Daniel J. Geiszler
Dec 1, 2020; 0:TIR120.002216v1-mcp.TIR120.002216
Technological Innovation and Resources

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1.

Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.

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     Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen than any other tissue and contains almost no intracellular organelles. The tear film lipid layer (TFLL) is also unique. The TFLL is a thin, 100 nm layer of lipid on the surface of tears covering the cornea that contributes to tear film stability. The major lipids of the TFLL are wax esters and cholesterol esters that are not found in the lens. The hydrocarbon chains associated with the esters are longer than those found anywhere in the body, as long as 32 carbons, and many are branched. Changes in the composition and structure of the 30,000 different moieties of TFLL contribute to the instability of tears. The focus of the current review is how spectroscopy has been used to elucidate the relationships between lipid composition, conformational order and function and the etiology of cataract and dry eye.

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1^WT versus Kir2.1^314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

Co-fractionation MS (CF-MS) is a technique with potential to characterize endogenous and unmanipulated protein complexes on an unprecedented scale. However this potential has been offset by a lack of guidelines for best-practice CF-MS data collection and analysis. To obtain such guidelines, this study thoroughly evaluates novel and published Saccharomyces cerevisiae CF-MS data sets using very high proteome coverage libraries of yeast gold standard complexes. A new method for identifying gold standard complexes in CF-MS data, Reference Complex Profiling, and the Extending 'Guilt-by-Association' by Degree (EGAD) R package are used for these evaluations, which are verified with concurrent analyses of published human data. By evaluating data collection designs, which involve fractionation of cell lysates, it is found that near-maximum recall of complexes can be achieved with fewer samples than published studies. Distributing sample collection across orthogonal fractionation methods, rather than a single high resolution data set, leads to particularly efficient recall. By evaluating 17 different similarity scoring metrics, which are central to CF-MS data analysis, it is found that two metrics rarely used in past CF-MS studies – Spearman and Kendall correlations – and the recently introduced Co-apex metric frequently maximize recall, whereas a popular metric—Euclidean distance—delivers poor recall. The common practice of integrating external genomic data into CF-MS data analysis is also evaluated, revealing that this practice may improve the precision and recall of known complexes but is generally unsuitable for predicting novel complexes in model organisms. If studying nonmodel organisms using orthologous genomic data, it is found that particular subsets of fractionation profiles (e.g. the lowest abundance quartile) should be excluded to minimize false discovery. These assessments are summarized in a series of universally applicable guidelines for precise, sensitive and efficient CF-MS studies of known complexes, and effective predictions of novel complexes for orthogonal experimental validation.

Withdrawn by Author.

The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/.

Glycopeptides in peptide or digested protein samples pose a number of analytical and bioinformatics challenges beyond those posed by unmodified peptides or peptides with smaller posttranslational modifications. Exact structural elucidation of glycans is generally beyond the capability of a single mass spectrometry experiment, so a reasonable level of identification for tandem mass spectrometry, taken by several glycopeptide software tools, is that of peptide sequence and glycan composition, meaning the number of monosaccharides of each distinct mass, for example HexNAc(2)Hex(5) rather than man5. Even at this level, however, glycopeptide analysis poses challenges:  finding glycopeptide spectra when they are a tiny fraction of the total spectra; assigning spectra with unanticipated glycans, not in the initial glycan database; and finding, scoring, and labeling diagnostic peaks in tandem mass spectra.  Here we discuss recent improvements to Byonic, a glycoproteomics search program, that address these three issues. Byonic now supports filtering spectra by m/z peaks, so that the user can limit attention to spectra with diagnostic peaks, for example, at least two out of three of 204.087 for HexNAc, 274.092 for NeuAc (with water loss), and 366.139 for HexNAc-Hex, all within a set mass tolerance, for example, ± 0.01 Daltons. Also new is glycan "wildcard" search, which allows an unspecified mass within a user-set mass range to be applied to N- or O-linked glycans and enables assignment of spectra with unanticipated glycans. Finally the next release of Byonic supports user-specified peak annotations from user-defined posttranslational modifications. We demonstrate the utility of these new software features by finding previously unrecognized glycopeptides in publicly available data, including glycosylated neuropeptides from rat brain.

Open searching has proven to be an effective strategy for identifying both known and unknown modifications in shotgun proteomics experiments. Rather than being limited to a small set of user-specified modifications, open searches identify peptides with any mass shift that may correspond to a single modification or a combination of several modifications. Here we present PTM-Shepherd, a bioinformatics tool that automates characterization of PTM profiles detected in open searches based on attributes such as amino acid localization, fragmentation spectra similarity, retention time shifts, and relative modification rates. PTM-Shepherd can also perform multi-experiment comparisons for studying changes in modification profiles, e.g. in data generated in different laboratories or under different conditions. We demonstrate how PTM-Shepherd improves the analysis of data from formalin-fixed paraffin-embedded samples, detects extreme underalkylation of cysteine in some datasets, discovers an artefactual modification introduced during peptide synthesis, and uncovers site-specific biases in sample preparation artifacts in a multi-center proteomics profiling study.

Giardia lamblia (G. lamblia) disease is a zoonosis with a-infection rate affecting the general population of the world. Despite the constant possibility of damage due to their own metabolism, G. lamblia have survived and evolved to adapt to various environments. However, research on energy-metabolism conversion in G. lamblia is limited. This study aimed to reveal the dynamic metabolism-conversion mechanism in G. lamblia under sugar starvation by detecting global lysine acetylation and 2-hydroxyisobutyrylation sites combined with quantitative proteome analyses. A total of 2999 acetylation sites on 956 proteins and 8877 2-hydroxyisobutyryl sites on 1546 proteins were quantified under sugar starvation. Integrated Kac and Khib data revealed that modified proteins were associated with arginine biosynthesis, glycolysis/gluconeogenesis, and alanine, aspartate, and glutamate metabolism. These findings suggested that lysine acetylation and 2-hydroxyisobutyrylation were ubiquitous and provided deep insight into the metabolism-conversion mechanism in G. lamblia under sugar starvation. Overall, these results can help understand the biology of G. lamblia infections and reveal the evolution rule from prokaryote to eukaryote.

DNA polymerase from bacteriophage T7 undergoes large, substrate-induced conformational changes that are thought to account for high replication fidelity, but prior studies were adversely affected by mutations required to construct a Cys-lite variant needed for site-specific fluorescence labeling. Here we have optimized the direct incorporation of a fluorescent un-natural amino acid, (7-hydroxy-4-coumarin-yl)-ethylglycine, using orthogonal amber suppression machinery in Escherichia coli. MS methods verify that the unnatural amino acid is only incorporated at one position with minimal background. We show that the single fluorophore provides a signal to detect nucleotide-induced conformational changes through equilibrium and stopped-flow kinetic measurements of correct nucleotide binding and incorporation. Pre-steady-state chemical quench methods show that the kinetics and fidelity of DNA replication catalyzed by the labeled enzyme are largely unaffected by the unnatural amino acid. These advances enable rigorous analysis to establish the kinetic and mechanistic basis for high-fidelity DNA replication.

Phillies manager Gabe Kapler believes the two most important spots in a lineup are the Nos. 2 and 4 holes. Rhys Hoskins and Carlos Santana hit there most of last season. But with J.T. Realmuto, Andrew McCutchen and Jean Segura joining the Phillies in the offseason, Kapler has more options.

Jean Segura became one of the Phillies' most notable offseason acquisitions, a two-time All-Star expected to give the organization its best overall production at shortstop since Jimmy Rollins left town, in part because of a little brawl he had late last season with Mariners teammate Dee Gordon.

Crisis in the international order 23 January 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 8 December 2022 Chatham House and Online

Why societies are challenging the international order?

Major global challenges, including the climate, refugee crises and the global pandemic, are increasingly revealing shortcomings in our international system and are bringing to the forefront calls for a more just world. But what is justice? 
 
Calls for justice come in many forms and from many directions - from the fair distribution of resources to the recognition of indigenous rights. While for some there is consensus on the importance of multilateral cooperation to tackle global issues, there is a sharp North/South divide at the centre of debates on issues such as the climate crisis, racial justice, and international law. Countries from the global South are demanding more equitable and redistributive solutions, for example in the distribution of COVID-19 vaccines, while the Global North seek the status quo. 
 
North/South division slows progress on reform. Some political actors are starting to challenge the very foundations of our global order, a move that could dramatically change the global system as we know it. 

Key questions to consider include:

• Why are there tensions between the global North and South?
• How can these issues be addressed?
• Does the global North ‘owe’ the global South some form of justice? Which form of justice?
• If these issues are not addressed, what are the implications for the current international order?

This event is held in conjunction with International Affairs.

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

Read the transcript.

A new nuclear order 7 February 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 26 January 2023 Chatham House and Online

In conversation with Rafael Mariano Grossi.

For more than half a century, the global nuclear non-proliferation framework has supported international security and facilitated the expansion of the many peaceful applications of nuclear science and technology. 

What is happening today in Ukraine, Iran and North Korea, not only challenges the way we deal with the existential threat of nuclear weapons, but also the impact it could have on addressing another existential threat – climate change.

Russia’s invasion of Ukraine is the biggest test to global resolve both in avoiding nuclear conflict and in ensuring the safety of one of the biggest nuclear power programmes in Europe.

Rafael Mariano Grossi of the International Atomic Energy Agency discusses key questions on global nuclear cooperation including:

• The impact of the war in Ukraine and issues with Iran and North Korea on countries’ risk assessment with regards to nuclear non-proliferation.

• What the IAEA’s on-the-ground presence and the director general’s missions to Ukraine, particularly the Zaporizhzhia Nuclear Power Plant, tells us about what is necessary – now and in the long term – to ensure the safety and security of nuclear material under all circumstances.

• The role of ensuring nuclear energy can play its vital part in mitigating climate change now and in the future.

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

Read the transcript.

Belarus-EU border crisis reveals wider security threat Expert comment NCapeling 8 December 2021

By engineering a crisis at the Belarus border, Lukashenka is attempting to exacerbate vulnerabilities within the EU. Securitizing migration is not the answer.

When thousands of migrants began freezing to death in the forests on the Belarus border with Poland, Belarusian leader Aliaksandr Lukashenka was forcing the European Union (EU) into a tough choice – either give in to blackmail and welcome migrants whose attempts to trespass the EU border were a result of his policy of luring them to Belarus to put pressure on the EU, or keep the borders closed and declare solidarity with Poland despite its known mistreatment and illegal pushbacks of potential asylum-seekers.

Lukashenka’s action was aptly exploiting three key pressure points of the EU – as a normative power where the human dignity of migrants is overlooked while the European border and coastguard agency Frontex stands by, as a geopolitical actor seeking to externalize its migration problem by signing readmission agreements with transit countries, and as a community of values with the EU-Poland dispute over rule of law.

His approach is typical ‘dictaplomacy’ and democracies which have confronted such a ‘continuation of war by other means’ in their past dealings with dictatorships know that blackmail mostly serves to divert attention away from a rogue leader’s misdemeanours towards his own population. But if this had been game of chess the EU would have been in check.

Thankfully checkmate was avoided – so far – as a compromise was found following weeks of heightened diplomatic efforts. Lukashenka was forced to back-pedal and take care of the migrants, and no humanitarian corridor was needed as the EU sent funds and took measures to support organizations providing shelter for the migrants in Belarus, while airlines and governments in the source countries were pressured to restrict flights to Minsk and started repatriating part of the migrants.

Causing a nuisance

‘Operation Gateway’ – the outline of which was allegedly drawn several years ago and tested by Russia in 2016 at its own borders with Norway and Finland – certainly caused a nuisance, but it ultimately backfired as Lukashenka now has to manage the remaining 2,000-5,000 migrants who refused to be flown back, as well as facing increased international sanctions. However, the fact that Angela Merkel had to personally call him made it look as if Lukashenka did not back down for nothing.

The EU and NATO, including the UK, only reacted collectively to this crisis once it was already out of hand, leaving questions over whether this experience of Lukashenka’s dictaplomacy is a wake-up call to boost resilience against rogue warfare, and to upgrade strategic assessments of the ‘Lukashenka problem’ too.

Back in June, the Belarus ministry of foreign affairs (MFA) announced its withdrawal from the Eastern Partnership and the visa facilitation and readmission agreement with the EU, while Lithuania sent early warnings about a ‘hybrid attack’ at its own border with Belarus. In August, Der Spiegel reported details of an alleged smuggling scheme whereby Tsentr Kurort – a company closely linked to the Administration of the President of Belarus with offices in the Middle East – was handling the shipping, accommodation, and relocation of migrants.

The smuggling of migrants was entirely predictable as Lukashenka has hinted many times Belarus could stop ‘protecting the EU from armed migrants’ seeking to enter it illegally. He has upped his rhetoric beyond notions of hybrid warfare by saying he needs Russian nuclear-capable bombers to ‘help him navigate the migrant crisis’, even hinting Belarus could station both Russian nuclear weapons and S-400 anti-aircraft missile systems. This shows Lukashenka is feeling increasingly cornered – which could lead to more unpredictable security crises.

Russia and Belarus are deepening relations

Although there is no smoking gun pointing to direct Russian involvement in orchestrating the hybrid attack at the EU’s borders, a new step in the military rapprochement between the two countries came when Putin and Lukashenka approved a new Military Doctrine of the Union-State of Russia and Belarus – a non-public document including a joint concept of migration policy. Lukashenka has also come off the fence over Crimea by openly accepting the legality of the peninsula’s integration with Russia.

Given Russia is also sabre-rattling over Ukraine, the risk of an accidental escalation into armed conflict is increasing in what feels like a return to classic Cold War logic, with the difference that the East is now offensively using the South for confronting the West. In recognition of the threat, the UK has joined the US, Canada, and the EU in the fresh sanctions on Belarus.

Ukraine exposes Europe’s double standards for refugees Expert comment NCapeling 30 March 2022

As European governments provide swift protection assurances to those fleeing Ukraine, non-European asylum-seekers continue to face violence at the EU’s borders.

One month after Russia’s invasion of Ukraine, the European Union (EU) already faces its largest refugee crisis since World War Two, with more than ten million people having fled their homes – 6.5 million displaced within Ukraine and 3.9 million escaping to neighbouring countries.

Acting quickly and decisively, European governments have opened borders and European citizens have opened their homes in an unprecedented showing of solidarity towards refugees. But, with all eyes on Ukraine, the Greek coastguard continues to illegally push back asylum-seekers crossing from Turkey while Spanish police forcefully repel those who dare to jump the fence in Melilla.

The painful contrast exposes the double standards in the EU’s approach to refugees. With Europe’s grim history of restrictive asylum policies, it is wishful thinking that the warm welcome to Ukrainians will extend to all asylum-seekers. The EU solidarity to displaced Ukrainians illustrates the deeply politicized – and often discriminatory – nature of providing refugee protection.

However, the hope is this turning point in European history can at least set an important precedent for treating refugees more humanely. Undoubtedly, EU solidarity towards people fleeing the horrors of Putin’s war is critically important and the initial response is positive in its efforts to meet immense humanitarian needs.

Solidarity with Ukrainians

The EU activation of the Temporary Protection Directive (TPD) is a significant step towards a more humane protection regime and fairer responsibility-sharing among member states. Without the need for the examination of individual applications, those fleeing Ukraine can access harmonized rights across the EU for three years – including residence, housing, medical assistance, and access to the labour market and education.

The TPD is also a move away from the strict ‘Dublin’ rules which put the pressure of hosting refugees onto the countries of ‘first arrival’. Ironically, the fiercest opponents of intra-EU solidarity, such as Poland and Hungary, are the ones benefiting from this change now but, in the case of Ukraine, geographical proximity and shared histories must be considered when analysing Europe’s response.

Eastern European and Baltic countries share a post-Soviet history and fear of Russian aggression, and Ukrainians already enjoyed 90 days of visa-free travel in the EU – with a large diaspora, many have established networks across Europe. But even considering these distinctive connections with Ukrainian displacement, the initial response still shows that European countries have both the political will and the capacity to host refugees.

Unlike the usual – often media-fuelled – narratives of refugee ‘invasions’ into Europe, the waves of women and children leaving Ukraine prompted a surge of humanitarian action but they are also a chilling reality check of Europe’s double standards.

The EU has used agreements with countries such as Turkey and Libya to prevent arrivals and outsource asylum responsibilities, while border violence, detention, and lengthy asylum procedures await the few asylum seekers who manage to enter Europe from the Middle East, Asia, and Africa.

These ‘fortress Europe’ legacies have even undercut the humanitarian response in Ukraine, with reports of incidents of discrimination towards people of colour at the EU borders being condemned by the United Nations (UN) and the African Union (AU), the media facing allegations of racist reporting, and comments from Bulgarian PM Kiril Petkov providing a stark reminder of the islamophobia, racism, and history of colonization which still pervades European asylum policies.

Foreign policy also influences how EU leaders treat the right to asylum, as the geopolitics of Europe’s efforts to create a united front against Russian aggression is an undercurrent to the prompt European response to Ukrainians. But only a few months ago, non-European asylum-seekers trapped in freezing forests at the Poland-Belarus border were used as political pawns by Belarusian leader Aliaksandr Lukashenka and then dehumanised as a ‘hybrid attack’ by EU leaders.

A turning point for asylum in Europe?

Despite entrenched discriminatory precedents, it is worth looking ahead at this moment of reckoning. Although policy changes remain far off, the unity shown over Ukraine can help reshape and refocus political efforts towards increased responsibility-sharing among EU member states – the perennial ‘hot potato’ of the EU asylum system.

Why the UK must deliver on Nordic-Baltic security Expert comment NCapeling 16 December 2022

Hard choices are needed but it is crucial the UK provides security and leadership to its European partners given the wider context of the war in Ukraine.

The UK’s role in Nordic-Baltic security has been growing over the past decade. The region is key to core British strategic interest and engagement, and UK threat assessment closely aligns with long-held regional perspectives – the 2021 Integrated Review defines Russia as ‘the most acute threat to our security’.

Since Russia’s invasion of Ukraine, the UK’s strong stance towards Moscow and the concrete steps taken to assist Ukraine and strengthen defence and deterrence on NATO’s eastern flank have been widely appreciated in the Nordic-Baltic region.

The UK is seen as a reliable partner but, for it to continue to deliver in the region, difficult choices must be made with regards to UK defence spending and military capabilities, and London’s more global ambitions.

The UK is a major contributor to NATO’s deterrence posture on the eastern flank, serving as a framework nation for NATO’s Enhanced Forward Presence (EFP) battlegroup in Estonia, and contributing to another battlegroup in Poland.

UK remains crucial to regional security

Coupled with its contribution to NATO’s Baltic Air Policing mission and maritime forces in the area, the UK is a crucial security partner both in the region and in a broader arch across Europe.

Over the past decade and a half, the UK has been developing a dense network of bilateral and minilateral relations in the region which are major assets in the current security environment.

It leads the Joint Expeditionary Force (JEF) which is a military cooperation format highly valued for its flexibility in responding to the needs of the participating nations – including non-NATO Sweden and Finland – and is increasingly focused on the North Atlantic, High North and wider Baltic areas. The UK has also seen increased bilateral defence cooperation with Norway, Denmark, Estonia, and other regional allies and partners.

There are reasonable expectations that Germany or France may at some point assume a greater role in this part of Europe, building on France’s participation in the EFP in Estonia, and Germany’s lead of the EFP in Lithuania.

However, while Paris remains more focused on NATO’s southern (and south-eastern) flank and building the European Union’s defence role, Berlin often underperforms as a leading or an organizing power of collaborative efforts across Europe.

Both also have a credibility problem in the Nordic-Baltic region due to their past policies towards Russia that occasionally reappear when discussing military support to Ukraine or how to treat Russia in the post-war European security order.

By contrast, the UK offers military capability, strong political will, a long-standing tradition of engagement in the Nordic-Baltic area, and fast decision-making.

The latter is exemplified by the bilateral security guarantees provided to Sweden and Finland during their accession to NATO, and the surge of assets sent to the region in the wake of Russia’s full-scale invasion of Ukraine such as an additional battlegroup and Chinook helicopters to Estonia, as well as forward-deployed elements of the Standing Joint Force Headquarters to Latvia and Lithuania as part of the JEF.

Such pragmatic and resolute engagement help substantiate the UK’s post-Brexit claim that although it left the EU, it did not leave Europe. London also understands and facilitates the pivotal role that the US plays in European security – a shared perspective with the Nordic-Baltic partners.

Only the US – which has just recently decided to step up its military presence in the Baltics – has a greater appeal than the UK as a major ally. But Washington’s truly global responsibilities make it more difficult for it to play a regional leadership role.

With the context of the war in Ukraine, the centre of gravity of European security is moving east. The Nordic-Baltic region is likely to feature more prominently in the upcoming refresh of the UK’s Integrated Review, as the war in Ukraine and NATO’s new forward defence approach will focus UK attention and military capabilities on Europe for the foreseeable future.

But the UK still has limited resources and, despite the worsening security environment, there is currently no commitment by the Rishi Sunak government to increase defence spending beyond two per cent of GDP, as set out in the recently-published Autumn Statement.

This difficult fiscal reality contrasts UK ambition to also increase its footprint and engagement in the Indo-Pacific, a region highlighted by Rishi Sunak in his first foreign policy speech. London is already confronted with increasing expectations from its Nordic and Baltic partners, which are rattled by Russia’s aggression and seek more engagement and commitments from larger and more resourceful allies, and are insisting on prompt implementation of NATO’s new defence and deterrence plans.

This all comes on top of the resources that further assistance to Ukraine will require in the coming months and years. Balancing competing priorities and demands from partners is routine for a major power with global ambition but, in the current context, if the UK government fails to prioritize and increase resources, over-extension is in sight for its armed forces.

The war in Ukraine confirms that, beyond the rhetoric around the ‘Indo-Pacific tilt’, the Euro-Atlantic is – and will remain – the priority theatre of engagement for the UK. To keep delivering in the Nordic-Baltic region and remain a reliable partner, UK ambitions should be set clearly, and expectations managed with regional partners.

A good example is the recent UK-Estonia joint statement and defence roadmap, which is an attempt to reconcile London’s vision of modern deterrence with Tallinn’s preference for ‘more boots on the ground’.

The joint statement also clarifies initial misunderstandings regarding the upcoming withdrawal of the second UK battlegroup deployed to Estonia in the wake of Russia’s invasion of Ukraine – support Tallinn expected to continue ‘as long as necessary’ but London saw as temporary. It offsets the poor political ‘optics’ of the withdrawal while providing solid ground for deepening the common agenda in the near future.

By the 2023 NATO summit in Vilnius, progress on implementing the roadmap will be a crucial measure of success for the bilateral relationship, and for the UK’s broader regional role. It should serve as an opportunity for the UK to reflect on its force development priorities and balance, with Baltic partners arguing in favour of the UK rebuilding some mass in its armed forces and providing more resources to the land component.

Much to gain for the UK

The UK gains many benefits from deepening and widening its engagement in the Nordic-Baltic region, and not only by showcasing its regional leadership at a time of dire need or having more weight in Europe and across the Atlantic in strategic debates about future security architecture.

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post–myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with ¹⁸F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with ¹⁸F a quinazolinone derivative ([¹⁸F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [¹⁸F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [¹⁸F]LCE470 was determined by time–activity curve and SUV analysis in 3 regions of the left ventricle—area of infarct, territory served by the left circumflex coronary artery, and remote myocardium—over a period of 1.5 y. Changes in cardiac perfusion were tracked by [¹³N]NH₃ PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [¹⁸F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [¹⁸F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [¹⁸F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [¹⁸F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

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

Oil giant Shell emerged victorious Tuesday from a Dutch court where it was appealing a ruling ordering it to slash its global carbon emissions by 45% by the end of the decade in line with the Paris climate agreement.

Canada ordered striking dock workers back to the ports of Vancouver, Prince Rupert and Montreal on Tuesday to clear out more than a week of container congestion bound for the United States and Canada.

Oct. 31, 2024 — SNIA is pleased to return to SC24 as part of the Open Standards Pavilion, Booth 1815. At SC24, five SNIA groups and six SNIA Alliance and Collaboration […]

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A hologram of a sex worker who was murdered in Amsterdam more than a decade ago could help solve the cold case, investigators hope.

Oil giant Shell emerged victorious Tuesday from a Dutch court where it was appealing a ruling ordering it to slash its global carbon emissions by 45% by the end of the decade in line with the Paris climate agreement.

Oct. 16, 2024 — The ISC High Performance Jack Dongarra Early Career Award and Lecture Series is an annual event that honors the remarkable contributions of Professor Jack Dongarra to […]

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Oct. 22, 2024 — In September, the U.S. Department of Energy (DOE) announced $65 million in funding for research to advance quantum computing at more than 20 institutions across the nation. […]

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PALO ALTO, Calif., Oct. 30, 2024 — D-Wave Quantum Inc. today announced the appointments of veteran technology industry leaders, John DiLullo and Rohit Ghai, to its board of directors. The new […]

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The Carolina Panthers signed running back Chuba Hubbard to a four-year contract extension worth $33.2 million, a league source told UPI on Thursday.

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.

Chicago Bears coach Matt Eberflus has fired offensive coordinator Shane Waldron, the team said Tuesday. The dismissal came less than a day after Eberflus committed to quarterback Caleb Williams, but promised "changes."

BEAVERTON, Ore., Oct. 29, 2024 — Ultra Accelerator Link (UALink) Consortium, led by Board Members from AMD, Amazon Web Services (AWS), Astera Labs, Cisco, Google, Hewlett Packard Enterprise (HPE), Intel, Meta […]

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The 2024 Egg Fair in Mexico broke a Guinness World Record when more than 2,000 young people participated in a race while balancing eggs on spoons.

A British YouTube star and professional wrestling superfan showed off his knowledge by breaking the Guinness World Record for the most WWE wrestlers identified by their entrance music in one minute.

After much anticipation, the National Institute of Standards and Technology (NIST) issued its first Post Quantum Cryptography (PQC) standards today. They are intended to defeat efforts by quantum computers powerful […]

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The Pentagon on Monday ordered all Department of Defense civilian employees to be fully vaccinated against COVID-19 by no later than Nov. 22.

COLLEGE PARK, Md., Nov. 7, 2024 — IonQ (NYSE: IONQ), a leader in the quantum computing industry, has announced financial results for the quarter ended September 30, 2024. “We had yet […]

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Q-CTRL, the Australia-based start-up focusing on quantum infrastructure software, today announced that its performance-management software, Fire Opal, will be natively integrated into four of the world’s most advanced quantum computing […]

The post Quantum Software Specialist Q-CTRL Inks Deals with IBM, Rigetti, Oxford, and Diraq appeared first on HPCwire.