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A mom’s worst nightmare - East Kingston mother mourns teen son after deadly clash with cops

Kadian Morgan was overwhelmed with grief as she leaned against a wall outside her gate on Jackson Lane, East Kingston, yesterday, tears streaming down her face. Her 19-year-old son, Kayshan 'Bem Bem' Smith, was lying in the morgue after being...




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Fluctuation in O-GlcNAcylation inactivates STIM1 to reduce store-operated calcium ion entry via down-regulation of Ser621 phosphorylation [Molecular Bases of Disease]

Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases.




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Chatham House History: Five Key Moments on Africa

9 July 2020

Christopher Vandome

Research Fellow, Africa Programme
To mark the centenary of Chatham House, the Africa programme curated an exhibition of archive material which charts how the institute has been both a major forum for discussion on Africa, and an important platform for African leaders to engage in international affairs.

Mandela1a.jpg

President Nelson Mandela of South Africa addresses an audience at an event co-hosted by Chatham House, the CBI and COSAT on July 10, 1996.

As with any history, Chatham House has a long and complex one. Progress has come in fits and starts, sometimes driven by wider social change, but often led by individuals within the institute. When examining the institute's work on Africa, five seminal moments from the history really stood out.

The Founders

Lionel Curtis is credited as the founder of the institute, having proposed the idea at a meeting at the Hotel Majestic while attending the Treaty of Versailles talks.

Curtis served in South Africa during the Second Boer war and subsequent period of unification. He was one of the cohort of officials that served under Lord Milner, later dubbed ‘Milner’s Kindergarten’. Several of this group were involved in the foundation of the institute.

A Century of Supporting African Engagement in International Affairs

A short presentation highlighting how Chatham House has been both a major forum for discussion on Africa, and an important platform for African leaders.

His experiences in South Africa undoubtedly informed his political philosophy - a strong belief in liberal imperialism. This is captured in the emblems of empire inlaid into the roundtable which is still in the Chatham House library, given to Curtis as a wedding gift.

But more importantly than his political philosophy, Curtis was an astute social networker and fundraiser who unlocked the finance required to establish the institute. Curtis’s papers in the Chatham House archives depict his almost obsessive following of the career of the South African diamond tycoon Sir Abe Bailey that eventually led to the first significant endowment to the institute - after the building. South African Prime Minister Jan Smuts, a friend of Curtis and early champion of the institute, spoke at a dinner in honour of Bailey’s contribution.

Curtis’s connections meant much of the early finance came from South Africa, including from Otto Beit and Percy Molteno, who was also an early financer of the African National Congress (ANC).

Hailey’s Africa Survey

In 1938, Chatham House published Lord Hailey’s monumental Africa Survey. Its detailed 1,837 pages of study came to represent a seismic shift in attitudes towards the continent. Lord Lothian’s foreword emphasises that it grew from an idea of Smuts from 1929, although these origins remain disputed.

What is known is that Oxford University had submitted a proposal for a study of the continent to an American foundation which rejected it on the grounds that they didn’t want American money to be used to expand Smut’s doctrine of dominion. The group then merged their own plan into an emerging study by progressive missionary Joseph Oldham.

Curtis brought in his friend Lord Hailey to lead the initiative. Hailey was a distinguished civil servant who served in India but never in Africa. The project moved to Chatham House and received a substantial grant from the Carnegie Foundation. Having been originally conceived as a study to reinforce segregationist ideas, the final survey was groundbreaking. Its underlying assumption of basic racial equality debunked the premises of segregation and re-set British attitudes towards Africa.

This shift in mindset was hugely significant at the time, but the work would later be criticized for not including any African voices. And, despite carrying his name, Lord Lothian wrote very little of the text. He fell ill, in part due to the pressure of the four-year project, and the work was largely written by notable Africanists Lucy Mair, Charlotte Leubuscher, and Margery Perham. The Africa Survey was updated and reprinted in 1956, including a pull-out map depicting newly-independent Sudan. A sign of real change.

Independence and National Liberation

The 1960s was a decade of transformation both on the continent and at Chatham House. The institute became an important conduit for newly-independent African states to engage in international affairs, hosting several independence presidents, including Prime Minister Modibo Keita of Mali, President Léopold Senghor of Senegal, and President Julius Nyerere of Tanzania. Many of these speeches were republished in the Institute’s journal, International Affairs.

In January 1962, the Nigerian government invited Chatham House to host a conference in Lagos on the external international relations of the newly-independent African states. But it wasn’t just presidents that were offered a platform. Liberation leaders were also invited to speak as well as conduct research.

African Liberation – The Historical and Contemporary Significance of Re-discovered Nationalist Speeches at Chatham House of Dr Eduardo Mondlane and Oliver Tambo

Two speeches at Chatham House in 1968 and 1985 by African nationalist leaders Dr Eduardo Mondlane and Oliver Tambo at key moments of their liberation struggle for majority rule are re-examined for their significance.

Dr Bernard Chidzero, a later finance minister in independent Zimbabwe, wrote on African nationalism in International Affairs in 1960, and conducted a multi-year study at the institute resulting in the publication of a book. In 1968, Eduardo Mondlane, founding president of FRELIMO, made an important speech on the nationalist fight for independence in Mozambique.

In 1961, Kenneth Younger, a new director of the institute, increased its research capacity on Africa through significant new hires. Catherine Hoskyns’s 1965 book on the Congo crisis became the seminal study on the topic. Dennis Austin, who had experience in West Africa, wrote the definitive work on Ghana’s transition to independence in 1964.

African Institutes

Chatham House has also been involved in the establishment of think-tanks across the world, including three in Africa.

The South African Institute of International Affairs (SAIIA) was founded in 1934, in response to proposals made by Chatham House the previous year at the inaugural British Commonwealth Relations Conference. An East African Institute of International Affairs was also established in Nairobi but did not survive. The Nigerian Institute of International Affairs (NIIA) was formed in 1961 in Lagos. Its founding director general Dr L A Fabunmi, said ‘the main task of the Nigerian Institute of International Affairs will be to create, develop, and sustain an African perspective in world affairs’.

Chatham House has maintained a good working relationship with its sister institutes. In 2005 a special edition of International Affairs was launched at NIIA, the first time in the journal’s history it was launched outside the UK. And SAIIA staff and leaders are regular contributors to Chatham House events and research, including a partnership on the study of Central and Eastern European relations with Africa.

The Africa Programme

Created in 2002. this was the first time Chatham House had a dedicated research team working on Africa, producing a sustained and balanced assessment of events on the continent. Throughout the 1980s and 1990s, work on Africa had been conducted by regionally-focused study groups, and the personal interests of the director for studies, Dr Jack Spence – a leading authority on South African foreign policy. An earlier attempt to create a more formal programme in the late 1990s fell victim to staff turnover.

In 1998, the British Angola Forum (BAF) was formed and found a home at Chatham House. It marked a departure from the institute’s focus on post-colonial 'Anglophone Africa'. At the end of Angola's civil war in 2002, under the leadership of Dr Alex Vines, the BAF morphed into a continent-wide programme.

Since then, the Africa Programme has produced more than 160 original research publications, and organizes between 120-140 events on Africa every year. The Africa Programme is marking the centenary of the institute with a major research theme on Foreign Relations and African Agency in International Relations.

Chatham House’s work on Africa has its roots in the liberal imperialism of the post war leaders. But throughout the last 100 years, it has been a platform for progress, playing a vital role in informing policymakers and facilitating debate on African affairs, as well as highlighting African perspectives on global issues.

The exhibition on the History of Africa at Chatham House was first displayed at the world-renowned fine art auctioneers and valuers Bonham’s in London for a reception in February 2020 marking the centenary of the Institute. It was curated by Christopher Vandome with the assistance of the Chatham House Library, and digitized with the help of the Institute’s communications department. Please contact the Library team for further information regarding the archive.

Chatham House Centenary:
Throughout our centenary year in 2020, Chatham House marks a century of influence, independent analysis and trusted dialogue with a number of exciting initiatives. Throughout the year, we explore key political moments from the institute's history and reflect on how Chatham House and other think-tanks should approach the future.




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Not the same old African story

Not the same old African story The World Today mhiggins.drupal 2 August 2022

Nollywood studio boss Mo Abudu and author Dipo Faloyin discuss how Africans are redefining how the world sees them.

Mo Abudu
EbonyLife’s latest TV drama series, Blood Sisters, was in Netflix’s global top 10. It’s a thriller and it may be slightly melodramatic because we Nigerians are melodramatic. But it deals with universal themes. Nigerians are no different to anyone else. I want EbonyLife productions increasingly to appeal to anyone in the world, even if it’s in our language. Oloture, one of our films, was about human trafficking. It was all done in pidgin English and subtitled. I watch a lot of Korean dramas and Spanish dramas that are subtitled. A good story is a good story.

Dipo Faloyin
The influence that African countries have had on the West, from music, food and film to literature, science and technology, is something people find difficult to take seriously. So, it’s good to see Netflix and other production companies take it more seriously. How has your discussion with them changed since the early days?

Mo Abudu
I have been going to an entertainment market in Cannes called Mipcom for about 12 years, and at first no one had any interest in African content. So, we focused on doing local content for local markets. Now, different communities around the world want representation in content that speaks to them. Specific countries are also saying to streamers: ‘What’s your local content strategy?’ 

I’m not telling broadcasters to commission original African content as a charity project – they can make money from this

Mo Abudu


Netflix was the first of the streamers to come into Africa, and it now has an Africa office. Amazon has also made inroads recently. Disney is arriving. In the United States and Britain, they just need to maintain subscriber numbers, but real growth for them is going to be in Asia and Africa. 

I’m not telling broadcasters or distributors to commission original African content as a charity project – they can make money from this. Within five days of launch, Blood Sisters registered 11 million hours of viewing on Netflix around the world. It was made on a budget five times smaller than productions outside Africa. But we need to be among the gatekeepers, too. 

Moving beyond Hollywood

Dipo Faloyin
The challenge that many creatives across Africa have is that people [elsewhere] don’t necessarily feel like they relate to this continent. They see ‘Africa’ and its cultures as very distant. Instead of intricate, specific stories, simple stories of simple people have been pushed about the continent. 

I still get asked questions like, ‘But, what should we do about Africa’s problems?’ My response is, ‘Stop seeing Africa as just a problem.’ 

A still from the Nigerian film ‘Oloture’, released in 2022, which deals with issues of human trafficking.

Mo Abudu
I was speaking at the Qatar Economic Forum recently and the panel started off talking about the ‘problems of Africa’ – and I had to jump in and say, ‘I get you guys talking about the problems, I’m not an economist, I’m just an entrepreneur, but from an entrepreneurial perspective, we have resources – like cobalt from the Democratic Republic of Congo that’s in all of our mobile phones.’ 

The problem is, we ship out all our resources and by the time they come back to us, they are 10-times more expensive than we can afford. I keep saying that they need to know they need us as much as we need them.
 
Dipo Faloyin
There are certainly issues within the continent like there are everywhere else; but more accurate stories will help people have a better sense of the context in which so many communities and their lives have been built up. 

Mo Abudu
The West doesn’t seem to have any interest in making films about Africa unless it’s about the worst of Africa: the slave trade, the Rwandan genocide, blood diamonds. That seems to be what has defined us. 

Dipo Faloyin
If you ask most people around the world to close their eyes and picture Africa, two images will come up: safari, and poverty and strife. Until the age of 12, I grew up in Lagos, a metropolis with no wild animals running around. There are slums, of course, but also traffic, shopping centres and overpriced restaurants. 

Writers who pitch ideas to Vice.com where I work often still don’t differentiate African countries. They’ll say, ‘There’s been a coup in Mali. Why can’t Africa get its head around democracy?’, and I remind them a small minority of countries on the continent is under any form of authoritarian rule. 

It’s frustrating that this perception hasn’t changed. For us to break through we need big cultural institutions – Hollywood, museums, literature – to allow people from across the regions to tell these stories. We are rarely portrayed as protagonists and forward thinkers. But I’m excited for the future.




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FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study

Visual Abstract




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Oncologist, Business Leader, and Investor Arie S. Belldegrun Discusses a Career in Innovative Medical Entrepreneurship: A Conversation with Ken Herrmann and Johannes Czernin




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Stoichiometry of Nucleotide Binding to Proteasome AAA+ ATPase Hexamer Established by Native Mass Spectrometry

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research




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Accelerating the field of epigenetic histone modification through mass spectrometry-based approaches

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review




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Pluripotency of embryonic stem cells lacking clathrin-mediated endocytosis cannot be rescued by restoring cellular stiffness [Molecular Biophysics]

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.




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Problem Notes for SAS®9 - 66537: SAS Customer Intelligence Studio becomes non-responsive when you delete a calculated variable from the Edit Value dialog box

In SAS Customer Intelligence Studio, you might notice that the user interface becomes unresponsive, as shown below: imgalt="SAS Customer Intelligence Studio UI becomes unresponsive" src="{fusion_66537




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Problem Notes for SAS®9 - 66539: A new calculated variable that you create in the Edit Value dialog box is not available for selection in SAS Customer Intelligence Studio

In SAS Customer Intelligence Studio, you can choose to create a new calculated variable in the Edit Value dialog box when you populate a treatment custom detail. Following creation of the new calculated




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Problem Notes for SAS®9 - 66544: You cannot clear warnings for decision campaign nodes in SAS Customer Intelligence Studio

In SAS Customer Intelligence Studio, you might notice that you cannot clear warnings for decision campaign nodes by selecting either the Clear Warnings  option or the Clear All Warnin




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Problem Notes for SAS®9 - 66527: Updating counts in a Link node in SAS Customer Intelligence Studio produces the error "Link: MAIQService:executeFastPath:"

In SAS Customer Intelligence Studio, the following error is displayed when you update a new Link  node in a diagram:   imgalt="Link: MAIQService:executeFastPath:" src="{fusion_665




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Problem Notes for SAS®9 - 48028: Custom Time Frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l




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Problem Notes for SAS®9 - 46544: Store layout view has some areas displayed with black fill rather than gray in SAS® Retail Space Management

In SAS Retail Space Management, it should be possible to click on any location object, then Show Properties, and change the location fill color. This can be done on the gray-filled objects. However, w




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Problem Notes for SAS®9 - 66511: A Russian translation shows the same value for two different variables in the Define Value dialog box for the Reply node in SAS Customer Intelligence Studio

In SAS Customer Intelligence Studio,  when you add  Reply- node variable values in the Define Value dialog box, you might notice that two identically labeled data-grid variables are




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WITHDRAWN: Structural and mechanistic studies of hydroperoxide conversions catalyzed by a CYP74 clan epoxy alcohol synthase from amphioxus (Branchiostoma floridae) [Research Articles]

This manuscript has been withdrawn by the Author.




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Trial of novel leukaemia drug is stopped for second time after two more deaths




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Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer [Research Articles]

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.




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Fast Quantitative Analysis of timsTOF PASEF Data with MSFragger and IonQuant [Technological Innovation and Resources]

Ion mobility brings an additional dimension of separation to LC–MS, improving identification of peptides and proteins in complex mixtures. A recently introduced timsTOF mass spectrometer (Bruker) couples trapped ion mobility separation to TOF mass analysis. With the parallel accumulation serial fragmentation (PASEF) method, the timsTOF platform achieves promising results, yet analysis of the data generated on this platform represents a major bottleneck. Currently, MaxQuant and PEAKS are most used to analyze these data. However, because of the high complexity of timsTOF PASEF data, both require substantial time to perform even standard tryptic searches. Advanced searches (e.g. with many variable modifications, semi- or non-enzymatic searches, or open searches for post-translational modification discovery) are practically impossible. We have extended our fast peptide identification tool MSFragger to support timsTOF PASEF data, and developed a label-free quantification tool, IonQuant, for fast and accurate 4-D feature extraction and quantification. Using a HeLa data set published by Meier et al. (2018), we demonstrate that MSFragger identifies significantly (~30%) more unique peptides than MaxQuant (1.6.10.43), and performs comparably or better than PEAKS X+ (~10% more peptides). IonQuant outperforms both in terms of number of quantified proteins while maintaining good quantification precision and accuracy. Runtime tests show that MSFragger and IonQuant can fully process a typical two-hour PASEF run in under 70 min on a typical desktop (6 CPU cores, 32 GB RAM), significantly faster than other tools. Finally, through semi-enzymatic searching, we significantly increase the number of identified peptides. Within these semi-tryptic identifications, we report evidence of gas-phase fragmentation before MS/MS analysis.




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Accurate MS-based Rab10 Phosphorylation Stoichiometry Determination as Readout for LRRK2 Activity in Parkinson's Disease [Research]

Pathogenic mutations in the Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD). They increase its activity, resulting in augmented Rab10-Thr73 phosphorylation and conversely, LRRK2 inhibition decreases pRab10 levels. Currently, there is no assay to quantify pRab10 levels for drug target engagement or patient stratification. To meet this challenge, we developed an high accuracy and sensitivity targeted mass spectrometry (MS)-based assay for determining Rab10-Thr73 phosphorylation stoichiometry in human samples. It uses synthetic stable isotope-labeled (SIL) analogues for both phosphorylated and nonphosphorylated tryptic peptides surrounding Rab10-Thr73 to directly derive the percentage of Rab10 phosphorylation from attomole amounts of the endogenous phosphopeptide. The SIL and the endogenous phosphopeptides are separately admitted into an Orbitrap analyzer with the appropriate injection times. We test the reproducibility of our assay by determining Rab10-Thr73 phosphorylation stoichiometry in neutrophils of LRRK2 mutation carriers before and after LRRK2 inhibition. Compared with healthy controls, the PD predisposing mutation carriers LRRK2 G2019S and VPS35 D620N display 1.9-fold and 3.7-fold increased pRab10 levels, respectively. Our generic MS-based assay further establishes the relevance of pRab10 as a prognostic PD marker and is a powerful tool for determining LRRK2 inhibitor efficacy and for stratifying PD patients for LRRK2 inhibitor treatment.




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Stoichiometry of Nucleotide Binding to Proteasome AAA+ ATPase Hexamer Established by Native Mass Spectrometry [Research]

AAA+ ATPases constitute a large family of proteins that are involved in a plethora of cellular processes including DNA disassembly, protein degradation and protein complex disassembly. They typically form a hexametric ring-shaped structure with six subunits in a (pseudo) 6-fold symmetry. In a subset of AAA+ ATPases that facilitate protein unfolding and degradation, six subunits cooperate to translocate protein substrates through a central pore in the ring. The number and type of nucleotides in an AAA+ ATPase hexamer is inherently linked to the mechanism that underlies cooperation among subunits and couples ATP hydrolysis with substrate translocation. We conducted a native MS study of a monodispersed form of PAN, an archaeal proteasome AAA+ ATPase, to determine the number of nucleotides bound to each hexamer of the WT protein. We utilized ADP and its analogs (TNP-ADP and mant-ADP), and a nonhydrolyzable ATP analog (AMP-PNP) to study nucleotide site occupancy within the PAN hexamer in ADP- and ATP-binding states, respectively. Throughout all experiments we used a Walker A mutant (PANK217A) that is impaired in nucleotide binding as an internal standard to mitigate the effects of residual solvation on mass measurement accuracy and to serve as a reference protein to control for nonspecific nucleotide binding. This approach led to the unambiguous finding that a WT PAN hexamer carried – from expression host – six tightly bound ADP molecules that could be exchanged for ADP and ATP analogs. Although the Walker A mutant did not bind ADP analogs, it did bind AMP-PNP, albeit at multiple stoichiometries. We observed variable levels of hexamer dissociation and an appearance of multimeric species with the over-charged molecular ion distributions across repeated experiments. We posit that these phenomena originated during ESI process at the final stages of ESI droplet evolution.




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WITHDRAWN: Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma [Research]

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.




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CIITA-transduced glioblastoma cells uncover a rich repertoire of clinically relevant tumor-associated HLA-II antigens [Research]

CD4+ T cell responses are crucial for inducing and maintaining effective anti-cancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17 and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared to interferon gamma (IFN) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor-antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire.




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Accelerating the field of epigenetic histone modification through mass spectrometry-based approaches [Review]

Histone post-translational modifications (PTMs) are one of the main mechanisms of epigenetic regulation. Dysregulation of histone PTMs leads to many human diseases, such as cancer. Due to its high-throughput, accuracy, and flexibility, mass spectrometry (MS) has emerged as a powerful tool in the epigenetic histone modification field, allowing the comprehensive and unbiased analysis of histone PTMs and chromatin-associated factors. Coupled with various techniques from molecular biology, biochemistry, chemical biology and biophysics, MS has been employed to characterize distinct aspects of histone PTMs in the epigenetic regulation of chromatin functions. In this review we will describe advancements in the field of MS that have facilitated the analysis of histone PTMs and chromatin biology.  




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Generics have a chequered recent history




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Weathering the storm: The UK’s role in the world today

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

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

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

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

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

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

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

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

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

Read the transcript. 




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EU-Turkey Customs Union: Lessons for Brexit

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.




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Taking Stock of Turkey's Trade Policy

Taking Stock of Turkey's Trade Policy 11 September 2018 — 5:00PM TO 6:15PM Anonymous (not verified) 23 August 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

As the only large economy outside of the EU with a customs union agreement, Turkey has a unique trade policy. Amid domestic economic challenges, Turkey’s trade minister, Ruhsar Pekcan, will discuss prospects for upgrading the EU-Turkey customs union. She will also discuss relations between the UK and Turkey and outline strategies for post-Brexit trade.

Attendance at this event is by invitation only.




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EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit

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.




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A Credit-fuelled Economic Recovery Stores Up Trouble for Turkey

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.

Headquarters of the Central Bank of the Republic of Turkey. Photo: Getty Images.

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.




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Turkey’s foreign and domestic policy: A story of mutual creation?

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.

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