achieved. Harmonization of all oxylipin extraction and analysis steps led to reliable, reproducible, and comparable oxylipin concentrations in independent laboratories, allowing the generation of biologically meaningful oxylipin patterns.

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.

Proportionality in the Conduct of Hostilities: The Incidental Harm Side of the Assessment Research paper sysadmin 6 December 2018

Clarification of international humanitarian law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups is also crucial.

Summary

• Military operations are taking place with increasing frequency in densely populated areas. Such operations result in loss of life and harm to civilians, as well as damage to civilian objects, (including infrastructure providing essential services). In order to protect civilians, it is imperative that armed forces and groups comply with the rules of international humanitarian law on the conduct of hostilities, including the rule of proportionality.
• The rule of proportionality prohibits attacks which may be expected to cause incidental loss of civilian life, injury to civilians, damage to civilian objects or a combination thereof, which would be excessive in relation to the concrete and direct military advantage anticipated. This research paper analyses the key steps that belligerents must take to give effect to the rule, with a particular focus on one side of proportionality assessments – the expected incidental harm.
• Those undertaking proportionality assessments before or during an attack must consider whether the expected harm will be caused by the attack, and whether that harm could be expected (that is, was it reasonably foreseeable).
• For the purpose of proportionality assessments, injury to civilians includes disease, and there is no reason in principle to exclude mental harm, even though it is currently challenging to identify and quantify it. Damage to civilian objects includes damage to elements of the natural environment.
• Once the incidental harm to be considered has been identified, a value or weight must be assigned to it. This is then balanced against the value or weight of the military advantage anticipated from the attack to determine whether the harm would be excessive.
• In the determination of whether the expected incidental harm would be excessive compared to the anticipated military advantage, ‘excessive’ is a wide but not indeterminate standard.
• Belligerents should develop methodologies so that those planning and deciding attacks are provided with all necessary information on expected incidental harm, and to assist them in assigning weight to the incidental harm to be considered.
• If it becomes apparent that the rule of proportionality will be contravened, the attack in question must be cancelled or suspended.
• Clarification of the law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups, inculcated by their leaders, is also crucial.

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide ¹⁷⁷Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: ¹⁷⁷Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of ¹⁷⁷Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and ^natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of ¹⁷⁷Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

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.

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for ¹⁷⁷Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP⁺) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([¹⁷⁷Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.

French President Emmanuel Macron was joined in Paris on Monday by British Prime Minister Keir Starmer for Armistice Day commemorations after a meeting at which both leaders reaffirmed "unwavering" support for Ukraine.