ex Proteomic analyses identify differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage lung adenocarcinoma and their prognostic impacts [Research] By www.mcponline.org Published On :: 2020-11-30T14:35:18-08:00 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. Full Article
ex A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia [Research] By www.mcponline.org Published On :: 2020-11-30T16:35:18-08:00 Extracellular vesicle (EV) proteins from acute myeloid leukemia (AML) cell lines were analyzed using mass spectrometry. The analyses identified 2450 proteins, including 461 differentially expressed proteins (290 upregulated and 171 downregulated). CD53 and CD47 were upregulated and were selected as candidate biomarkers. The association between survival of patients with AML and the expression levels of CD53 and CD47 at diagnosis was analyzed using mRNA expression data from The Cancer Genome Atlas database. Patients with higher expression levels showed significantly inferior survival than those with lower expression levels. Enzyme-linked immunosorbent assay results of the expression levels of CD53 and CD47 from EVs in the bone marrow of patients with AML at diagnosis and at the time of complete remission with induction chemotherapy revealed that patients with downregulated CD53 and CD47 expression appeared to relapse less frequently. Network model analysis of EV proteins revealed several upregulated kinases, including LYN, CSNK2A1, SYK, CSK, and PTK2B. The potential cytotoxicity of several clinically applicable drugs that inhibit these kinases was tested in AML cell lines. The drugs lowered the viability of AML cells. The collective data suggest that AML-derived EVs could reflect essential leukemia biology. Full Article
ex A potential role for the Gsdf-eEF1{alpha} complex in inhibiting germ cell proliferation: A protein-interaction analysis in medaka (Oryzias latipes) from a proteomics perspective [Research] By www.mcponline.org Published On :: 2020-12-08T12:35:19-08:00 Gonadal soma-derived factor (gsdf) has been demonstrated to be essential for testicular differentiation in medaka (Oryzias latipes). To understand the protein dynamics of Gsdf in spermatogenesis regulation, we used a His-tag "pull-down" assay coupled with shotgun LC-MS/MS to identify a group of potential interacting partners for Gsdf, which included cytoplasmic dynein light chain 2, eukaryotic polypeptide elongation factor 1 alpha (eEF1α), and actin filaments in mature medaka testis. As for the interaction with TGFβ-dynein being critical for spermatogonial division in Drosophila melanogaster, the physical interactions of Gsdf-dynein and Gsdf-eEF1α were identified through a yeast 2-hybrid (Y2H) screening of an adult testis cDNA library using Gsdf as bait, which were verified by a paired Y2H assay. Co-immunoprecipitation of Gsdf and eEF1α was defined in adult testes as supporting the requirement of a Gsdf and eEF1α interaction in testis development. Proteomics analysis (data are available via ProteomeXchange with identifier PXD022153) and ultrastrutural observations showed that Gsdf deficiency activated eEF1α-mediated protein synthesis and ribosomal biogenesis, which in turn led to the differentiation of undifferentiated germ cells. Thus, our results provide a framework and new insight into the coordination of a Gsdf (TGFβ and eEF1α complex in the basic processes of germ cell proliferation, transcriptional and translational control of sexual RNA which may be fundamentally conserved across phyla during sexual differentiation. Full Article
ex Systematic identification of P. falciparum sporozoite membrane protein interactions reveals an essential role for the p24 complex in host infection [Research] By www.mcponline.org Published On :: 2020-12-22T08:35:40-08:00 Sporozoites are a motile form of malaria-causing Plasmodium falciparum parasites that migrate from the site of transmission in the dermis through the bloodstream to invade hepatocytes. Sporozoites interact with many cells within the host, but the molecular identity of these interactions and their role in the pathology of malaria is poorly understood. Parasite proteins that are secreted and embedded within membranes are known to be important for these interactions, but our understanding of how they interact with each other to form functional complexes is largely unknown. Here, we compile a library of recombinant proteins representing the repertoire of cell surface and secreted proteins from the P. falciparum sporozoite and use an assay designed to detect extracellular interactions to systematically identify complexes. We identify three protein complexes including an interaction between two components of the p24 complex that is involved in the trafficking of glycosylphosphatidylinositol (GPI)-anchored proteins through the secretory pathway. Plasmodium parasites lacking either gene are strongly inhibited in the establishment of liver stage infections. These findings reveal an important role for the p24 complex in malaria pathogenesis and show that the library of recombinant proteins represents a valuable resource to investigate P. falciparum sporozoite biology. Full Article
ex Exploring Transatlantic Responses to Far-right Populism in Europe: Simulation Exercise By www.chathamhouse.org Published On :: Tue, 01 May 2018 14:51:32 +0000 Exploring Transatlantic Responses to Far-right Populism in Europe: Simulation Exercise Research paper sysadmin 1 May 2018 A new paper summarizes the findings of a recent simulation exercise exploring how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state. — Young protester, Serbia. Photo: urbazon/Getty Images. Summary To better understand how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state, Chatham House organized a simulation event involving a group of experts drawn from the public sector, academia and NGOs. Simulation exercises enable the testing and modelling of the responses of different actors when presented with specific situations; participants’ interactions in a given set of circumstances are explored, and patterns of negotiation are captured and analysed. In this simulation, European, US and multilateral representatives were given the task of managing relations with Baltia, a fictional Eastern European state on the verge of electing a far-right nationalist, Eurosceptic government. They were then challenged to manage their relationship with Baltia after it had elected such a government, which was pushing for a ‘leave’ vote in a planned referendum on the country’s continued EU membership. The simulation highlighted a number of issues: Limited instruments are available to liberal democratic governments where there is cause for concern regarding the outcome of an election in an allied country. There are relatively few tools at the disposal of governments to support political allies, or to prevent outcomes that are perceived as threatening democratic norms. The simulation reinforced the view that interventionist moves, either from the European Commission or from individual national governments, would be more likely to come in response to an unfavourable development rather than pre-emptively. The EU, and caucuses of European states, are the main international interlocutors in this type of political crisis involving an EU member state. The US opted to play a limited role in the negotiations; the same was largely true for NATO, aside from its action in sharing intelligence about a potential coup in Baltia. France and Germany formed a natural working partnership, taking meetings together and coordinating policies first before discussing them with a wider European circle, although their positions did not always align. The UK’s capacity to shape the outcome of collective EU discussions appeared more restricted, while Brexit also seemed to shape the response of other EU states to the developing situation in Baltia. Although member states were undoubtedly reluctant to see another country go down this route, they were also resolute in demonstrating a unity of approach and limited flexibility in the face of the new populist government’s attempt to divide them. 2018-05-03-exploring-transatlantic-responses-far-right-populism-europe-parakilas-raines-NEW (PDF) Full Article
ex Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part One By www.chathamhouse.org Published On :: Mon, 29 Oct 2018 16:37:47 +0000 Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part One Other resource sysadmin 29 October 2018 As part of a roundtable series, Chatham House and China University of Political Science and Law (CUPL) jointly organized this four-day meeting at Chatham House for international lawyers to discuss a wide range of issues related to public international law and the rights of individuals. — The Representative of China at the 19th Session of the Human Rights Council, Palais des Nations, Geneva. 27 February 2012. Photo: UN Photo Geneva/Violaine Martin. The specific objectives were to: create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China; build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it; support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law. The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law. For China University of Political Science and Law, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field. The roundtable had a total of 22 participants, 10 Chinese (from universities and other academic institutions in Beijing and Shanghai) and 12 non-Chinese (from Australia, Germany, the Netherlands, Switzerland, the United Kingdom and the United States). All discussions were held in English under the Chatham House Rule. 20140414PublicInternationalLawChina (PDF) Full Article
ex Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part Two By www.chathamhouse.org Published On :: Tue, 30 Oct 2018 08:46:37 +0000 Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part Two Other resource sysadmin 30 October 2018 As part of a roundtable series, Chatham House and China University of Political Science and Law (CUPL) held a two-day roundtable meeting in Beijing on public international law and the rights of individuals. — The Representative of China at the 19th Session of the Human Rights Council, Palais des Nations, Geneva. 27 February 2012. Photo: UN Photo Geneva/Violaine Martin. The specific objectives were to: create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China; build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it; support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law. The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law. For CUPL, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field. The meeting in Beijing was hosted by CUPL and involved 20 participants, 10 Chinese (from universities and other academic institutions in Beijing) and 10 non-Chinese (from Australia, the Netherlands, South Africa, Switzerland, the United Kingdom and the United States). To ensure continuity while also expanding the experts network being built, the second meeting included a mix of participants from the first meeting and some new participants. All discussions were held in English under the Chatham House Rule. 23711Roundtable2-summary (PDF) Full Article
ex Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part Three By www.chathamhouse.org Published On :: Tue, 30 Oct 2018 08:55:48 +0000 Exploring Public International Law and the Rights of Individuals with Chinese Scholars - Part Three Other resource sysadmin 30 October 2018 As part of a roundtable series, Chatham House, China University of Political Science and Law (CUPL) and the Graduate Institute Geneva held a two-day roundtable meeting in Geneva on public international law and the rights of individuals. — The Representative of China at the 19th Session of the Human Rights Council, Palais des Nations, Geneva. 27 February 2012. Photo: UN Photo Geneva/Violaine Martin. The specific objectives were to: create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China; build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it; support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law. The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law. For CUPL, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field. The meeting in Geneva was co-hosted by the Graduate Institute Geneva and involved 19 participants, 9 Chinese (from six research institutions in Beijing and Shanghai) and 11 non-Chinese (from eight research institutions in Australia, Germany, the Netherlands, Switzerland, the United Kingdom and the United States). To ensure continuity while also expanding the expert network being built, the third meeting included a mix of participants from the first two meetings and some new participants All discussions were held in English under the Chatham House Rule. 2016-03-05-Roundtable3-summary (PDF) Full Article
ex Exploring Public International Law Issues with Chinese Scholars – Part Four By www.chathamhouse.org Published On :: Tue, 30 Oct 2018 09:01:59 +0000 Exploring Public International Law Issues with Chinese Scholars – Part Four Other resource sysadmin 30 October 2018 As part of a roundtable series, Chatham House and the China University of Political Science and Law (CUPL) held a two-day roundtable in Beijing on emerging issues of public international law. — The Representative of China at the 19th Session of the Human Rights Council, Palais des Nations, Geneva. 27 February 2012. Photo: UN Photo Geneva/Violaine Martin. The specific objectives were to: create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China; build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it; support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law. The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law. For CUPL, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field. The meeting was co-hosted with CUPL and involved 28 participants, consisting of 19 Chinese participants (from six leading research institutions in Beijing and Shanghai) and nine nonChinese participants (from eight leading research institutions in Australia, the Netherlands, the UK, Switzerland, Canada and Singapore). To ensure continuity while also expanding the expert network being built, the fifth meeting included a mix of participants from the previous meetings and some new participants. All discussions were held in English under the Chatham House Rule. 2018-06-02-Roundtable4-summary (PDF) Full Article
ex Adopting a Market-based Approach to Boost Energy Access in Displaced Contexts By www.chathamhouse.org Published On :: Mon, 25 Mar 2019 10:18:12 +0000 Adopting a Market-based Approach to Boost Energy Access in Displaced Contexts Research paper sysadmin 25 March 2019 This paper evaluates the market-based approaches adopted in the MEI projects in Kenya and Burkina Faso. It articulates how such commercial strategies can be applied to the delivery of energy in displacement settings and compares this to real world examples. — A shop selling fabric and electronics inside the Dagahaley Camp, one of five camps that make up Dadaab, the world’s largest and oldest camp for refugees. Photo: Michelle Shephard/Toronto Star via Getty Images. Development of long-term energy solutions in displacement settings tends to be perceived as investment that falls outside the remit of emergency responses. In addition, when emergency energy supply measures are implemented they often result in expensive, unreliable and unhealthy energy provision for those in protracted or recurrent crises. There is widespread agreement among humanitarian and development experts that an effective refugee response should include long-term development solutions as well as emergency relief. The energy access imperative is more pronounced when considering the need for effective energy distribution in practically all camp activities and basic necessities: pumping and treatment of clean water; heating and cooling for food storage and cooking; energy for livelihood activities; and provision of light for schooling, hospitals and the prevention of violence against women and children. Minor shifts in household energy use to basic solar lighting options and non-wood fuels would save $303 million annually on refugee fuel costs. Within refugee contexts in Kenya and Burkina Faso, the MEI sought to examine opportunities to use market interventions, rather than in-kind distributions, to improve clean energy access over the long-term and test the delivery of market-based approaches. 2019-03-25-MEIWhitehouse (PDF) Full Article
ex Centenary Series: Exploring the International Affairs Archive By www.chathamhouse.org Published On :: Mon, 14 Sep 2020 09:18:37 +0000 Centenary Series: Exploring the International Affairs Archive dora.popova 14 September 2020 International Affairs has been a central part of the institute’s history, both as a record of speeches made by dignitaries such as Mahatma Gandhi and Henry Kissinger, and as a forum for policy-relevant academic research. Delving into the International Affairs archive brings out stories behind some of the most significant players of the last century. Full Article
ex COP26: What happened, what does this mean, and what happens next? By www.chathamhouse.org Published On :: Mon, 15 Nov 2021 15:53:27 +0000 COP26: What happened, what does this mean, and what happens next? Chatham House briefing NCapeling 15 November 2021 Analysing a crucial opportunity for enhancing ambitions on climate finance, adaptation, and ‘loss and damage’, and the implementation of the Paris Agreement. Key findings Raising the ambition of national emission reduction targets (nationally determined contributions – NDCs) was a critical task for COP26. On this front, governments fell short: although over 120 parties have submitted new or updated NDCs, the new targets only narrow the gap to 1.5°C by 15–17 per cent, and are, if fully implemented (and this is far from certain), projected to result in warming of 2.4°C by the end of the century. If warming is to be limited to 1.5°C above pre-industrial levels, additional emissions reductions before 2030, over and above current NDC pledges, will need to equate to reducing emissions by the equivalent of two years of current annual emissions. To keep warming to 2°C, the equivalent reductions would be needed of one year’s total emissions. The Glasgow Climate Pact – the main political outcome of COP26 – requests governments to revisit and strengthen their NDCs before the end of 2022 to bring these in line with the Paris Agreement’s temperature goal. To keep 1.5°C within reach, it will be absolutely essential that governments return to the table with significantly enhanced offers ahead of COP27, which will take place at Sharm El-Sheikh, Egypt, in 2022. Another key feature of the Glasgow Climate Pact is the reference to ‘accelerating efforts towards the phasedown of unabated coal power and phase-out of inefficient fossil fuel subsidies’. Although the language was watered down over the course of the negotiations, COP26 marks the first time ever reducing fossil fuels is mentioned in a COP decision. Discussions around climate finance, adaptation, and loss and damage were centre stage in Glasgow, and were critical points of contention. Although the Glasgow Climate Pact urges developed countries to ‘fully’ deliver on the $100 billion annual climate finance pledge through to 2025, it remains unclear when this sum will actually be raised in full – and if a total of $500 billion will be mobilized between 2020 and 2025 to make up for initial shortfalls. And while the Pact urges developed countries to double their adaptation finance by 2025, and establishes a dialogue on loss and damage finance, much more will need to be done to address the needs of climate-vulnerable developing countries. COP26 saw a flurry of plurilateral deals on key issues such as phasing out various forms of fossil fuels and ending deforestation. These initiatives have the potential to accelerate decarbonization, but monitoring their implementation and holding governments and other institutions to account will be critical. Future COPs provide a platform for doing this, and governments should seek to incorporate the pledges made outside the formal remits of the UNFCCC process in their NDCs. While some progress was made at COP26, the next 12 months will be crucial in determining if the formal agreements reached in Glasgow provide grounds for optimism that 1.5°C remains firmly in sight, and are sufficient to build trust between countries and between citizens and governments. Read the full analysis COP26 What happened, what does this mean, and what happens next (PDF) Full Article
ex Mycobacteria excise DNA damage in 12- or 13-nucleotide-long oligomers by prokaryotic-type dual incisions and performs transcription-coupled repair [Genomics and Proteomics] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 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. Full Article
ex Kinetic investigation of the polymerase and exonuclease activities of human DNA polymerase ϵ holoenzyme [DNA and Chromosomes] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 In eukaryotic DNA replication, DNA polymerase ε (Polε) is responsible for leading strand synthesis, whereas DNA polymerases α and δ synthesize the lagging strand. The human Polε (hPolε) holoenzyme is comprised of the catalytic p261 subunit and the noncatalytic p59, p17, and p12 small subunits. So far, the contribution of the noncatalytic subunits to hPolε function is not well understood. Using pre-steady-state kinetic methods, we established a minimal kinetic mechanism for DNA polymerization and editing catalyzed by the hPolε holoenzyme. Compared with the 140-kDa N-terminal catalytic fragment of p261 (p261N), which we kinetically characterized in our earlier studies, the presence of the p261 C-terminal domain (p261C) and the three small subunits increased the DNA binding affinity and the base substitution fidelity. Although the small subunits enhanced correct nucleotide incorporation efficiency, there was a wide range of rate constants when incorporating a correct nucleotide over a single-base mismatch. Surprisingly, the 3'→5' exonuclease activity of the hPolε holoenzyme was significantly slower than that of p261N when editing both matched and mismatched DNA substrates. This suggests that the presence of p261C and the three small subunits regulates the 3'→5' exonuclease activity of the hPolε holoenzyme. Together, the 3'→5' exonuclease activity and the variable mismatch extension activity modulate the overall fidelity of the hPolε holoenzyme by up to 3 orders of magnitude. Thus, the presence of p261C and the three noncatalytic subunits optimizes the dual enzymatic activities of the catalytic p261 subunit and makes the hPolε holoenzyme an efficient and faithful replicative DNA polymerase. Full Article
ex Polymerase {gamma} efficiently replicates through many natural template barriers but stalls at the HSP1 quadruplex [Enzymology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we identified a specific G-quadruplex–forming sequence at the heavy-strand promoter (HSP1) that has the potential to cause significant stalling of mtDNA replication. Furthermore, this structured region of DNA corresponds to the break site for a large (3,895 bp) deletion observed in mitochondrial disease patients. The presence of this deletion in humans correlates with UV exposure, and we have found that efficiency of polymerase γ DNA synthesis is reduced after this quadruplex is exposed to UV in vitro. Full Article
ex Phosphorylation of SMURF2 by ATM exerts a negative feedback control of DNA damage response [DNA and Chromosomes] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Timely repair of DNA double-strand breaks (DSBs) is essential to maintaining genomic integrity and preventing illnesses induced by genetic abnormalities. We previously demonstrated that the E3 ubiquitin ligase SMURF2 plays a critical tumor suppressing role via its interaction with RNF20 (ring finger protein 20) in shaping chromatin landscape and preserving genomic stability. However, the mechanism that mobilizes SMURF2 in response to DNA damage remains unclear. Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20. We demonstrate that a SMURF2 mutant with an S384A substitution has reduced capacity to ubiquitinate RNF20 while promoting Smad3 ubiquitination unabatedly. More importantly, mouse embryonic fibroblasts expressing the SMURF2 S384A mutant show a weakened ability to sustain the DSB response compared with those expressing WT SMURF2 following etoposide treatment. These data indicate that SMURF2-mediated RNF20 ubiquitination and degradation controlled by ataxia telangiectasia mutated–induced phosphorylation at Ser384 constitutes a negative feedback loop that regulates DSB repair. Full Article
ex Realmuto 'excited' to compete for title with Phils By mlb.mlb.com Published On :: Tue, 12 Feb 2019 19:32:42 EDT The Phillies introduced J.T. Realmuto, their new All-Star catcher, in a news conference Tuesday at the team's Spring Training complex in Clearwater, Fla. Full Article
ex Inbox: Which Angels will surpass expectations? By mlb.mlb.com Published On :: Thu, 7 Feb 2019 10:00:00 EDT With less than a week left until Angels pitchers and catchers report to Spring Training, it's time for the final Angels Inbox of the offseason. Full Article
ex The next Ohtani? Walsh to get two-way shot By mlb.mlb.com Published On :: Thu, 14 Feb 2019 16:36:35 EDT 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. Full Article
ex Ohtani focused on next step of hitting off tee By mlb.mlb.com Published On :: Sun, 17 Feb 2019 14:55:01 EDT Shohei Ohtani is continuing to make progress in his rehab from Tommy John surgery. On Sunday, he said he is hopeful he'll be able to start hitting off a tee in the next week. Full Article
ex Politicians are failing to prepare for next pandemic, warns head of European health agency By www.bmj.com Published On :: Thursday, September 26, 2024 - 11:21 Full Article
ex Correction: Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. [Additions and Corrections] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 VOLUME 279 (2004) PAGES 33438–33446For Fig. 1B, the second, third, and fifth panels were mistakenly duplicated during article preparation as no yeast colonies were observed in these conditions. The corrected images are presented in the revised Fig. 1B. This correction does not affect the results or conclusions of the work. The authors apologize for the error.jbc;295/50/17382/F1F1F1Figure 1B. Full Article
ex POSTPONED: Zimbabwe Futures 2025: Financial Sector Expansion and Policy Priorities By www.chathamhouse.org Published On :: Mon, 06 Nov 2017 15:00:00 +0000 POSTPONED: Zimbabwe Futures 2025: Financial Sector Expansion and Policy Priorities 15 November 2017 — 9:00AM TO 11:30AM Anonymous (not verified) 6 November 2017 Harare, Zimbabwe This roundtable will draw on current best practice and senior level expertise to identify policy options for financial stability and sector growth. A depoliticized analysis of the development agenda will highlight requisite conditions and prospective policies for a business-driven roadmap to the economic recovery of Zimbabwe, with a specific focus on the financial sector.Participants will discuss macro-economic policy and stability, retail banking products and services, fintech, mobilizing domestic finance for national infrastructure and balancing consumer price index and inflation. This event is being held in partnership with the Zimbabwe Business Club.PLEASE NOTE, THIS EVENT HAS BEEN POSTPONED UNTIL FURTHER NOTICE. Full Article
ex Zimbabwe Futures 2030: Policy Priorities for Economic Expansion By www.chathamhouse.org Published On :: Thu, 07 Feb 2019 12:36:52 +0000 Zimbabwe Futures 2030: Policy Priorities for Economic Expansion 28 February 2019 — 9:00AM TO 1:00PM Anonymous (not verified) 7 February 2019 Harare, Zimbabwe This roundtable draws on current best practice and senior level expertise to identify policy options for long term economic expansion in Zimbabwe and pathways for inclusive development.Participants discuss the necessary policies and business strategies to enable and support the effective implementation of the Transitional Stabilization Programme and longer term national development plans.The discussions highlight requisite conditions for a business-driven and inclusive process towards Zimbabwe’s long-term economic recovery.This event was held in partnership with the Zimbabwe Business Club and Konrad Adenauer Stiftung. Full Article
ex South Africa's Economic Reform and Employment in the Context of the Coronavirus Pandemic By www.chathamhouse.org Published On :: Wed, 26 Aug 2020 11:10:01 +0000 South Africa's Economic Reform and Employment in the Context of the Coronavirus Pandemic 3 September 2020 — 3:00PM TO 4:00PM Anonymous (not verified) 26 August 2020 Online President of COSATU, Zingiswa Losi, discusses the organization’s priorities for protecting jobs and workers, and working with other stakeholders to build a sustainable post-pandemic economy. Employment in South Africa fell by an estimated 18 per cent between February and April 2020. The measures imposed to control the spread of COVID-19 suffocated an already weak economy and unemployment has hit a new high. The stated aims of the government’s economic reform plans include the support of job creation in labour intensive industries, but the reform of the state and rebalancing of the economy and fiscus could lead to further job losses in state agencies and enterprises. Protecting jobs while ensuring the health and safety of workers are dual priorities, and require the joint commitment and ‘social compact’ of labour, business and government. Full Article
ex Expanding and enhancing the global cyber workforce By www.chathamhouse.org Published On :: Wed, 05 Oct 2022 07:37:13 +0000 Expanding and enhancing the global cyber workforce 17 November 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 5 October 2022 Chatham House and Online How can we address the cybersecurity workforce shortage and skills gap? Accelerated digital transformation and heightened geopolitical tensions on the international stage have increased the need for effective cybersecurity practices and policies as well as a skilled workforce. Despite this, the demand for cybersecurity professionals continues to outpace the supply for societies and businesses globally, resulting in a cybersecurity workforce gap. To ensure that digital transformation is available, safe and beneficial to all, significant efforts are needed to encourage cyber workforce capacity-building and knowledge-sharing at both national and international levels. This discussion, supported by (ISC)2 and the UK Cyber Security Council, will explore how to effectively address the twin challenges of the global cyber workforce shortage and skills gap. What are the implications of the global cyber workforce and skills gaps for businesses and societies? What shape do these gaps take within society? Where are they most prevalent and how do they vary? What is the role of education and private-public partnerships in effectively addressing these gaps? How does the UK National Cyber Strategy seek to address these challenges? What are the key lessons from this strategy? What other efforts are being made internationally to bridge this gap? What opportunities are there for knowledge-sharing and capacity-building? What is the role of diversity, equity and inclusion in tackling these gaps? As with all members events, questions from the audience drive the conversation. If you are not a member of Chatham House but would still like to attend the event please email Eleanor Macmillan-Fox to enquire about registration. Read the transcript. Full Article
ex Members' drinks and exhibition By www.chathamhouse.org Published On :: Fri, 07 Oct 2022 11:07:14 +0000 Members' drinks and exhibition 27 October 2022 — 6:00PM TO 8:00PM Anonymous (not verified) 7 October 2022 Chatham House A showcase of a selection of the Black Cultural Archives photo exhibition of up-and-coming Black British leaders. Chatham House is pleased to showcase a selection of the Black Cultural Archives photo exhibition of up-and-coming Black British leaders. These portraits illuminate the talent and pipeline of ‘next gen’ leaders in the Black British community – some of whom will be in attendance at the reception. The chair of the Black British Cultural Archives, Dr Yvonne Thompson, will make short remarks at around 18:20 BST. We hope you will join your fellow members and Chatham House staff for a chance to connect and celebrate. You are welcome to attend the event Black perspectives on International Relations preceding the reception. Please note as space is limited, this event is operating a ballot for registrations. Your place will be confirmed by Tuesday 25 October if you are successful. Full Article
ex What’s next in UK monetary policy? By www.chathamhouse.org Published On :: Wed, 19 Oct 2022 11:32:14 +0000 What’s next in UK monetary policy? 4 November 2022 — 4:00PM TO 5:30PM Anonymous (not verified) 19 October 2022 Chatham House and Online A panel of leading experts discuss the future direction of UK monetary policy. The UK’s so-called ‘mini-budget’ on 23 September led to a severe market reaction and a wave of criticism at home and abroad that ultimately forced the sacking of UK chancellor Kwasi Kwarteng and contributed to the downfall of Liz Truss’s government. The new chancellor Jeremy Hunt is due to deliver what will essentially be an entirely new budget in mid-November, with a full assessment from the Office of Budget Responsibility. This will follow the meeting of the Bank of England’s interest rate setting Monetary Policy Committee (MPC) on Thursday 3 November. Given rising inflationary pressures worldwide, it seems highly likely that the MPC will increase interest rates once again, but by how much and how far there will have to be an additional premium linked to the government’s fiscal strategy is far from clear. Chatham House’s Global Economy and Finance programme is pleased to partner with Fathom Consulting to host a special session of Fathom’s Monetary Policy Forum. A presentation of Fathom’s latest economic outlook, fully updated to take account of the previous day’s MPC decision, will be followed by a discussion among four of the MPC’s original former external members. Key questions will include: How far has the government been able to restore its fiscal credibility? Did the MPC make the right decision on 3 November? What is the likely pace and extent of monetary tightening in the UK going forward? What will be the long-term consequences for the UK economy of the past month’s policy experiment? What are the international implications? As with all members events, questions from the audience drive the conversation. This event is in partnership with Fathom Consulting. Full Article
ex Brexit: Then, now and the future By www.chathamhouse.org Published On :: Wed, 30 Nov 2022 14:37:14 +0000 Brexit: Then, now and the future 2 February 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 30 November 2022 Chatham House and Online How has Britain’s negotiations with the EU set it on a post-EU path? The Brexit negotiations went down to the wire between the UK and the EU in December 2020. By January 2021, the UK’s departure from the EU had taken place, but the new relationship was by no means stable. The UK and EU have since clashed on trade, migration and the Northern Ireland Protocol which are all left unresolved. This year, both sides have had to deal with domestic political instability, Russia’s invasion of Ukraine and a global energy crisis that has changed the dynamics of its relationship. In the years ahead, both sides will need to address shared challenges, from the rise of China and climate change to security on the European continent. This discussion includes those who were in the room during the Brexit negotiations, including Michel Barnier’s adviser, to get an inside look on how the UK and EU negotiated Brexit. Combining insight from the new book, Inside the Deal – How the EU Got Brexit Done, with expert analysis the panel assesses where the post-Brexit negotiations are today. Key questions include: What issues in the deal still need to be fixed? How has the EU evolved since Brexit? How would a future Labour government approach the UK-EU relationship? What are the best and worst case scenarios for UK-EU relations in 2030? As with all members events, questions from the audience drive the conversation. Read the transcript. Full Article
ex Chatham House exhibition - In conversation with the future By www.chathamhouse.org Published On :: Fri, 31 Mar 2023 09:42:13 +0000 Chatham House exhibition - In conversation with the future 19 April 2023 — 6:00PM TO 8:00PM Anonymous (not verified) 31 March 2023 Chatham House Hear from the innovative leaders and companies driving change towards a more sustainable future. This event is an opportunity to hear from the innovative leaders and companies driving change towards a more sustainable future. The evening begins with a panel discussion then, over sustainably sourced drinks and canapés, you are invited to walk through Chatham House and explore the innovative and experimental ideas enabling radical shifts to allow us to prosper without exhausting our planet’s resources. Our exhibiting partners include Earthshot Prize winner NotPla, Hawkins Brown, Polymateria, and BEEN London. Bronwen Maddox, director of Chatham House, opens the evening at 6pm and introduces our panel of experts, chaired by Ana Yang, head of Chatham House’s Sustainability Accelerator. Please note that this event is operating a ballot for in-person attendance. Your place will be confirmed by Wednesday 12 April if you are successful. Full Article
ex The future of Europe post-Brexit By www.chathamhouse.org Published On :: Tue, 17 Aug 2021 16:36:41 +0000 The future of Europe post-Brexit 28 September 2021 — 5:00PM TO 6:00PM Anonymous (not verified) 17 August 2021 Online In conversation with Michel Barnier, Chief Brexit Negotiator, European Union (2016-2019). Drawing on the diary he kept during the 1600 days of complex and acrimonious Brexit negotiations, Michel Barnier explores the political and practical implications for Europe post-Brexit. Britain’s departure from the European Union has been a long and difficult journey. Many questions remain about what future lies ahead for the UK and EU and the relations between them. To what extent were UK negotiating positions shaped by politics within the ruling Conservative government? How did domestic politics in EU member states shape EU positions? What were key turning points in the negotiations? What are the hopes and expectations for bilateral relations between the UK and EU states? What is the scope for UK – EU cooperation on transatlantic issues and relations with China This event forms part of Chatham House’s ongoing work on Effective Multilateralism. Read a transcript. As with all Chatham House member events, questions from members drive the conversation. Attending this event and watching the full event video is for Chatham House members only. Not a member? Find out more. Full Article
ex Limited expectations as Scholz heads to Kyiv and Moscow By www.chathamhouse.org Published On :: Mon, 14 Feb 2022 14:08:25 +0000 Limited expectations as Scholz heads to Kyiv and Moscow Expert comment NCapeling 14 February 2022 After heavy criticism for an initially timid response, the approach of Germany’s new government to the Ukraine crisis is improving as its position on Russia evolves. Olaf Scholz is a famously quiet and cautious communicator and, as concerns mounted in Washington and London about the possibility of a Russian invasion of Ukraine, the new German chancellor remained silent. This time his silence reflected the fact that his government was unprepared for its first major foreign policy test, with marked divisions between the SPD and the Greens on how to manage a rapidly deteriorating relationship with Russia. When he did speak, Scholz caused dismay in several NATO capitals by defending the controversial Nord Stream 2 pipeline. He called it ‘a purely private economic project’ even though the company building the pipeline is a subsidiary of Russia’s state-owned Gazprom. Scholz has prepared the ground carefully for his visits to Kyiv and Moscow, extensively coordinating with NATO allies, such as France and Poland – as part of the Weimar Triangle – and the three Baltic states The absence of crisis management from Berlin was a stark reminder of the gap left by Angela Merkel. Her knowledge of Russia and Ukraine, and her personal experience of dealing with Vladimir Putin, were key assets in 2014 in developing a unified western response to Russia’s annexation of Crimea and its destabilization of south-eastern Ukraine. Germany has coordinated with its allies Scholz has prepared the ground carefully for his visits to Kyiv and Moscow, extensively coordinating with NATO allies, such as France and Poland – as part of the Weimar Triangle – and the three Baltic states. His inaugural visit to Washington helped align positions on US-EU efforts to develop an economic deterrent against further Russian intervention in Ukraine. Scholz has also repeated Merkel’s language from 2014 to signal to Moscow that Germany and its partners are ‘united and determined’ to stand their ground. And he has spoken of Germany’s continuing double strategy of ‘clear announcements’ to Moscow of the price it would pay for further aggression accompanied by a readiness to use all possible channels of dialogue to preserve peace. The continuation of Germany’s established policy will not surprise Moscow. But under the surface Germany’s discourse on Russia is evolving as the political class internalizes the fact that the current Russian leadership is openly threatening to use military force to impose its will on Ukraine and re-configure Europe’s security arrangements. Despite deep concerns about Germany’s dependence on Russian gas – more than half of the gas it consumes comes from Russia – there is broad acceptance that Nord Stream 2 cannot go ahead if Russia invades Ukraine. But typically, Scholz has not yet said as much publicly, limiting himself to stating ‘all options are on the table.’ Despite its mantra that there is no alternative to the Minsk Agreements, Berlin now admits these currently offer no prospect of resolving the war in Donbas Robert Habeck, Germany’s vice-chancellor as well as economic affairs and climate action minister, says the ‘geopolitical situation’ requires Germany to diversify its gas supplies and infrastructure for importing gas. For years, a strong pro-Russian gas lobby has dominated the thinking of the Economics Ministry and one consequence is the complete absence of facilities to import liquefied natural gas. The German debate on Russia is shifting A public debate has also started about weapons deliveries to Ukraine, even though this runs counter to deeply embedded pacifist tendencies in German society. Some MPs, former diplomats, and experts have begun to make the case for Germany to supply weapons to Ukraine so it can exercise its right to self-defence and deter military attack. Christoph Heusgen, a former long-standing foreign policy adviser in the Federal Chancellery, says Berlin’s decision not to deliver arms to Ukraine to avoid endangering the Minsk peace process requires revision now Moscow has abandoned the path of negotiation. Despite its mantra that there is no alternative to the Minsk Agreements, Berlin now admits these currently offer no prospect of resolving the war in Donbas because Russia is not prepared to implement them properly. Other taboos are also being broken inside Germany. Heavyweight left-of-centre Die Zeit published the first results of its investigation into the SPD’s links with Russia and their place in Russia’s channels of influence in Germany. And even the SPD’s Sigmar Gabriel, an outspoken champion of Nord Stream 2 during his time as a government minister, has raised the question of Germany terminating energy imports from Russia if there is a drastic deterioration of the security situation. Full Article
ex Ukraine exposes Europe’s double standards for refugees By www.chathamhouse.org Published On :: Wed, 30 Mar 2022 13:20:31 +0000 Ukraine exposes Europe’s double standards for refugees Expert comment NCapeling 30 March 2022 As European governments provide swift protection assurances to those fleeing Ukraine, non-European asylum-seekers continue to face violence at the EU’s borders. One month after Russia’s invasion of Ukraine, the European Union (EU) already faces its largest refugee crisis since World War Two, with more than ten million people having fled their homes – 6.5 million displaced within Ukraine and 3.9 million escaping to neighbouring countries. Acting quickly and decisively, European governments have opened borders and European citizens have opened their homes in an unprecedented showing of solidarity towards refugees. But, with all eyes on Ukraine, the Greek coastguard continues to illegally push back asylum-seekers crossing from Turkey while Spanish police forcefully repel those who dare to jump the fence in Melilla. The painful contrast exposes the double standards in the EU’s approach to refugees. With Europe’s grim history of restrictive asylum policies, it is wishful thinking that the warm welcome to Ukrainians will extend to all asylum-seekers. The EU solidarity to displaced Ukrainians illustrates the deeply politicized – and often discriminatory – nature of providing refugee protection. The waves of women and children leaving Ukraine prompted a surge of humanitarian action but they are also a chilling reality check of Europe’s double standards However, the hope is this turning point in European history can at least set an important precedent for treating refugees more humanely. Undoubtedly, EU solidarity towards people fleeing the horrors of Putin’s war is critically important and the initial response is positive in its efforts to meet immense humanitarian needs. Solidarity with Ukrainians The EU activation of the Temporary Protection Directive (TPD) is a significant step towards a more humane protection regime and fairer responsibility-sharing among member states. Without the need for the examination of individual applications, those fleeing Ukraine can access harmonized rights across the EU for three years – including residence, housing, medical assistance, and access to the labour market and education. The TPD is also a move away from the strict ‘Dublin’ rules which put the pressure of hosting refugees onto the countries of ‘first arrival’. Ironically, the fiercest opponents of intra-EU solidarity, such as Poland and Hungary, are the ones benefiting from this change now but, in the case of Ukraine, geographical proximity and shared histories must be considered when analysing Europe’s response. Eastern European and Baltic countries share a post-Soviet history and fear of Russian aggression, and Ukrainians already enjoyed 90 days of visa-free travel in the EU – with a large diaspora, many have established networks across Europe. But even considering these distinctive connections with Ukrainian displacement, the initial response still shows that European countries have both the political will and the capacity to host refugees. Unlike the usual – often media-fuelled – narratives of refugee ‘invasions’ into Europe, the waves of women and children leaving Ukraine prompted a surge of humanitarian action but they are also a chilling reality check of Europe’s double standards. The EU has used agreements with countries such as Turkey and Libya to prevent arrivals and outsource asylum responsibilities, while border violence, detention, and lengthy asylum procedures await the few asylum seekers who manage to enter Europe from the Middle East, Asia, and Africa. These ‘fortress Europe’ legacies have even undercut the humanitarian response in Ukraine, with reports of incidents of discrimination towards people of colour at the EU borders being condemned by the United Nations (UN) and the African Union (AU), the media facing allegations of racist reporting, and comments from Bulgarian PM Kiril Petkov providing a stark reminder of the islamophobia, racism, and history of colonization which still pervades European asylum policies. The unity shown over Ukraine can help reshape and refocus political efforts towards increased responsibility-sharing among EU member states – the perennial ‘hot potato’ of the EU asylum system Foreign policy also influences how EU leaders treat the right to asylum, as the geopolitics of Europe’s efforts to create a united front against Russian aggression is an undercurrent to the prompt European response to Ukrainians. But only a few months ago, non-European asylum-seekers trapped in freezing forests at the Poland-Belarus border were used as political pawns by Belarusian leader Aliaksandr Lukashenka and then dehumanised as a ‘hybrid attack’ by EU leaders. A turning point for asylum in Europe? Despite entrenched discriminatory precedents, it is worth looking ahead at this moment of reckoning. Although policy changes remain far off, the unity shown over Ukraine can help reshape and refocus political efforts towards increased responsibility-sharing among EU member states – the perennial ‘hot potato’ of the EU asylum system. Full Article
ex War on Ukraine: Exploring the humanitarian response to the conflict By www.chathamhouse.org Published On :: Wed, 06 Apr 2022 08:42:16 +0000 War on Ukraine: Exploring the humanitarian response to the conflict 12 April 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 6 April 2022 Online This event explores the implications of the humanitarian realities from Russia’s invasion of Ukraine, the largest ground campaign in Europe since World War Two. Reports from humanitarian organizations working in Ukraine are dire and reveal that a humanitarian disaster on an epic scale is unfolding. The United Nations (UN) and other organizations estimate 12 million of Ukraine’s population are in need of assistance, 4.1 million have been displaced to neighbouring countries, and 6.4 million have become internally displaced. Gillian Triggs, the assistant secretary-general and assistant high commissioner for protection at the UNHCR, joins other experts to discuss the humanitarian situation in Ukraine. The panel considers: What are the greatest needs in Ukraine now? How can aid agencies meet those needs? What are the short and long-term implications of the crisis for Ukraine and Europe? How do international organizations work with local NGOs to provide food, medical aid and shelter? This event is part of a regular series of events offering insight and analysis from experts and policymakers on how the war is affecting Ukraine, the region and the world. This event is part of Chatham House’s ongoing work on the future of conflict. Read the transcript Full Article
ex Gorbachev's complex legacy is beyond the popular belief By www.chathamhouse.org Published On :: Sat, 03 Sep 2022 09:45:59 +0000 Gorbachev's complex legacy is beyond the popular belief Expert comment NCapeling 3 September 2022 The last major figure with a decisive Cold War role, Mikhail Gorbachev was not as bad as Putin’s Russia portrays him, but also not as heroic as the West thinks. Arguably the worst year of the Cold War since the Cuban Missile Crisis was 1983, with three major incidents which escalated East-West tensions – and any one of them could have led to a full-scale war. The first was the Korean Airline KAL007 being shot down by an SU15 fighter aircraft for straying into Soviet airspace, killing all 269 passengers and crew. Then came the identification of signals from Soviet satellites as being incoming US intercontinental ballistic missiles – Colonel Stanislav Petrov, going against all protocols, thankfully decided to report them as a false alarm before he could be sure. The third was perhaps the most dangerous, being the misinterpretation of a live-fire NATO exercise which was believed by some in both East Germany and Russia to be a front for an imminent attack. The greatest disappointment in Gorbachev’s legacy was he completely believed the USSR could be reformed and still survive as an entity while others, such as Boris Yeltsin and Ronald Reagan, understood it had to be dismantled All three incidents occurred in the few months following the infamous March 1983 ‘Star Wars’ speech by US president Ronald Reagan, in which he talked about nuclear arms control and laid out the US case for a ballistic missile defence programme. At that time Mikhail Sergeyevich Gorbachev was the youngest serving member of the USSR Politburo, known to be a favourite of Soviet leader Yuri Andropov, and it is highly likely he had been aware of these close calls and was part of discussions within Kremlin decision-making circles. A changemaker both inside and outside the USSR Following the deaths of Andropov in 1984 and his replacement Konstantin Chernenko in 1985, Gorbachev’s appointment as general secretary of the Communist Party saw him immediately begin to change the Soviet Union from within – and also change relationships with the major Western powers, especially the US, Germany, and the UK. His policies of glasnost (openness) and perestroika (restructuring) were primarily aimed at internal reforms but translated into a major reset of international relations and international security. During his six years as leader, Gorbachev initiated many arms control negotiations which resulted in treaties and increased both the transparency and the confidence between the USSR and the US. These included the 1986 Stockholm Accord which emanated from the Helsinki Process and allowed for the observation and inspection of large-scale military exercises, the 1985 resumption of the Strategic Arms Reduction Talks which lead to START I, and the 1987 INF Treaty in which the USSR ‘out-yessed’ the US – the most open and transparent disarmament treaty in terms of notification and verification measures ever agreed. There was also a reciprocal moratorium on nuclear weapons tests starting from 1985 – which laid the groundwork for the 1996 CTBT – the 1991 Chemical Weapons Convention, and the 1990 Conventional Forces in Europe (CFE) Treaty. The most dramatic moment of all was when Gorbachev and Reagan met at a summit in Reykjavik and came close to deciding to eliminate nuclear weapons – but the initiative failed to reach agreement, mainly because Reagan could not drop his commitment to ballistic missile defences and Gorbachev could not accept the offer of joint development. Nonetheless, all these nuclear arms control treaties led the way for their descendants which have kept nuclear weapons in check ever since and are still in place in the form of the New START agreement. During his six years as leader, Gorbachev initiated many arms control negotiations which resulted in treaties and increased both the transparency and the confidence between the USSR and the US But despite these outstanding achievements, Gorbachev had blind spots – such as enabling rather than destroying the USSR bioweapons programme, unlike the US which had dismantled its own bioweapons offensive capability by 1973. And it is now known that, despite negotiating the Chemical Weapons Convention, Russia withheld information on new chemical weapons agents – Novichoks – which have since been used to lethal effect by Russia in Salisbury and against figures opposing the current regime. His misguided faith in a Soviet future Gorbachev was markedly different to his predecessors as secretary general. He was neither as decrepit nor as hardline, and he understood from the outset that the Soviet Union was, by the 1980s, finally dying. Using the intellectual abilities of Aleksandr Yakovlev, he forced through the reforms which simultaneously captured the imagination of the free world and liberated his countrymen and women. But although he built solid relationships – even friendships – with the world’s major heads of state and improved the USSR’s human rights, releasing dissidents such as Andrei Sakharov, but many – especially Ukrainian dissidents – continued to languish in camps. The greatest disappointment in Gorbachev’s legacy was he completely believed the USSR could be reformed and still survive as an entity while others, such as Boris Yeltsin and Ronald Reagan, understood it had to be dismantled. This shortcoming is especially uncomfortable as today’s Russia continues to insist it has a given right to control other former Soviet states, to the extent it is willing to destroy them if they do not concede. Full Article
ex Optimizing the Therapeutic Index of sdAb-Based Radiopharmaceuticals Using Pretargeting By jnm.snmjournals.org Published On :: 2024-10-01T04:08:08-07:00 Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for 177Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP+) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [177Lu]Lu-DOTA-PEG7-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [177Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [177Lu]Lu-DOTA-PEG7-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([177Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX. Full Article
ex EU-Turkey Customs Union: Lessons for Brexit By www.chathamhouse.org Published On :: Mon, 05 Mar 2018 12:30:00 +0000 EU-Turkey Customs Union: Lessons for Brexit 15 March 2018 — 11:00AM TO 12:00PM Anonymous (not verified) 5 March 2018 Chatham House, London Turkey and the EU are preparing to open negotiations to modernize their 22 year old customs union and expand its scope beyond goods to include services, public procurement and a more liberal regime for agriculture. At the same time, the UK is debating whether to seek a customs union with the EU to facilitate a frictionless flow of goods and to prevent a hard border with Ireland. The speaker will discuss Turkey’s customs union modernization agenda and share his insights on the lessons for the UK’s future relationship with the EU.Attendance at this event is by invitation only. Full Article
ex How to Explain Turkey's Early Elections By www.chathamhouse.org Published On :: Tue, 29 May 2018 09:30:00 +0000 How to Explain Turkey's Early Elections 14 June 2018 — 12:30PM TO 1:30PM Anonymous (not verified) 29 May 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE On 24 June 2018 Turkey will go to the polls to vote in early presidential and parliamentary elections. Following a constitutional referendum last spring and against the backdrop of Turkey’s continued intervention in Syria and rising economic problems, President Erdogan has argued that an early election would help reduce uncertainty and set the country on a course to greater prosperity. The elections, likely to be held under the state of emergency in place since the attempted coup in July 2016, will also mark the country’s transformation from a parliamentary democracy to one with a powerful executive presidency.In this session, the speaker will discuss what other factors led President Erdogan to call for an early election, what the state of the opposition is and what we can expect from Turkey should Erdogan win another term.Attendance at this event is by invitation only. Full Article
ex EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit By www.chathamhouse.org Published On :: Mon, 26 Nov 2018 15:20:01 +0000 EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit 12 December 2018 — 12:30PM TO 1:30PM Anonymous (not verified) 26 November 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE Turkey and the EU have been in a customs union since 1995. Both sides recognize that the current agreement is in need of modernization and have agreed to open negotiations to expand its scope to include services, public procurement, agriculture and other elements that would help bring it into the 21st century.At the same time, the UK Parliament is debating whether to approve the agreement on the UK’s withdrawal from the EU. It includes a backstop which – if triggered – would keep the UK and the EU in a single customs territory which would limit the disruption of withdrawal but hamper Britain’s ability to pursue an independent trade policy. The political declaration proposes building on this customs arrangement as the basis for the future relationship.In this context, the speaker will discuss the current EU-Turkey customs union arrangement and its shortcomings, examine the prospects for its modernization and share his insights on the lessons for the UK’s future trading relationship with the EU.The event will launch the briefing paper ‘EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit’.Attendance at this event is by invitation only. Full Article
ex Mexico 'anxious' on eve of U.S. presidential election By www.upi.com Published On :: Sun, 03 Nov 2024 19:39:25 -0500 Officials in Mexico and across Latin America are anxiously watching the outcome of Tuesday's U.S. Presidential contest in light of GOP candidate Donald Trump's campaign promise to "deport 11 million criminal aliens." Full Article
ex Report: SpaceX signs battery deal with South Korea-based LG Energy Solution to power Starship By www.upi.com Published On :: Mon, 11 Nov 2024 17:29:20 -0500 SpaceX has reportedly struck a deal with LG Energy Solution Ltd. to supply cylindrical lithium-ion batteries for Elon Musk's Starship rocket, expected to launch early next year, according to industry sources. Full Article
ex 11 hospitalized after explosion at Louisville food-coloring factory By www.upi.com Published On :: Tue, 12 Nov 2024 20:00:56 -0500 An explosion at a food-coloring factory in Louisville, Ky., hospitalized at least 11, including two in critical condition, on Tuesday afternoon. Full Article
ex Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing By www.hpcwire.com Published On :: Wed, 23 Oct 2024 12:07:23 +0000 CHANDLER, Ariz., Oct. 23, 2024 — The global edge computing market is expected to grow by more than 30 percent in the next five years, serving mission-critical applications in the […] The post Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing appeared first on HPCwire. Full Article
ex SDSC Leads Expansion of Open Storage Network to More Campus Computing Sites By www.hpcwire.com Published On :: Thu, 24 Oct 2024 16:35:54 +0000 Oct. 24, 2024 — The San Diego Supercomputer Center (SDSC), part of the School of Computing, Information and Data Sciences at UC San Diego, has been leading the Open Storage Network (OSN) program for years, and along […] The post SDSC Leads Expansion of Open Storage Network to More Campus Computing Sites appeared first on HPCwire. Full Article
ex NextSilicon Launches Maverick-2, Introducing Software-Defined Acceleration for HPC Workloads By www.hpcwire.com Published On :: Wed, 30 Oct 2024 12:47:17 +0000 TEL AVIV, Israel and MINNEAPOLIS, Oct. 30, 2024 — NextSilicon, a pioneer in high-performance computing (HPC) innovation, today announced its emergence from stealth with the launch of Maverick-2, the industry’s first […] The post NextSilicon Launches Maverick-2, Introducing Software-Defined Acceleration for HPC Workloads appeared first on HPCwire. Full Article
ex Dutch police hope to solve cold-case murder of sex worker using hologram By www.upi.com Published On :: Sun, 10 Nov 2024 13:53:31 -0500 A hologram of a sex worker who was murdered in Amsterdam more than a decade ago could help solve the cold case, investigators hope. Full Article
ex D-Wave Expands Board with Industry Veterans John DiLullo and Rohit Ghai By www.hpcwire.com Published On :: Wed, 30 Oct 2024 13:41:31 +0000 PALO ALTO, Calif., Oct. 30, 2024 — D-Wave Quantum Inc. today announced the appointments of veteran technology industry leaders, John DiLullo and Rohit Ghai, to its board of directors. The new […] The post D-Wave Expands Board with Industry Veterans John DiLullo and Rohit Ghai appeared first on HPCwire. Full Article
ex Capitals' Alex Ovechkin nets game winner vs. Predators, extends goal streak By www.upi.com Published On :: Thu, 07 Nov 2024 08:11:02 -0500 Alex Ovechkin calmly slid into the right circle and sniped a snapshot past a blinded Juuse Saros to lead the Washington Capitals to a 3-2 triumph over the Nashville Predators. Full Article
ex Carolina Panthers sign running back Chuba Hubbard to $33.2M extension By www.upi.com Published On :: Thu, 07 Nov 2024 10:23:52 -0500 The Carolina Panthers signed running back Chuba Hubbard to a four-year contract extension worth $33.2 million, a league source told UPI on Thursday. Full Article
ex Detroit Lions overcome 5 Jared Goff interceptions in comeback win over Houston Texans By www.upi.com Published On :: Mon, 11 Nov 2024 08:58:08 -0500 A struggling Detroit Lions offense awoke late, scoring 19-unanswered points to rally past the Houston Texans and improve to 8-1 this season. The Lions overcame a career-high five interceptions Jared Goff threw. Full Article