Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.

The neuronal basis of complex social behavior is still poorly understood. In honeybees, reproductive investment decisions are made at the colony-level. Queens develop from female-destined larvae that receive alloparental care from nurse bees in the form of ad-libitum royal jelly (RJ) secretions. Typically, the number of raised new queens is limited but genetic breeding of "royal jelly bees" (RJBs) for enhanced RJ production over decades has led to a dramatic increase of reproductive investment in queens. Here, we compare RJBs to unselected Italian bees (ITBs) to investigate how their cognitive processing of larval signals in the mushroom bodies (MBs) and antennal lobes (ALs) may contribute to their behavioral differences. A cross-fostering experiment confirms that the RJB syndrome is mainly due to a shift in nurse bee alloparental care behavior. Using olfactory conditioning of the proboscis extension reflex, we show that the RJB nurses spontaneously respond more often to larval odors compared with ITB nurses but their subsequent learning occurs at similar rates. These phenotypic findings are corroborated by our demonstration that the proteome of the brain, particularly of the ALs differs between RJBs and ITBs. Notably, in the ALs of RJB newly emerged bees and nurses compared with ITBs, processes of energy and nutrient metabolism, signal transduction are up-regulated, priming the ALs for receiving and processing the brood signals from the antennae. Moreover, highly abundant major royal jelly proteins and hexamerins in RJBs compared with ITBs during early life when the nervous system still develops suggest crucial new neurobiological roles for these well-characterized proteins. Altogether, our findings reveal that RJBs have evolved a strong olfactory response to larvae, enabled by numerous neurophysiological adaptations that increase the nurse bees' alloparental care behavior.

Glutathionylation is an important posttranslational modification that protects proteins from further oxidative damage as well as influencing protein structure and activity. In the present study, we demonstrate that the cysteine-42 residue in protein arginine N-methyltransferase 5 (PRMT5) is glutathionylated in aged mice or in cells that have been exposed to oxidative stress. Deglutathionylation of this protein is catalyzed by glutaredoxin-1 (Grx1). Using mutagenesis and subsequent biochemical analyses, we show that glutathionylation decreased the binding affinity of PRMT5 with methylosome protein-50 (MEP50) and reduced the methyltransferase activity of PRMT5. Furthermore, overexpression of PRMT5-C42A mutant caused a significant increase in histone methylation in HEK293T and A549 cells and promoted cell growth, whereas overexpression of the PRMT5-C42D mutant, a mimic of glutathionylated PRMT5, inhibited cell proliferation. Taken together, our results demonstrate a new mechanism of regulation of PRMT5 methyltransferases activity and suggest that PRMT5 glutathionylation is partly responsible for reactive oxygen species-mediated cell growth inhibition.

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

Cross-linking MS (XL-MS) has been recognized as an effective source of information about protein structures and interactions. In contrast to regular peptide identification, XL-MS has to deal with a quadratic search space, where peptides from every protein could potentially be cross-linked to any other protein. To cope with this search space, most tools apply different heuristics for search space reduction. We introduce a new open-source XL-MS database search algorithm, OpenPepXL, which offers increased sensitivity compared with other tools. OpenPepXL searches the full search space of an XL-MS experiment without using heuristics to reduce it. Because of efficient data structures and built-in parallelization OpenPepXL achieves excellent runtimes and can also be deployed on large compute clusters and cloud services while maintaining a slim memory footprint. We compared OpenPepXL to several other commonly used tools for identification of noncleavable labeled and label-free cross-linkers on a diverse set of XL-MS experiments. In our first comparison, we used a data set from a fraction of a cell lysate with a protein database of 128 targets and 128 decoys. At 5% FDR, OpenPepXL finds from 7% to over 50% more unique residue pairs (URPs) than other tools. On data sets with available high-resolution structures for cross-link validation OpenPepXL reports from 7% to over 40% more structurally validated URPs than other tools. Additionally, we used a synthetic peptide data set that allows objective validation of cross-links without relying on structural information and found that OpenPepXL reports at least 12% more validated URPs than other tools. It has been built as part of the OpenMS suite of tools and supports Windows, macOS, and Linux operating systems. OpenPepXL also supports the MzIdentML 1.2 format for XL-MS identification results. It is freely available under a three-clause BSD license at https://openms.org/openpepxl.

Over the past decade, modern methods of MS (MS) have emerged that allow reliable, fast and cost-effective identification of pathogenic microorganisms. Although MALDI-TOF MS has already revolutionized the way microorganisms are identified, recent years have witnessed also substantial progress in the development of liquid chromatography (LC)-MS based proteomics for microbiological applications. For example, LC-tandem MS (LC-MS²) has been proposed for microbial characterization by means of multiple discriminative peptides that enable identification at the species, or sometimes at the strain level. However, such investigations can be laborious and time-consuming, especially if the experimental LC-MS² data are tested against sequence databases covering a broad panel of different microbiological taxa. In this proof of concept study, we present an alternative bottom-up proteomics method for microbial identification. The proposed approach involves efficient extraction of proteins from cultivated microbial cells, digestion by trypsin and LC–MS measurements. Peptide masses are then extracted from MS¹ data and systematically tested against an in silico library of all possible peptide mass data compiled in-house. The library has been computed from the UniProt Knowledgebase covering Swiss-Prot and TrEMBL databases and comprises more than 12,000 strain-specific in silico profiles, each containing tens of thousands of peptide mass entries. Identification analysis involves computation of score values derived from correlation coefficients between experimental and strain-specific in silico peptide mass profiles and compilation of score ranking lists. The taxonomic positions of the microbial samples are then determined by using the best-matching database entries. The suggested method is computationally efficient – less than 2 mins per sample - and has been successfully tested by a test set of 39 LC-MS¹ peak lists obtained from 19 different microbial pathogens. The proposed method is rapid, simple and automatable and we foresee wide application potential for future microbiological applications.

Plasmodium, the malaria parasite, undergoes a complex life cycle alternating between a vertebrate host and a mosquito vector of the genus Anopheles. In red blood cells of the vertebrate host, Plasmodium multiplies asexually or differentiates into gamete precursors, the male and female gametocytes, responsible for parasite transmission. Sexual stage maturation occurs in the midgut of the mosquito vector, where male and female gametes egress from the host erythrocytes to fuse and form a zygote. Gamete egress entails the successive rupture of two membranes surrounding the parasite, the parasitophorous vacuole membrane and the erythrocyte plasma membrane. In this study, we used the rodent model parasite Plasmodium berghei to design a label-free quantitative proteomic approach aimed at identifying gender-related proteins differentially released/secreted by purified mature gametocytes when activated to form gametes. We compared the abundance of molecules secreted by wild type gametocytes of both genders with that of a transgenic line defective in male gamete maturation and egress. This enabled us to provide a comprehensive data set of egress-related molecules and their gender specificity. Using specific antibodies, we validated eleven candidate molecules, predicted as either gender-specific or common to both male and female gametocytes. All of them localize to punctuate, vesicle-like structures that relocate to cell periphery upon activation, but only three of them localize to the gametocyte-specific secretory vesicles named osmiophilic bodies. Our results confirm that the egress process involves a tightly coordinated secretory apparatus that includes different types of vesicles and may put the basis for functional studies aimed at designing novel transmission-blocking molecules.

Pour de nombreuses personnes, perte de poids rime obligatoirement avec privations. Et si vous appreniez aujourd’hui que vous pouvez perdre efficacement vos kilos en trop sans pour autant vous priver excessivement ? De nombreux programmes minceur et de rééquilibrage, notamment Croq’kilos offrent ce genre d’alternative. Mais de quoi s’agit-il réellement ? C’est quoi Croq’Kilos ? Croq’Kilos […]

L’article Croq’Kilos : programme minceur, rééquilibrage alimentaire est apparu en premier sur Ortho Doc France.

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.

Mass spectrometry-based glycoproteomics has gone through some incredible developments over the last few years. Technological advances in glycopeptide enrichment, fragmentation methods, and data analysis workflows have enabled the transition of glycoproteomics from a niche application, mainly focused on the characterization of isolated glycoproteins, to a mature technology capable of profiling thousands of intact glycopeptides at once. In addition to numerous biological discoveries catalyzed by the technology, we are also observing an increase in studies focusing on global protein glycosylation and the relationship between multiple glycosylation sites on the same protein. It has become apparent that just describing protein glycosylation in terms of micro- and macro-heterogeneity, respectively the variation and occupancy of glycans at a given site, is not sufficient to describe the observed interactions between sites. In this perspective we propose a new term, meta-heterogeneity, to describe a higher level of glycan regulation: the variation in glycosylation across multiple sites of a given protein. We provide literature examples of extensive meta-heterogeneity on relevant proteins such as antibodies, erythropoietin, myeloperoxidase and a number of serum and plasma proteins. Furthermore, we postulate on the possible biological reasons and causes behind the intriguing meta-heterogeneity observed in glycoproteins.

The choice for adjuvant chemotherapy in stage II colorectal cancer (CRC) is controversial as many patients are cured by surgery alone and it is difficult to identify patients with high-risk of recurrence of the disease. There is a need for better stratification of this group of patients. Mass spectrometry imaging could identify patients at risk. We report here the N-glycosylation signatures of the different cell populations in a group of stage II CRC tissue samples. The cancer cells, compared to normal epithelial cells, have increased levels of sialylation and high-mannose glycans, as well as decreased levels of fucosylation and highly branched N-glycans. When looking at the interface between cancer and its microenvironment, it seems that the cancer N-glycosylation signature spreads into the surrounding stroma at the invasive front of the tumor. This finding was more outspoken in patients with a worse outcome within this sample group.

Paramphistomosis, caused by the rumen fluke, Calicophoron daubneyi, is a parasitic infection of ruminant livestock which has seen a rapid rise in prevalence throughout Western Europe in recent years. Following ingestion of metacercariae (parasite cysts) by the mammalian host, newly-excysted juveniles (NEJs) emerge and invade the duodenal submucosa which causes significant pathology in heavy infections. The immature larvae then migrate upwards, along the gastrointestinal tract, and enter the rumen where they mature and begin to produce eggs. Despite their emergence, and sporadic outbreaks of acute disease, we know little about the molecular mechanisms used by C. daubneyi to establish infection, acquire nutrients and to avoid the host immune response. Here, transcriptome analysis of four intra-mammalian life-cycle stages, integrated with secretome analysis of the NEJ and adult parasites (responsible for acute and chronic disease respectively), revealed how the expression and secretion of selected families of virulence factors and immunomodulators are regulated in accordance with fluke development and migration. Our data show that whilst a family of cathepsins B with varying S2 sub-site residues (indicating distinct substrate specificities) are differentially secreted by NEJs and adult flukes, cathepsins L and F are secreted in low abundance by NEJs only. We found that C. daubneyi has an expanded family of aspartic peptidases, which is up-regulated in adult worms, although they are underrepresented in the secretome. The most abundant proteins in adult fluke secretions were helminth defence molecules (HDMs) that likely establish an immune environment permissive to fluke survival and/or neutralise pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide in the microbiome-rich rumen. The distinct collection of molecules secreted by C. daubneyi allowed the development of the first coproantigen-based ELISA for paramphistomosis which, importantly, did not recognise antigens from other helminths commonly found as co-infections with rumen fluke.

The early detection of pancreatic ductal adenocarcinoma is a complex clinical obstacle yet is key to improving the overall likelihood of patient survival. Current and prospective carbohydrate biomarkers CA19-9 and sTRA are sufficient for surveilling disease progression yet are not approved for delineating PDAC from other abdominal cancers and non-cancerous pancreatic pathologies. To further understand these glycan epitopes, an imaging mass spectrometry approach was utilized to assess the N-glycome of the human pancreas and pancreatic cancer in a cohort of PDAC patients represented by tissue microarrays and whole tissue sections. Orthogonally, these same tissues were characterized by multi-round immunofluorescence which defined expression of CA19-9 and sTRA as well as other lectins towards carbohydrate epitopes with the potential to improve PDAC diagnosis. These analyses revealed distinct differences not only in N-glycan spatial localization across both healthy and diseased tissues but importantly between different biomarker-categorized tissue samples. Unique sulfated bi-antennary N-glycans were detected specifically in normal pancreatic islets. N-glycans from CA19-9 expressing tissues tended to be bi-, tri- and tetra-antennary structures with both core and terminal fucose residues and bisecting N-acetylglucosamines. These N-glycans were detected in less abundance in sTRA-expressing tumor tissues, which favored tri- and tetra-antennary structures with polylactosamine extensions. Increased sialylation of N-glycans was detected in all tumor tissues. A candidate new biomarker derived from IMS was further explored by fluorescence staining with selected lectins on the same tissues. The lectins confirmed the expression of the epitopes in cancer cells and revealed different tumor-associated staining patterns between glycans with bisecting GlcNAc and those with terminal GlcNAc. Thus, the combination of lectin-IHC and IMS techniques produces more complete information for tumor classification than the individual analyses alone. These findings potentiate the development of early assessment technologies to rapidly and specifically identify PDAC in the clinic that may directly impact patient outcomes.

Secrets and Spies: UK Intelligence Accountability After Iraq and Snowden Book sysadmin 15 January 2020

How can democratic governments hold intelligence and security agencies to account when what they do is largely secret? Jamie Gaskarth explores how intelligence professionals view accountability in the context of 21st century politics.

Using the UK as a case study, this book provides the first systematic exploration of how accountability is understood inside the secret world. It is based on new interviews with current and former UK intelligence practitioners, as well as extensive research into the performance and scrutiny of the UK intelligence machinery.

The result is the first detailed analysis of how intelligence professionals view their role, what they feel keeps them honest, and how far external overseers impact on their work.

The UK gathers material that helps inform global decisions on such issues as nuclear proliferation, terrorism, transnational crime, and breaches of international humanitarian law. On the flip side, the UK was a major contributor to the intelligence failures leading to the Iraq war in 2003, and its agencies were complicit in the widely discredited U.S. practices of torture and ‘rendition’ of terrorism suspects. UK agencies have come under greater scrutiny since those actions, but it is clear that problems remain.

Secrets and Spies is the result of a British Academy funded project (SG151249) on intelligence accountability. The book is published as part of the Insights series.

Praise for Secrets and Spies

About the author

Jamie Gaskarth is Professor of Foreign Policy and International Relations at The Open University. He was previously senior lecturer at the University of Birmingham where he taught strategy and decision-making. His research focused on the ethical dilemmas of leadership and accountability in intelligence, foreign policy, and defence. He is author/editor or co-editor of six books and served on the Academic Advisory panel for the 2015 UK National Security Strategy and Strategic Defence and Security Review.

Purchase

• UK (via Amazon)
• Rest of world (via Brookings Institution Press)
• Students (via Browns Books)

Belarusians’ views on the political crisis - April 2021 Other resource NCapeling 11 June 2021

Results of a public opinion poll conducted between 20 and 30 April 2021.

Chatham House surveyed a total of 937 respondents between 20 and 30 April 2021. Our survey sample corresponds to the general structure of Belarus’s urban population and is corrected and weighted by gender, age, size of respondents’ town of residence and education level.

Summary

• After Lukashenka, the most known political figures in Belarus are pro-protest politicians: Tsikhanouskaya, Babaryka, Tsikhanouski, Kalesnikava, Tsapkala and Latushka. Viktar Babaryka is the most popular presidential candidate among Belarusian urban citizens, and Lukashenka comes second to him.
• State organizations and bodies are still mistrusted by more than half the population, while the army is slightly more popular than other bodies. Independent media, labour unions and human rights organizations are trusted far more than state ones.
• Russia leads when it comes to positive attitudes to foreign states: one in three Belarusians feel very positive about their neighbour and 79 per cent feel positive in general. 71 per cent Belarusians feel positive about China, which is the next highest indicator. Despite propaganda efforts, Ukraine, Lithuania, Poland and EU states in general are still perceived positively by more than 60 per cent of Belarusians, with fewer than 20 per cent feeling negative about them.
• The position on Russian interference in the Belarusian political crisis is consolidated enough: 58 per cent think that Russia should remain neutral. The rest are almost equally divided between those who think Russia should support the protest movement (19 per cent) and those who think Russia should support Lukashenka (23 per cent).
• 40 per cent have changed their attitude to the Russian government since it supported Lukashenka in the crisis, and 73 per cent are sure that Russia is his sole support.
• While 32 per cent of Belarusians see union with Russia as the most appropriate foreign policy, 46 per cent would like to be in a union with both Russia and the EU simultaneously.
• Almost half the population thinks that Belarusian foreign policy in the event of a pro-protest government coming to power would be oriented toward friendship and cooperation with both Russia and the West, which correlates with how the majority thinks it should be. Although 42 per cent expect foreign policy would lean toward the EU in that situation, which is less acceptable: only 25 per cent think it ‘should’.
• The proportion of respondents who think Belarus should remain in the Collective Security Treaty Organization is 58 per cent, while 35 per cent would like to see Belarus not belonging to any military bloc and a small share (seven per cent) would prefer Belarus to join NATO.
• Almost half of the population considers Lukashenka to be the major obstacle for political stability and economic development and is sure he does not care about, and in fact is a threat to, independence.
• In general, most Belarusians have a consolidated opinion that the authorities should start negotiating with opponents and free all political prisoners.
• More than half of Belarusians think that Lukashenka must leave immediately or before the end of 2021, while 27 per cent think he should leave when his term ends in 2025. The opinion that Lukashenka should rule for another term beginning in 2025 is marginal – only ten per cent support this.
• Expectations are not so optimistic though: only 26 per cent believe he will leave office this year. One in three thinks he will leave in 2025; a further 19 per cent say that he will stay on for further terms in office.
• If Lukashenka doesn’t leave, people expect an increase in emigration and unemployment, the continuation of repression in all areas of life, falling exchange rates and the tightening of dependency on Russia.
• Opinion on abortions is still consolidated, with only 19 per cent thinking they should be banned in most or all cases. The same applies to Lukashenka’s infamous statement that society in Belarus is not ready to have a female president: only 20 per cent agree with the opinion.
• 52 per cent don’t think there is a problem of wage inequality between men and women in Belarus, while 37 per cent do see an issue.

Download a presentation of the survey’s main findings

Belarusians’ views on the political crisis - Nov 2021 Other resource NCapeling 20 January 2022

Results of a public opinion poll conducted between 1 and 10 November 2021.

Chatham House surveyed a total of 767 respondents between 1 and 10 November 2021. Our survey sample corresponds to the general structure of Belarus’s urban population and is adjusted by gender, age, education level and the size of respondents’ place of residence.

Summary

• After Aliaksandr Lukashenka, the most well-known political figures in Belarus are the protest leaders: Sviatlana Tsikhanouskaya, Viktar Babaryka, Siarhei Tsikhanouski, Valery Tsapkala, Marya Kalesnikava and Pavel Latushka.
• Lukashenka and Babaryka have the highest popularity ratings among Belarus’s urban population. At the same time, Lukashenka has a high negative rating: half of the city residents surveyed say that they would never vote for him. Babaryka has one of the lowest negative ratings in the country.
• The popularity ratings of pro-government politicians are low, and their negative ratings remain extremely high, although the latter have decreased slightly in comparison with July 2021. The popularity ratings of protest leaders are significantly higher than those of politicians who support the current government.
• Trust in state and independent organizations is polarized along political lines. Thus, respondents classed as hardcore protesters do not trust state structures and do trust independent ones, while Lukashenka’s supporters hold the opposite positions.
• Belarusians’ geopolitical orientations remain stable. The most widely preferred option for a geopolitical union is simultaneous integration with the EU and Russia.
• Belarusians have become increasingly negative about the possibility that Russian airbases could be established on Belarusian territory (48 per cent in November 2021, compared to 39 per cent in July 2021).
• Belarusians are now feeling more strongly that the situation concerning the COVID-19 pandemic has worsened: in November, more than half were beginning to respond that Belarus is unable to cope with the spread of coronavirus.
• Sanctions against Lukashenka and those around him are supported more widely than sanctions against state enterprises.
• Belarusians feel there is acute social tension in their country: almost everyone surveyed states that social tension exists, while one in every five respondents considers the situation catastrophic. A perception that there is social tension is closely related to many factors, with the strongest of all being a sense of a lack of personal safety.
• Only one-third of Belarusians are prepared to call the state built under Lukashenka their own. Most of the survey respondents do not trust this state to some degree, and do not believe that the state protects the interests of Belarusian citizens.

Download a presentation of the survey’s main findings

• Belarusians’ views on the political crisis (PDF)

• Взгляды белорусов на политический кризис (PDF)

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

The faithful segregation, or “partition,” of many low-copy number bacterial plasmids is driven by plasmid-encoded ATPases that are represented by the P1 plasmid ParA protein. ParA binds to the bacterial nucleoid via an ATP-dependent nonspecific DNA (nsDNA)-binding activity, which is essential for partition. ParA also has a site-specific DNA-binding activity to the par operator (parOP), which requires either ATP or ADP, and which is essential for it to act as a transcriptional repressor but is dispensable for partition. Here we examine how DNA binding by ParA contributes to the relative distribution of its plasmid partition and repressor activities, using a ParA with an alanine substitution at Arg351, a residue previously predicted to participate in site-specific DNA binding. In vivo, the parAR351A allele is compromised for partition, but its repressor activity is dramatically improved so that it behaves as a “super-repressor.” In vitro, ParAR351A binds and hydrolyzes ATP, and undergoes a specific conformational change required for nsDNA binding, but its nsDNA-binding activity is significantly damaged. This defect in turn significantly reduces the assembly and stability of partition complexes formed by the interaction of ParA with ParB, the centromere-binding protein, and DNA. In contrast, the R351A change shows only a mild defect in site-specific DNA binding. We conclude that the partition defect is due to altered nsDNA binding kinetics and affinity for the bacterial chromosome. Furthermore, the super-repressor phenotype is explained by an increased pool of non-nucleoid bound ParA that is competent to bind parOP and repress transcription.

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

VOLUME 289 (2014) PAGES 6604–6618In Fig. 4G, in the foxi1 panel, the images in Fig. 4G, i and l, corresponding to “smad1 MO” and “smad5 MO + samd1/9 mRNA” samples, respectively, were inadvertently reused during figure preparation. This error has now been corrected using images pertaining to each treatment and sample. This correction does not affect the results or conclusions of the work.jbc;295/52/18650/F4F1F4Figure 4G.

War on Ukraine: The energy crisis and Europe’s impending long winter 2 November 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 4 October 2022 Online

Can Europe remain unified over the long winter?

Since Russia’s invasion of Ukraine, the global community has been responding to significant price shocks, especially energy. As Europe heads into a particularly difficult winter, policymakers are grappling with the costs, both political and economic, required to make sure Russian energy blackmail does not succeed.

Retaining a unified front against Russia and providing continued support to the Ukrainian government will be great challenges. As the cold begins to bite, war fatigue may accelerate among the populations of Europe. Providing their people with adequate heat will not come cheaply for governments across the continent at a time of economic uncertainty.

At this critical moment of Russia’s invasion, experts discuss:

• Have European preparations been sufficient to stave off an energy crisis this winter?
• What will be Russia’s reaction during and after the winter period, particularly if Europe avoids energy market failures?
• How will this ‘energy crisis’ ensure future dependencies on single state actors of goods and services do not occur in the future?

Read the transcript. 

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

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

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

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

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

Key questions discussed include:

• What has been learned from the January 6 Committee?

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

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

• What are the broader ramifications of the Trump era?

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

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

Read the transcript. 

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.

Chatham House Primer: Social media and democracy 21 March 2023 — 6:00PM TO 6:45PM Anonymous (not verified) 23 February 2023 Chatham House

From the Arab Spring to the 2016 Trump election win, how have democracies benefited and suffered from the impact of social media? 

With social media now a well-entrenched, yet still recent, component of societies, democracies are still grappling with the impact bought about by this new form of communication and promotion.

For all that social media has bought people closer together and brought government, business and civic leaders, it has also been said to have fuelled divisions and hate. Governments and businesses are now drawing battle lines on the legal responsibilities required of social media platforms as we slowly determine the role they play in our society.

This Primer will discuss key questions including:

• What are the current legal responsibilities of social media companies? What sort of laws and regulations must they abide by?
• How are governments looking to change to this?
• How have some countries manipulated social media to monitor and censor their populations?
• Can social media truly tackle harmful and dangerous content?
• Is it possible to combat disinformation and what role should social media platforms play?
• How can we make social media best fit our society in the future?
• How should we govern online space?

A drinks reception will follow this event.

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

Russia’s aggression and a crisis for multilateralism 30 March 2023 — 1:00PM TO 2:00PM Anonymous (not verified) 23 March 2023 Chatham House and Online

In conversation with Dmytro Kuleba, minister of foreign affairs of Ukraine, about how multilateral organizations struggle to respond adequately to Russia’s full-scale invasion of Ukraine.

As a permanent member of the UN Security Council, Russia pursues this war in defiance of the umbrella organization’s multiple resolutions condemning the invasion, along with its war crimes, annexation of territory, deliberate targeting of civilian nuclear infrastructure, cultural extermination, and global disinformation campaign. 

This event explores the following questions: 

• How should the response of the UN to Russian aggression be assessed? 
• What can be done to uphold the guiding principles of the UN Charter? 
• Is there a ‘UN problem’ or a ‘Russia problem’? 
• How can trust and the legitimacy of multilateral cooperation be restored in times of strategic rivalry and rising global tensions?
• Who can drive such an effort? 
• Is post-Soviet transfer of the UN Security Council seat to Russia a cause of current impunity? 

This event features a live in-person audience in Kyiv as well as in London and online.

Turkey at a crossroads 4 May 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 4 April 2023 Chatham House and Online

What is at stake in the upcoming presidential and parliamentary elections?

Turkey is heading towards a fateful presidential and parliamentary elections in May 2023. These elections are taking place against the background of a deepening economic downturn and a devastating earthquake. The elections will bear a major impact on the future of Turkish democracy, economy and foreign policy. At stake is the nature of Turkey’s political system, its geopolitical identity and the health of its democracy.

To unpack the significance and implications of this election, this event aims to address the following questions:

• What kind of political visions do the main presidential candidates offer for the country?
• How do they differ on the main domestic and foreign policy issues?
• How do the presidential candidates feature in public surveys?
• What does this election mean for Turkey’s foreign policy?
• What is the likely impact of the election on Turkey’s place in the transatlantic alliance and its relations with Europe?

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

How do Eurasian kleptocracies earn and use their money? 9 November 2021 — 1:00PM TO 2:30PM Anonymous (not verified) 22 October 2021 Chatham House and Online

This event explores the presence of corrupt funds from Eurasia in Western democracies, what they are used for, and how they can be constrained.

The Pandora Papers once again shone the spotlight on the UK being home to corrupt funds from kleptocracies, where the ruling elite abuse their political power for private gain.

In recent years much focus has been placed on this term, and the possible effects such money could have on Western democracies.

• How do such states create this wealth in the first place?
• How do these funds make their way to the UK?
• Is the term kleptocracy appropriate for the majority of countries in Eurasia?
• What evidence is there that such funds are ‘weaponized’ to achieve foreign policy goals?

This event discusses the term, how it can be applied, and the differences between how ’grey’ funds are used by various countries. It also highlights how the UK and the wider international community can counteract these flows, both from a legal point of view, and via other methods.

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.

Crisis on Europe’s doorstep 2 February 2022 — 4:00PM TO 5:00PM Anonymous (not verified) 4 January 2022 Online

Domestic instability and foreign interference is destabilizing Bosnia, with the declining strength of the 1995 Dayton Agreement symbolic of the troubles growing within the country. 

Milorad Dodik’s continuing efforts to remove the international judicial and security presence in Bosnia, along with calls for the secession of Republic Sprska and increasing Russian efforts to destabilize the country are concerning many, particularly nearby European Union (EU) member states.

On 3 November 2021, the United Nations (UN) Security Council voted unanimously to extend the EU-led multinational stabilization force for another year, as well as NATO Headquarters Sarajevo.

However, the role played by the Office of High Representative was absent from the outcome and leaves the implementation of civilian aspects emanating from the Dayton Accords in a position of uncertainty.

Against a background of ongoing troubles in the country and the growing proxy conflict between the West and Russia, the situation in Bosnia is worrying.

The expert panel discusses:

• Why has the situation in Bosnia been allowed to deteriorate to such a condition?
• What is Europe’s best solution to resolve issues in Bosnia and how is it acting to remedy them?
• How have international efforts been hampered to support development in Bosnia?
• What are Russia’s aims in the country? 
• Does US foreign policy recognize Bosnia as a strategic partner?

Read the transcript

This event forms part of Chatham House’s work on Reinvigorating Multilateralism.

Ukraine crisis could trigger cascading risks globally Expert comment NCapeling 16 March 2022

The effects on the wider world from the Ukraine invasion go far beyond the waves of shock and horror being felt from this escalating conflict.

Russia and Ukraine rank 11th and 55th respectively in terms of their national economies but, for the global supply of critical resources such as energy, food, and minerals, these two countries together are far bigger hitters – and both the threat and reality of resource flows from them being reduced have already driven up global prices.

The world is already facing a cost-of-living squeeze coming out of the COVID-19 pandemic, so further price spikes or supply constraints have the potential to seriously undermine food and energy security, equitable access to basic goods and services, and social stability around the world – which can then potentially create systemic risks for economies and societies.

The global implications of the Ukraine conflict are only just beginning to be explored fully but the immediate impacts of the crisis on global markets are already well-documented. In the first few days after Russia’s invasion, energy prices spiked, triggering further fertilizer price rises – as fertilizer production is highly energy intensive – which in turn is contributing to food price rises because fertilizer costs are an important factor in food production.

Interruptions to shipping in the region around Ukraine – as well as globally – have impeded the flow of goods which pushed prices up even further, while economic sanctions on cross-border flows of goods and finance are further adding to market pressures. But this is just the start – these impacts will bring ripple effects which propagate far beyond their point of origin, known as ‘cascading risks’.

Risk is a combination of hazard, exposure, and vulnerability – in terms of the Ukraine invasion, the hazard is the conflict and its immediate impacts on the societies and economies of Ukraine and Russia, while exposure relates to the degree to which other countries are likely to be affected depending on how much they are integrated into the global economy or the ‘just in time’ nature of their supply chains.

Vulnerability relates to a society’s capacity to mitigate the harmful impacts of the conflict, such as controlling borders, sourcing alternative goods from suppliers, or protecting against price or supply shocks.

Risk cascades – the second- and third-order impacts of the original hazard and of responses to that hazard – can interact across sectoral boundaries – as with energy and food, for example – and their compound effect can lead to overall systemic risks for society.

Anticipating this potential is essential to understanding the nature and scale of the global ramifications being felt from the Ukraine conflict. Recent work in the UK to assess levels of cascading risks resulting from a changing climate – the UK Climate Change Risk Assessment – provides a valuable framework for thinking about this area.

It examines key pathways for risk to cascade through global systems – when applied to the situation in Ukraine, these pathways and their interactions offer an indication of the scale of crisis that citizens face far beyond Ukraine’s and Russia’s borders.

Interruptions to the flows of goods and energy

In globalized trade networks, localized disruption to supply chains rapidly yields widespread international impacts – of particular concern is the immediate supply of food because most countries rely on lean supply chains and some may only have a few days food within their own borders.

Experience from previous food price crises indicate even small interruptions to trade can result in runs on the market and rapid price inflation. In the case of this conflict, the trade interruption will be far from small because, between them, Russia and Ukraine export around one-quarter of all traded wheat, more than three-quarters of traded sunflower oil, and one-sixth of traded maize.

Energy markets are also a concern because many countries use more energy than they produce and therefore rely on imports of energy or fuel for domestic use. Russia produces around ten per cent of the world’s commercial energy with a concentration of sales in major regions such as the European Union (EU) and China.

As with food, a shortfall in energy provision leads to market runs and rapid inflation as actors compete in a tightening space, while poorly designed policy interventions by nations trying to ensure their own security add further pressure to global supply and worsen price rises. In addition, the closely interconnected nature of energy markets means disruption to one fuel – such as gas in this case – affects global prices for other forms of energy.

The impact of moving people and money

As the last decade richly illustrates, the cross-border flows of people impact those societies absorbing them – for example, contributing to a rise in nationalism – as well as increase the costs of supplying essential resources. Given many people are understandably fleeing this conflict, other countries may struggle to cope as the cost-of-living crisis and urgent efforts to bolster national security infrastructure may squeeze available public funds.

Financial flows are crucial to the functioning of global economies, whether for inward investment or insurance and – as Russian citizens may be about to discover – restricting the global flow of money has a serious impact on households. Beyond Russia, the outflow of money from major financial centres such as London to meet insurance claims or to enable infrastructure reinvestment post-conflict may also have severe knock-on economic impacts.

The impact on governance and health

The global spikes in energy and food prices resulting from these supply chain disruptions will see many countries struggle with rising food and energy insecurity as well as increased inequality. Taken together these conditions create many issues beyond immigration pressures and the associated politics, including increased inequality and civil unrest.

This potentially destabilizes governments which has consequences for the stability of an entire region such as interrupted supply chains, the need to deploy peacekeeping forces, or significant flows of aid – all with global consequences far beyond the countries in question.

Populations may suffer mental health impacts arising from the Ukraine invasion, whether from the trauma of being forced to leave home to escape conflict, anxiety for the wellbeing and safety of families and friends caught up in it, or a more general anxiety arising from the perception of living in an unstable world.

President Maia Sandu on democracy and politics in Moldova Video jon.wallace 4 July 2022

The president covers Moldova’s challenges as it seeks closer integration with the European Union.

President Maia Sandu discusses challenges to Moldovan democracy and society during an interview at Chatham House’s 2022 London Conference.

She covers issues including corruption, the presence of Russian troops in the Transnistria region, neutrality in Moldova’s constitution, popular support for EU membership and refugees from Russian aggression in Ukraine.

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.

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

Our purpose was to prospectively assess the distribution of NETPET scores in well-differentiated (WD) grade 2 and 3 gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and to determine the impact of the NETPET score on clinical management. Methods: This single-arm, institutional ethics review board–approved prospective study included 40 patients with histologically proven WD GEP NETs. ⁶⁸Ga-DOTATATE PET and ¹⁸F-FDG PET were performed within 21 d of each other. NETPET scores were evaluated qualitatively by 2 reviewers, with up to 10 marker lesions selected for each patient. The quantitative parameters that were evaluated included marker lesion SUV_max for each tracer; ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios; functional tumor volume (FTV) and metabolic tumor volume (MTV) on ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET, respectively; and FTV/MTV ratios. The treatment plan before and after ¹⁸F-FDG PET was recorded. Results: There were 22 men and 18 women (mean age, 60.8 y) with grade 2 (n = 24) or grade 3 (n = 16) tumors and a mean Ki-67 index of 16.1%. NETPET scores of P0, P1, P2A, P2B, P3B, P4B, and P5 were documented in 2 (5%), 5 (12.5%), 5 (12.5%) 20 (50%), 2 (5%), 4 (10%), and 2 (5%) patients, respectively. No association was found between the SUV_max of target lesions on ⁶⁸Ga-DOTATATE and the SUV_max of target lesions on ¹⁸F-FDG PET (P = 0.505). ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios were significantly lower for patients with low (P1–P2) primary NETPET scores than for those with high (P3–P5) primary NETPET scores (mean ± SD, 0.20 ± 0.13 and 1.68 ± 1.44, respectively; P < 0.001). MTV on ¹⁸F-FDG PET was significantly lower for low primary NETPET scores than for high ones (mean ± SD, 464 ± 601 cm³ and 66 ± 114 cm³, respectively; P = 0.005). A change in the type of management was observed in 42.5% of patients after ¹⁸F-FDG PET, with the most common being a change from systemic therapy to peptide receptor radionuclide therapy and from debulking surgery to systemic therapy. Conclusion: There was a heterogeneous distribution of NETPET scores in patients with WD grade 2 and 3 GEP NETs, with more than 1 in 5 patients having a high NETPET score and a frequent change in management after ¹⁸F-FDG PET. Quantitative parameters including ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios in target lesions and FTV/MTV ratios can discriminate between patients with high and low NETPET scores.

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

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret ¹⁸F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus–positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 ¹⁸F-FDG PET/CT and 134 ¹⁸F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no ¹⁸F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of ¹⁸F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if ¹⁸F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUV_max was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement ( = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement ( = 0.86). Quantitative assessment with an estimated best SUV_max ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement ( = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement ( = 0.86). Conclusion: Nuclear medicine physicians without ¹⁸F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

Turkey Is on the Road to a Severe Economic Crisis Expert comment sysadmin 12 July 2018

The deteriorating state of the economy is President Erdoğan’s Achilles’ heel and the biggest threat to his currently unrivalled leadership.

Fifteen days after Turkey’s parliamentary and presidential elections, Turkish President Recep Tayyip Erdoğan appointed a new government under radically enhanced executive powers granted by the constitution. He chose 16 loyalists and partisan figures to ensure that he remains front and centre in decision-making and policy formation.

Most notably, Erdoğan sacrificed the former deputy prime minister and ex-Merrill Lynch chief economist Mehmet Şimşek in favour of his inexperienced son-in-law Berat Albayrak as finance and treasury minister to manage the fragile economy. Whether he has the competence to placate jittery financial markets and foreign investors is debatable.

Erdoğan will prioritize short-term growth at all costs to the detriment of macroeconomic and financial stability. That entails foregoing interest rate hikes needed to contain runaway double-digit inflation and to support a plummeting lira that depreciated nearly 20 per cent this year. It also means loosening the purse strings, flooding the markets with cheap credit and sponsoring rampant construction and mega-infrastructure projects.

True to his promise, he has appropriated to himself, by presidential decree, the right to hire the central bank governor, deputies and monetary policy committee members for a four-year term. This completes the politicization of the once-respected and independent central bank and is in line with his unorthodox monetary views that higher interest rates equates with higher inflation.

Erdoğan associates progress with gleaming high-rise buildings, gargantuan infrastructure show-pieces and elevated growth rates. He is spiking the fuel to boost the speed of the sputtering mid-sized Audi-style Turkish economy to achieve superior Ferrari growth rates. As any mechanic knows, these tactics are unsustainable in the long term. Eventually, the engine will burn out.

He does not seem to appreciate that Turkey’s growth model requires an overhaul to join the league of rich economies. It is too reliant on consumer spending and government-sponsored infrastructure and construction projects funded by speculative financial flows rather than on sustained private investment and exports.

Net result: the corporate sector’s foreign-exchange liabilities have climbed to a record $328 billion as of the end of 2017. When netted against foreign-exchange assets, it is still a worrying $214 billion. Its US dollar and euro debt pile has more than doubled since 2008, 80 per cent of which is held by domestic banks. Given these acute balance-of-payments conditions, it is not farfetched that Turkey may impose capital controls in the short-to-medium term to restrict the outflow of foreign assets. At $50 billion, the current account deficit – defined as the sum of the trade balance and financial flows – is not even covered by the central bank’s net international reserves at nearly $45 billion.

Unsurprisingly, some major Turkish companies are negotiating with their bondholders to restructure their sizeable foreign loan obligations as lira devaluation increases the financial burden. Should a significant number of Turkish corporates default on their foreign obligations, this would reverberate across the Turkish economy, cause mass consumer panic, shake the confidence of international financial markets and potentially lead to a crisis within the Turkish financial system and to a deep and prolonged economic recession.

Revealingly, Erdoğan’s nationalist allies, the Nationalist Movement Party (MHP), refused to join his government. Perhaps Devlet Bahçeli, the MHP leader, learned the lessons of the 2001 financial crisis as a member of a three-party government. So he is opting to project influence from the outside, rather than risk being tainted with responsibility for an economic downturn.

Turkey’s president is doubling down on his singular approach to governance irrespective of the fallout. Notwithstanding his current political dominance, the deteriorating state of the economy is his Achilles’ heel and the biggest threat to his currently unrivalled leadership.

A Credit-fuelled Economic Recovery Stores Up Trouble for Turkey Expert comment sysadmin 17 February 2020

Turkey is repeating the mistakes that led to the 2018 lira crisis and another freefall for the currency may not be far off.

Since the 2018 economic crisis, when the value of the lira plummeted and borrowing costs soared, Turkey’s economy has achieved a miraculous ‘V-shaped’ economic recovery from a recession lasting three quarters to a return back to quarterly growth above 1 per cent in the first three months of 2019.

But this quick turnaround has been built on vast amounts of cheap credit used to re-stimulate a consumption and construction boom. This so-called ‘triple C’ economy generated a rapid growth spurt akin to a modestly able professional sprinter injected with steroids.

This has made the currency vulnerable. The lira has steadily depreciated by 11 per cent against the US dollar since the beginning of 2019 and crossed the rate of 6 lira versus the US dollar on 7 February. And there are further warning signs on the horizon.

Credit bonanza

Statistics reveal that Turkish domestic credit grew by around 13 per cent on average throughout 2019. The credit bonanza is still ongoing. Mortgage-backed home sales jumped by a record high of 600 per cent last December alone and the 2019 budget deficit catapulted by 70 per cent due to higher government spending.

Turkey’s central bank fuelled this credit expansion by cutting interest rates aggressively to below inflation and, since the start of this year, purchasing lira-denominated bonds equivalent to around one-third of total acquisitions last year to push yields lower.

Equally, it has linked bank lending to reserve requirements – the money that banks have to keep at the central bank – to boost borrowings via state and private banks. Banks with a ‘real’ loan growth (including inflation) of between 5 and 15 per cent enjoy a 2 per cent reserve ratio on most lira deposits, which authorities adjusted from an earlier band of 10-20 per cent that did not consider double-digit inflation.

Cumulatively, bond purchases (effectively quantitative easing) and reserve management policies have also contributed to eased credit conditions.

Commercial banks have also reduced deposit rates on lira accounts to less than inflation to encourage consumption over saving. Together with low lending rates, the boost to the economy has flowed via mortgages, credit card loans, vehicle leasing transactions and general business borrowings.

Accordingly, stimulus is at the forefront of the government’s economic approach, as it was in 2017 and 2018. It does not seem to be implementing structural change to re-orient growth away from consumption towards productivity.

In addition, governance is, again, a central issue. President Recep Tayyip Erdogan’s near total monopolization of policymaking means he guides all domestic and external policies. He forced out the previous central bank governor, Murat Cetinkaya, in July 2019 because he did not share the president’s desire for an accelerated pace of interest rate reductions.

New challenges

Despite the similarities, the expected future financial turbulence will be materially different from its 2018 predecessor in four crucial respects.

Firstly, foreign investors will only be marginally involved. Turkey has shut out foreign investors since 2018 from lira-denominated assets by restricting lira swap arrangements. Unsurprisingly, the non-resident holdings of lira bonds has plummeted from 20 per cent in 2018 to less than 10 per cent today.

Secondly, the Turkish government has recently introduced indirect domestic capital controls by constraining most commercial transactions to the lira rather than to the US dollar or euro to reduce foreign currency demand in light of short-term external debt obligations of $191 billion.

Thirdly, the Turkish state banks are intervening quite regularly to soften Lira volatility, thereby transitioning from a ‘free float’ to a ‘managed float’. So far, they have spent over $37 billion over the last two years in a futile effort to buttress the lira. This level of involvement in currency markets cannot be maintained.

Fourthly, the Turkish state is being far more interventionist in the Turkish stock exchange and bond markets to keep asset prices elevated. Government-controlled local funds have participated in the Borsa Istanbul and state banks in sovereign debt to sustain rallies or reverse a bear market.

All these measures have one running idea: exclude foreign investors and no crisis will recur. Yet, when the credit boom heads to a downturn sooner or later, Turks will probably escalate lira conversions to US dollars; 51 per cent of all Turkish bank deposits are already dollar-denominated and the figure is still rising.

If Turkey’s limited foreign reserves cannot satisfy the domestic dollar demand, the government may have to impose comprehensive capital controls and allow for a double digit depreciation in the value of the lira to from its current level, with significant repercussions on Turkey’s political stability and economic climate.

To avoid this scenario, it needs to restore fiscal and monetary prudence, deal the with the foreign debt overhang in the private sector and focus on productivity-improving economic and institutional reforms to gain the confidence of global financial markets and Turks alike.

Turkey’s foreign and domestic policy: A story of mutual creation? 1 November 2022 — 2:00PM TO 3:00PM Anonymous (not verified) 12 October 2022 Online

Panellists discuss the link between Turkey’s domestic and foreign policies under President Erdoğan.

From Turkey’s ongoing rapprochement with its erstwhile Middle Eastern antagonists to its Syria policy and earlier approach towards the West, there has been extensive discussion on the domestic drivers behind Ankara’s foreign policy.

Less discussed but no less important is how Turkish foreign affairs have shaped its internal politics. Under the rule of the Justice and Development Party (AKP) government and President Recep Tayyip Erdoğan, Turkey’s foreign and domestic policies have mutually reshaped each other.

In this webinar, launching Gönül Tol’s new book Erdoğan’s War: A Strongman’s Struggle at Home and in Syria, panellists will take stock of how Turkey’s domestic and foreign policies under the leadership of President Erdoğan have influenced and shaped each other. Speakers will also discuss the internal drivers behind Turkey’s current reset in relations with the Middle East, and examine how Ankara’s foreign affairs play into the country’s political and identity fault lines.

The event will be held on the record and will be live-streamed on the MENA Programme’s Facebook page.

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