Members Event Webinar

Event participants

Xenia Wickett, Head, US and the Americas Programme; Dean, The Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

Ulrich Rothbauer
Feb 1, 2008; 7:282-289
Research

29 July 2019

The growth of China's wealth and military power represents an epochal change in international politics. This briefing argues that China’s rise has worrying implications for the liberal international order and explores how this will affect the transatlantic relationship.

A joint Chatham House-RUSI project that focuses on strengthening common understanding across the Atlantic and develop new ideas for how the US and Europe can better engage with and respond to China’s rise.

More on Transatlantic Dialogue on China

Webinar Research Event

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews

Webinar Research Event

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

Expert

Expert

K. D. Cherednichenko, Yu. Yu. Ershova, A. V. Kiselev and S. N. Naboko
Trans. Moscow Math. Soc. 80 (2020), 251-294.
Abstract, references and article information

Chris Gayle had every reason to celebrate West Indies' seven-wicket victory over Australia on Saturday

Noah Taylor
Trans. Amer. Math. Soc. 373 (2020), 3541-3559.
Abstract, references and article information

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

(NASA/Goddard Space Flight Center) NASA has selected a new pathfinding CubeSat mission to gather data not collected since the agency flew the Dynamics Explorer in the early 1980s.

(University of Washington) By comparing new measurements from NASA's ICESat-2 mission with the original ICESat mission, which operated from 2003 to 2009, scientists were able to measure precisely how the Greenland and Antarctic ice sheets have changed over 16 years.

Omar D. Fernandes
Jul 1, 2010; 23:194-198
Care Innovations

Hours after he was released from police lock-up last week, dancehall artiste Dexta Daps dropped some new music on his eager fans. The track, Breaking News, explores an all-too-familiar domestic violence storyline, but incorporates a controversial...

A Conversation with John Faraci, executive chairman of the Carrier Corporation, and former CEO of International Paper

The Sanford C. Bernstein & Co. Center for Leadership and Ethics spoke with Anna Houseman '21 about her daily routine, personal ethics, and staying productive during the pandemic. 

Taewook Kang
Apr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882
Research

Research Event

Event participants

Andrew Sullivan, President and CEO Internet Society
Chair: Emily Taylor, Associate Fellow, International Security Department, Chatham House; Editor, Journal of Cyber Policy

We developed a first-of-kind dasatinib-derivative imaging agent, ¹⁸F-SKI-249380 (¹⁸F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using ¹⁸F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of ¹⁸F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of ¹⁸F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03–0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30–90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, ¹⁸F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion: ¹⁸F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

Background: Patients with NHL who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next generation β-particle emitting radioimmunoconjugate ¹⁷⁷Lu-lilotomab-satetraxetan (Betalutin®) was shown to up-regulate CD20 expression in different rituximab-sensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that ¹⁷⁷Lu-lilotomab-satetraxetan may be used to reverse rituximab-resistance in NHL. Methods: The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. ADCC was measured by a bioluminescence reporter assay. The efficacies of combined treatments with ¹⁷⁷Lu-lilotomab-satetraxetan (150MBq/kg or 350MBq/kg) and rituximab (4x10mg/kg) were compared with those of single agents or saline in a Raji2R-xenograft model. Cox-regression and the Bliss independence model were used to assess synergism. Results: Rituximab-binding in Raji2R cells was 36±5% of that in the rituximab-sensitive Raji cells. ¹⁷⁷Lu-lilotomab-satetraxetan treatment of Raji2R cells increased the binding to 53±3% of the parental cell line. Rituximab ADCC-induction in Raji2R cells was 20±2% of that induced in Raji cells, while treatment with ¹⁷⁷Lu-lilotomab-satetraxetan increased the ADCC-induction to 30±3% of the Raji cells, representing a 50% increase (p<0.05). The combination of rituximab with 350MBq/kg ¹⁷⁷Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1^nu mice. Conclusion: ¹⁷⁷Lu-lilotomab-satetraxetan has the potential to reverse rituximab-resistance; it increases binding and ADCC-activity in-vitro and can synergistically improve anti-tumor efficacy in-vivo.

Host Matt Egan leads a three pronged tech attack on the week's news with David Price and Scott Carey. The gang discuss 'BBC Dad' and why the professor's hilarious children are the perfect example of viral video. David Price also examines the news cycle of such treats, and why ambulance drivers aren't on Twitter all the time. With Marissa Mayer leaving Yahoo! in tatters, renamed, but with a wad of cash reportedly in her account, Scott leads the line in exploring where it went wrong and why it has been such a public fall from grace. But at age 41, surely there's another chapter in Mayer's story?  

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The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell’s adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking—core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.

We conducted a two-sample Mendelian randomisation study to investigate the causal associations of type 2 diabetes mellitus (T2DM) with risk of overall cancer and 22 site-specific cancers. Summary-level data for cancer were extracted from the Breast Cancer Association Consortium and UK Biobank. Genetic predisposition to T2DM was associated with higher odds of pancreatic, kidney, uterine and cervical cancer, lower odds of oesophageal cancer and melanoma, but not associated with 16 other site-specific cancers or overall cancer. The odds ratios (95% confidence interval) were 1.13 (1.04, 1.22), 1.08 (1.00, 1.17), 1.08 (1.01, 1.15), 1.07 (1.01, 1.15), 0.89 (0.81, 0.98), and 0.93 (0.89, 0.97) for pancreatic, kidney, uterine, cervical, and oesophageal cancer and melanoma, respectively. The association between T2DM and pancreatic cancer was also observed in a meta-analysis of this and a previous Mendelian randomisation study (odds ratio 1.08; 1.02, 1.14; p=0.009). There was limited evidence supporting causal associations between fasting glucose and cancer. Genetically predicted fasting insulin levels were positively associated with cancers of the uterus, kidney, pancreas and lung. The present study found causal detrimental effects of T2DM on several cancers. We suggested to reinforce the cancers screening in T2DM patients to enable the early detection of cancer.

Webinar Research Event

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

Obat Pembesar Pantat Buttooks Krim Usa Adalah adalah Cream formula khusus untuk pembesaran di sekitar pinggul dan pantat yang ingin tampil lebih Besar

The Open Arms Development Centre, a homeless shelter in downtown Kingston, and Jamaica’s COVID-19 Response Fund Food Relief are among 25 charitable and community organisations across the island to benefit from the latest round of grants from US-...