Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.

Genome-wide association studies (GWAS) have implicated ~380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in ‘interferon signaling’, ‘autoimmune/immune activation’, ‘visual transduction’, and ‘protein catabolism’ were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate, of ceramides containing diverse N-acyl chains is different. By means of a pulse-labeling protocol using stable-isotope, deuterated free fatty acids, and following their incorporation into ceramide and downstream SLs, we show that very-long-chain (VLC) ceramides containing C24:0 or C24:1 fatty acids turn over much more rapidly than long-chain (LC) ceramides containing C16:0 or C18:0 fatty acids due to the more rapid metabolism of the former into VLC sphingomyelin and VLC hexosylceramide. In contrast, d16:1 and d18:1 ceramides show similar rates of turnover, indicating that the length of the sphingoid LCB does not influence the flux of ceramides through the biosynthetic pathway. Together, these data demonstrate that the N-acyl chain length of SLs may not only affect membrane biophysical properties but also influence the rate of metabolism of SLs so as to regulate their levels and perhaps their biological functions.

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed Ldlr^–/– mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr^–/–/Bco1^–/– mice despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

Phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol and regulates the synthesis of membrane phospholipids. There is much interest in this enzyme because it controls the cellular levels of its substrate, phosphatidate (PA), and product, DAG; defects in the metabolism of these lipid intermediates are the basis for lipid-based diseases such as obesity, lipodystrophy, and inflammation. The measurement of PAP activity is required for studies aimed at understanding its mechanisms of action, how it is regulated, and for screening its activators and/or inhibitors. Enzyme activity is determined through the use of radioactive and nonradioactive assays that measure the product, DAG, or P_i. However, sensitivity and ease of use are variable across these methods. This review summarizes approaches to synthesize radioactive PA, to analyze radioactive and nonradioactive products, DAG and P_i, and discusses the advantages and disadvantages of each PAP assay.

As the COVID-19 pandemic continues to spread, thousands of scientists around the globe have changed research direction to understand better how the virus works and to find out how it may be tackled. The number of manuscripts on preprint servers is soaring and peer-reviewed publications using MS-based proteomics are beginning to emerge. To facilitate proteomic research on SARS-CoV-2, the virus that causes COVID-19, this report presents deep-scale proteomes (10,000 proteins; >130,000 peptides) of common cell line models, notably Vero E6, Calu-3, Caco-2, and ACE2-A549 that characterize their protein expression profiles including viral entry factors such as ACE2 or TMPRSS2. Using the 9 kDa protein SRP9 and the breast cancer oncogene BRCA1 as examples, we show how the proteome expression data can be used to refine the annotation of protein-coding regions of the African green monkey and the Vero cell line genomes. Monitoring changes of the proteome on viral infection revealed widespread expression changes including transcriptional regulators, protease inhibitors, and proteins involved in innate immunity. Based on a library of 98 stable-isotope labeled synthetic peptides representing 11 SARS-CoV-2 proteins, we developed PRM (parallel reaction monitoring) assays for nano-flow and micro-flow LC–MS/MS. We assessed the merits of these PRM assays using supernatants of virus-infected Vero E6 cells and challenged the assays by analyzing two diagnostic cohorts of 24 (+30) SARS-CoV-2 positive and 28 (+9) negative cases. In light of the results obtained and including recent publications or manuscripts on preprint servers, we critically discuss the merits of MS-based proteomics for SARS-CoV-2 research and testing.

Pathway analyses are key methods to analyze 'omics experiments. Nevertheless, integrating data from different 'omics technologies and different species still requires considerable bioinformatics knowledge.

Here we present the novel ReactomeGSA resource for comparative pathway analyses of multi-omics datasets. ReactomeGSA can be used through Reactome's existing web interface and the novel ReactomeGSA R Bioconductor package with explicit support for scRNA-seq data. Data from different species is automatically mapped to a common pathway space. Public data from ExpressionAtlas and Single Cell ExpressionAtlas can be directly integrated in the analysis. ReactomeGSA greatly reduces the technical barrier for multi-omics, cross-species, comparative pathway analyses.

We used ReactomeGSA to characterize the role of B cells in anti-tumor immunity. We compared B cell rich and poor human cancer samples from five of the Cancer Genome Atlas (TCGA) transcriptomics and two of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics studies. B cell-rich lung adenocarcinoma samples lacked the otherwise present activation through NFkappaB. This may be linked to the presence of a specific subset of tumor associated IgG+ plasma cells that lack NFkappaB activation in scRNA-seq data from human melanoma. This showcases how ReactomeGSA can derive novel biomedical insights by integrating large multi-omics datasets.

Ankylosing Spondylitis (AS) is a common, inflammatory rheumatic disease, which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine if plasma from patients with AS contained autoantibodies and if so, characterize and quantify this response in comparison to patients with Rheumatoid Arthritis (RA) and healthy controls. Two high-density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis in order to determine patterns of signalling cascades or tissue origin. 44% of patients with Ankylosing Spondylitis demonstrated a broad autoantibody response, as compared to 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The AS patients autoantibody responses were targeted towards connective, skeletal and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic Acid Programmable Protein Arrays constitute a powerful tool to study autoimmune diseases.

Electrospray ionization is today the most widely used ionization technique in chemical and bio-chemical analysis. Interfaced with a mass spectrometer it allows to investigate the molecular composition of liquid samples. With electrospray a large variety of chemical substances can be ionized. There is no limitation in mass which enables even the investigation of large non-covalent protein complexes. Its high ionization efficiency profoundly changed bio-molecular sciences because proteins can be identified and quantified on trace amounts in a high throughput fashion. This review article focusses mainly on the exploration of the underlying ionization mechanism. Some ionization characteristics are discussed which are related to this mechanism. Typical spectra of peptides, proteins and non-covalent complexes are shown and the quantitative character of spectra is highlighted. Finally the possibilities and limitations in measuring the association constant of bivalent non-covalent complexes are described.

As the capability of mass spectrometry-based proteomics has matured, tens of thousands of peptides can be measured simultaneously, which has the benefit of offering a systems view of protein expression. However, a major challenge is that with an increase in throughput, protein quantification estimation from the native measured peptides has become a computational task. A limitation to existing computationally-driven protein quantification methods is that most ignore protein variation, such as alternate splicing of the RNA transcript and post-translational modifications or other possible proteoforms, which will affect a significant fraction of the proteome. The consequence of this assumption is that statistical inference at the protein level, and consequently downstream analyses, such as network and pathway modeling, have only limited power for biomarker discovery. Here, we describe a Bayesian model (BP-Quant) that uses statistically derived peptides signatures to identify peptides that are outside the dominant pattern, or the existence of multiple over-expressed patterns to improve relative protein abundance estimates. It is a research-driven approach that utilizes the objectives of the experiment, defined in the context of a standard statistical hypothesis, to identify a set of peptides exhibiting similar statistical behavior relating to a protein. This approach infers that changes in relative protein abundance can be used as a surrogate for changes in function, without necessarily taking into account the effect of differential post-translational modifications, processing, or splicing in altering protein function. We verify the approach using a dilution study from mouse plasma samples and demonstrate that BP-Quant achieves similar accuracy as the current state-of-the-art methods at proteoform identification with significantly better specificity. BP-Quant is available as a MatLab ® and R packages at https://github.com/PNNL-Comp-Mass-Spec/BP-Quant.

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

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

To identify novel autoantibodies of Takayasu arteritis (TAK) using HuProt array-based approach. A two-phase approach was adopted. In Phase I, serum samples collected from 40 TAK patients, 15 autoimmune disease patients, and 20 healthy subjects were screened to identify TAK-specific autoantibodies using human protein (HuProt) arrays. In Phase II, the identified candidate autoantibodies were validated with TAK-focused arrays using an additional cohort comprised of 109 TAK patients, 110 autoimmune disease patients, and 96 healthy subjects. Subsequently, the TAK-specific autoantibodies validated in Phase II were further confirmed using Western blot analysis. We identified and validated eight autoantibodies as potential TAK-specific diagnostic biomarkers, including anti-SPATA7, -QDPR, -SLC25A2, -PRH2, -DIXDC1, -IL17RB, -ZFAND4, and -NOLC1 antibodies, with AUC of 0.803, 0.801, 0.780, 0.696, 0.695, 0.678, 0.635 and 0.613, respectively. SPATA7 could distinguish TAK from healthy and disease controls with 73.4% sensitivity at 85.4% specificity, while QDPR showed 71.6% sensitivity at 86.4% specificity. SLC25A22 showed the highest sensitivity of 80.7%, but at lower specificity of 67.0%. In addition, PRH2, IL17RB and NOLC1 showed good specificities of 88.3%, 85.9% and 86.9%, respectively, but at lower sensitivities (<50%). Finally, DIXDC1 and ZFAND4 showed moderate performance as compared with the other autoantibodies. Using a decision tree model, we could reach a specificity of 94.2% with AUC of 0.843, a significantly improved performance as compared to that by each individual biomarker. The performance of three autoantibodies, namely anti-SPATA7, -QDPR and -PRH2, were successfully confirmed with Western blot analysis. Using this two-phase strategy, we identified and validated eight novel autoantibodies as TAK–specific biomarker candidates, three of which could be readily adopted in a clinical setting.

The Phillies acquired All-Star catcher J.T. Realmuto from the Marlins on Thursday for catcher Jorge Alfaro, right-hander Sixto Sanchez, left-hander Will Stewart and $250,000 in international bonus slot money, the latest move in a busy and ambitious offseason for a team eager to return to the postseason.

Phillies pitchers and catchers have their first workout Wednesday morning at Carpenter Complex. Almost anything can happen between Wednesday and Opening Day. That said, here is a very early prediction of the Phillies' Opening Day roster, knowing the Phillies remain in the hunt to sign Bryce Harper or Manny Machado.

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

Gabe Kapler is trying to keep the focus on his players in 2019, but it might be an impossible task.

Will Rhys Hoskins be bummed if Bryce Harper signs elsewhere?

MLB.com looked at each team's two highest-ranked position players in WAR, according to the Steamer projections. Here are the top 10, but keep in mind that things could change once Manny Machado and Bryce Harper find homes.

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

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

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

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.

Angels first baseman Albert Pujols met with the media for the first time this spring on Sunday and said he's fully healthy after undergoing arthroscopic surgery on his left knee in late August.

Thinking out loud: Is disinformation here to stay? 10 November 2022 — 6:00PM TO 6:45PM Anonymous (not verified) 25 October 2022 Chatham House

This event is postponed.

Have you ever wondered how Chatham House researchers approach the big deals that become research? Do you enjoy meeting other Chatham House members and engaging with questions that open your mind? ‘Thinking Out Loud’ invites a small group of members to a live, unscripted discussion with a Chatham House researcher. This in-person event is a way for researchers and members to think out loud to help shape ideas for future research.

Kate Jones, Associate Fellow, International Law Programme at Chatham House will pose some key questions facing how speech is governed in an online world:

• How has big tech influenced the way we think about speech and its limitations?

• Can disinformation be eliminated or even greatly reduced?

• Where should the responsibilities fall between government and business when it comes to speech regulation?

• What might the information landscape look like in 10 years’ time? Should that affect how we tackle disinformation today?

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

Weathering the storm: The UK’s role in the world today 29 November 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 7 November 2022 Chatham House and Online

In conversation with David Miliband, examining the risks and opportunities for the UK in a critical year ahead. 

With a new government in the midst of a global order in flux, the UK’s position in the world needs re-examining.

Just 20 months since the UK’s Integrated Review on international policy and security, Britain’s global blueprint is being reviewed and updated in light of major global developments.

Today, Brexit and the Russia’s invasion of Ukraine require adjustments to the UK’s strategic thinking and positioning in the world.

As the economic and political turmoil of previous weeks begins to abate, this is an important moment to once again determine Britain’s role in Europe and beyond. 
 
Realigning British foreign policy in a rapidly shifting international order will be a major challenge for the new administration.  

International Rescue Committee’s CEO and President, and former UK Foreign Secretary, David Miliband, examines the risks and opportunities for a critical year ahead. 
 
Key questions include:

• What are the crucial decisions the UK needs to make in the coming 12 months?
• What should the UK’s priorities be for its role in the world? How should it project itself amidst geopolitical fracturing?
• How can Britain best respond to humanitarian crises around the world?
• Does the UK have the strategic and economic clout to keep up with its foreign policy and development commitments?

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

Read the transcript. 

The National Institute for Health and Care Excellence (NICE) has recommended that all women with suspected endometriosis be offered an early transvaginal ultrasound scan, even if the pelvic or abdominal examination is normal.In its updated guideline1 on the diagnosis and management of endometriosis, NICE recommends specialist ultrasound as an alternative to magnetic resonance imaging for investigating suspected cases of the condition in secondary care.The updated guideline follows recent reports from both the National Confidential Enquiry into Patient Outcome and Death2 and Endometriosis UK which highlighted problems with delayed diagnoses, partly owing to a lack of awareness among healthcare professionals of the condition and how it presents. Such delays can result in prolonged suffering, ill health, and risks to fertility, the reports warned.Other new and updated recommendations include asking women with suspected endometriosis if any first degree relatives have a history of the condition, and considering neurodiversity when taking into account...

Putin’s Eurasian dream may soon become a nightmare Expert comment NCapeling 3 May 2022

The Ukraine invasion has detrimental consequences for the Russia-led Eurasian Economic Union, a project which has been stumbling since its inception.

The Eurasian Economic Union (EAEU) – consisting of Russia with Armenia, Belarus, Kazakhstan, and Kyrgyzstan – represents the culmination of Russia’s pursuit of regional integration with its post-Soviet neighbours.

Officially, the Union has an ambitious economic goal – the creation of a market based on common rules for its five member states and their 180 million citizens – and Russia likes to portray the EAEU as an Eurasian replica of the European Union (EU).

But although a common market was placed at the heart of the EAEU as a way to appeal to member states, it is of marginal importance for the Russian economy. For Moscow, the EAEU is primarily a geopolitical tool to help re-assert its regional and global role.

In a world of evermore powerful trading blocs, Moscow wants to use the EAEU to establish its own economic power base in the new polycentric world order. But Russia’s limited interest in the technocratic intricacies needed for the economic union to live up to its lofty proclamations exposes the real geopolitical ambitions.

The Kremlin has no qualms about disregarding the common rules when they clash with Russia’s own foreign policy, and it soon became evident the EAEU was a means to an end rather than an equitable institution within which Russia would accept constraints on its unilateral behaviour.

A crisis in the making

Although the EAEU has enabled some internal trade liberalization as well as the movement of people and labour to the benefit of its members reliant on labour migrant remittances, it has failed to tackle institutional barriers or promote growth and development policies.

It has been hampered by weak common institutions and a lack of institutional capacity of its member states, while Russia’s dubious commitment is also problematic. The EAEU lacks the institutional features of a genuine common market and any attempts to address these shortcomings have been essentially empty promises.

EAEU membership does benefit the political elites of its member states, because its hub-and-spoke model relies on bilateral high-level political deals between Russia and each member state individually. And by using the enticement of security guarantees and both political and financial support, Moscow has succeeded in attracting new members to join.

But a member’s political survival – or defence against political and economic reform – is dependent on military, economic, financial, and political support from Russia. This has been evidenced by the Armenian-Azerbaijan conflict, and by Russia’s backing of the Lukashenka regime in Belarus and the Tokayev government in Kazakhstan.

The design of the EAEU ties it to Russia’s own fate, and so the impact of harsh sanctions imposed on Russia for invading Ukraine are in stark evidence across its member states. Both Kazakhstan and Kyrgyzstan are reeling from the adverse effects on their domestic currencies and remittances, and the trade bans of key commodities.

And although the ban Russia imposed on grain export to EAEU members has softened, it shows the extent to which Russia was prepared to disregard the rules and sacrifice the EAEU to rescue its own economy. Members are incurring direct economic losses from Putin’s war against Ukraine and the fluctuation of the rouble has created a major impediment to trade with Russia.

Russia seems to increasingly view the Union as a convenient tool to bypass sanctions, with massive implications for its partner countries. And the supposed advantages of EAEU membership – enhanced trade, growth, and modernization – have simply not materialized.

Due to the rapid economic decline of Russia – a fall of 10-15 per cent is anticipated for 2022 – the EAEU is even less likely to deliver the promised economic benefits, while also putting members at risk of secondary sanctions.

The Ukraine invasion has also reignited domestic sensitivities and regional tensions. In Kazakhstan, Tokayev has failed to endorse Russia’s justification for the invasion and refuses to recognize the ‘independence’ of the separatist LNR and DNR.

Meanwhile Azerbaijan has pursued territorial gains in Nagorno-Karabakh while Russia is distracted by its invasion of Ukraine, and has requested the withdrawal of Russian peacekeeping from the disputed territory.

Russia is keen for partner countries to help mitigate the economic impact of sanctions by providing alternative transit routes for imports to Russia. But the EAEU faces challenges even at its most basic level because the sharing of custom duties among member states was denominated in dollars, which Russia now wants to move away from.

No easy escape

Russia’s invasion of Ukraine clearly reduces the benefits of Eurasian integration even further than before and imposes higher cost on the partner countries than were envisaged when they joined. They have been dragged into a geopolitical calamity over which they have no control – the inability of EAEU institutions to mediate or constrain Russia’s behaviour is stark.

Interview: Sviatlana Tsikhanouskaya The World Today mhiggins.drupal 25 May 2022

Belarus’s exiled democratic opposition leader tells Roxanne Escobales about her unexpected political career and President Lukashenka’s wavering support for Putin

Sviatlana Tsikhanouskaya is the face of the Belarusian democratic movement. In 2020, she stood as a presidential candidate against Aliaksandr Lukashenka after her husband, an anti-corruption campaigner and the main opposition candidate, was arrested on the campaign trail and imprisoned. Lukashenka, autocratic ruler of Belarus for more than 30 years, was re-elected. Since then, Sviatlana has lived in exile in Lithuania meeting with western leaders and calling for regime change in her native land. Her husband Sergey remains in prison serving an 18-year sentence.

You have said in the past that there will be no free Belarus without a free Ukraine. How is the fate of the two countries connected?

The Kremlin wants to drag our countries into the past, and we are looking into a future which we want to choose for ourselves. The Kremlin doesn’t recognize Ukraine or Belarus as independent countries – it sees them as part of Russia. While the current regime is in our country, there will be a constant threat of aggression from Russia. But we are absolutely independent countries with our own languages, cultures and so on.

The fate of Belarus depends a lot on the outcome of the war in Ukraine, it is evident. When Ukraine wins – and they definitely will win – it will mean the Kremlin is weak and that Lukashenka is weak. Every day we create multiple points of pressure on the regime from within the country, from outside the country. For countries like Ukraine and Belarus the support of strong democracies is very important.

It is very important for European society to understand that it is not just a war between Russia and Ukraine. It is a war between democratic values and dictatorship on the territory of Ukraine. It is very important for democracy to have a strong voice at the moment.

Recently Lukashenka said the war was taking too long. Do you think he understood what he was getting into when he supported Vladimir Putin by allowing his illegal invasion to be launched from Belarus?

The support between the Kremlin and Lukashenka has always been situational – it is not a real friendship. Lukashenka got huge political and economic support in 2020 after the protests, and now he owes a debt to the Kremlin and had to show his loyalty.

And we see how his rhetoric is changing because the situation in Ukraine is changing. At the beginning Lukashenka always said that, ‘Me and Putin will take Ukraine in three days’, and when this blitzkrieg failed, now he wants to get out of the situation. Now he wants to say, ‘Look, we are for peace. We didn’t have any intention to invade Ukraine.’ He wants to act like he is a peacemaker.

He only cares about his own interest, not his country or its people. He just wants to keep his power.

You have been living in exile in Lithuania for two years, and a lot has happened in that time. What is the state of the Belarusian democratic movement now?

We have been a grassroots movement since the first day. There is no leader who says you have to do this or that. My role is to work on the political level. My task is to go to the European Union, to the United States, and ask for packages to assist civil society. With this technical assistance from our democratic partners, we have managed to build structures in exile, and people in Belarus have managed to build structures inside the country.

Another task of mine is to inspire people, and to explain to the international community what is going on and to show them that Belarus is not just Lukashenka’s regime – it is people who want change.

I communicate with Belarusian people almost every day, especially those who are in the country. We have to keep close ties. It is important to understand how dangerous it is in Belarus to communicate on different channels like Telegram or even to subscribe to some media sources. But people do this. They understand the threats and the consequences, but their energy is still so alive.

We have to keep this energy strong and to give this assurance to people that in case something happens to them, or their families, they will get help from outside. This is how it works.

This struggle has come at a very personal cost to you and your husband, Sergey, who is in prison for his political activities. How is he doing?

I communicate with my husband through his lawyer, who visits him once a week. It has to be short messages because there is no privacy. Our children can send him letters and they receive letters back from him.

There are thousands of people like Sergey, and we have to take care of all of them. The treatment of political prisoners is much worse than criminals because they are like Lukashenka’s personal enemies. That is why it is so important to support human rights organizations who provide lawyers to political prisoners. It is important to fund support for them and for families of political prisoners.

You were a teacher when you took over your husband’s presidential campaign. If you could go back in time, what advice would you give yourself?

I would wish I could have had more confidence. I didn’t have any political experience – I was an ordinary woman and wife, the same as millions of other Belarusians. At the beginning, I didn’t feel confident because I didn’t know about politics. I didn’t know how to communicate with the political leaders of different countries. I was scared.

What motivated you to step into your husband’s shoes?

It was an accidental choice. It was terrible for my husband. But I saw millions of people on the streets, and when you see people standing shoulder to shoulder it inspires you. Every day thousands of people call me who want to help, and I understand that we are not alone. This motivates me.

Also, the fact that thousands of children want to see their mothers and fathers who are in jail gives me strength. When sometimes you think you can’t do this any more because it is so difficult, you think about those who haven’t seen their children for two years. It is awful.

So, every day, you find something that gives you a small energy and it doesn’t let you give up.

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.

McKesson Medical-Surgical Inc. entered into an agreement with the Labor Department on Monday resolving employment discrimination issues involving nearly 900 Black, Hispanic, and White applicants at a distribution center

Trump Media and Technology Group shares rose 15% in value on Tuesday as voters cast ballots on Election Day.