pro Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution By www.mcponline.org Published On :: 2007-12-01 Hasmik KeshishianDec 1, 2007; 6:2212-2229Research Full Article
pro PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life By www.mcponline.org Published On :: 2012-08-01 M. WangAug 1, 2012; 11:492-500Technological Innovation and Resources Full Article
pro The Proteome of the Mouse Photoreceptor Sensory Cilium Complex By www.mcponline.org Published On :: 2007-08-01 Qin LiuAug 1, 2007; 6:1299-1317Research Full Article
pro A "Proteomic Ruler" for Protein Copy Number and Concentration Estimation without Spike-in Standards By www.mcponline.org Published On :: 2014-12-01 Jacek R. WiśniewskiDec 1, 2014; 13:3497-3506Research Full Article
pro Comparative Proteomic Analysis of Eleven Common Cell Lines Reveals Ubiquitous but Varying Expression of Most Proteins By www.mcponline.org Published On :: 2012-03-01 Tamar GeigerMar 1, 2012; 11:M111.014050-M111.014050Special Issue: Prospects in Space and Time Full Article
pro Complementary Profiling of Gene Expression at the Transcriptome and Proteome Levels in Saccharomyces cerevisiae By www.mcponline.org Published On :: 2002-04-01 Timothy J. GriffinApr 1, 2002; 1:323-333Research Full Article
pro Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics By www.mcponline.org Published On :: 2012-11-01 Amelia C. PetersonNov 1, 2012; 11:1475-1488Technological Innovation and Resources Full Article
pro A Proteomic Analysis of Human Cilia: Identification of Novel Components By www.mcponline.org Published On :: 2002-06-01 Lawrence E. OstrowskiJun 1, 2002; 1:451-465Research Full Article
pro Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues By www.mcponline.org Published On :: 2015-05-01 Roland BrudererMay 1, 2015; 14:1400-1410Research Full Article
pro A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles By www.mcponline.org Published On :: 2011-10-01 Sebastian A. WagnerOct 1, 2011; 10:M111.013284-M111.013284Research Full Article
pro Quantitative Phosphoproteomics of Early Elicitor Signaling in Arabidopsis By www.mcponline.org Published On :: 2007-07-01 Joris J. BenschopJul 1, 2007; 6:1198-1214Research Full Article
pro A Tandem Affinity Tag for Two-step Purification under Fully Denaturing Conditions: Application in Ubiquitin Profiling and Protein Complex Identification Combined with in vivoCross-Linking By www.mcponline.org Published On :: 2006-04-01 Christian TagwerkerApr 1, 2006; 5:737-748Research Full Article
pro Discordant Protein and mRNA Expression in Lung Adenocarcinomas By www.mcponline.org Published On :: 2002-04-01 Guoan ChenApr 1, 2002; 1:304-313Research Full Article
pro Integrated Genomic and Proteomic Analyses of Gene Expression in Mammalian Cells By www.mcponline.org Published On :: 2004-10-01 Qiang TianOct 1, 2004; 3:960-969Research Full Article
pro Interpretation of Shotgun Proteomic Data: The Protein Inference Problem By www.mcponline.org Published On :: 2005-10-01 Alexey I. NesvizhskiiOct 1, 2005; 4:1419-1440Tutorial Full Article
pro Comparison of Label-free Methods for Quantifying Human Proteins by Shotgun Proteomics By www.mcponline.org Published On :: 2005-10-01 William M. OldOct 1, 2005; 4:1487-1502Research Full Article
pro Quantitative Mass Spectrometric Multiple Reaction Monitoring Assays for Major Plasma Proteins By www.mcponline.org Published On :: 2006-04-01 Leigh AndersonApr 1, 2006; 5:573-588Research Full Article
pro A Human Protein Atlas for Normal and Cancer Tissues Based on Antibody Proteomics By www.mcponline.org Published On :: 2005-12-01 Mathias UhlénDec 1, 2005; 4:1920-1932Research Full Article
pro A Multidimensional Chromatography Technology for In-depth Phosphoproteome Analysis By www.mcponline.org Published On :: 2008-07-01 Claudio P. AlbuquerqueJul 1, 2008; 7:1389-1396Research Full Article
pro Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis By www.mcponline.org Published On :: 2012-06-01 Ludovic C. GilletJun 1, 2012; 11:O111.016717-O111.016717Research Full Article
pro The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra By www.mcponline.org Published On :: 2007-09-01 Ignat V. ShilovSep 1, 2007; 6:1638-1655Technology Full Article
pro Quantitative Phosphoproteomics Applied to the Yeast Pheromone Signaling Pathway By www.mcponline.org Published On :: 2005-03-01 Albrecht GruhlerMar 1, 2005; 4:310-327Research Full Article
pro Absolute Quantification of Proteins by LCMSE: A Virtue of Parallel ms Acquisition By www.mcponline.org Published On :: 2006-01-01 Jeffrey C. SilvaJan 1, 2006; 5:144-156Research Full Article
pro The Human Plasma Proteome: History, Character, and Diagnostic Prospects By www.mcponline.org Published On :: 2002-11-01 N. Leigh AndersonNov 1, 2002; 1:845-867Reviews/Perspectives Full Article
pro A Versatile Nanotrap for Biochemical and Functional Studies with Fluorescent Fusion Proteins By www.mcponline.org Published On :: 2008-02-01 Ulrich RothbauerFeb 1, 2008; 7:282-289Research Full Article
pro Exponentially Modified Protein Abundance Index (emPAI) for Estimation of Absolute Protein Amount in Proteomics by the Number of Sequenced Peptides per Protein By www.mcponline.org Published On :: 2005-09-01 Yasushi IshihamaSep 1, 2005; 4:1265-1272Research Full Article
pro Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics By www.mcponline.org Published On :: 2014-02-01 Linn FagerbergFeb 1, 2014; 13:397-406Research Full Article
pro Phosphate-binding Tag, a New Tool to Visualize Phosphorylated Proteins By www.mcponline.org Published On :: 2006-04-01 Eiji KinoshitaApr 1, 2006; 5:749-757Technology Full Article
pro Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents By www.mcponline.org Published On :: 2004-12-01 Philip L. RossDec 1, 2004; 3:1154-1169Research Full Article
pro Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ By www.mcponline.org Published On :: 2014-09-01 Jürgen CoxSep 1, 2014; 13:2513-2526Technological Innovation and Resources Full Article
pro Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics By www.mcponline.org Published On :: 2002-05-01 Shao-En OngMay 1, 2002; 1:376-386Research Full Article
pro Enhanced enzyme kinetics of reverse transcriptase variants cloned from animals infected with SIVmac239 lacking viral protein X [Microbiology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages. Full Article
pro ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) [Microbiology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens. Full Article
pro A drug-resistant {beta}-lactamase variant changes the conformation of its active-site proton shuttle to alter substrate specificity and inhibitor potency [Microbiology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance. Full Article
pro G20's lack of progress highlights challenge for COP26 By www.chathamhouse.org Published On :: Mon, 01 Nov 2021 11:34:03 +0000 G20's lack of progress highlights challenge for COP26 Expert comment NCapeling 1 November 2021 A positive outcome from the G20 summit was committing to end international financing for coal projects but, on other issues, the communique was ultimately weak. Success at Glasgow depends on bridging fault lines Renata Dwan The G20 summit’s lack of progress on climate highlights the scale of the challenge – and the stakes – for COP26. The countries responsible for 80 per cent of global emissions recognized but failed to agree concrete action to limit global warming to 1.5C. The leaders’ gathering reveals multilateralism’s fault lines. One is the tension between domestic politics and international priorities, reflected in the lack of ambition to reduce coal dependency. The second is the tension between industrialized and developing states over responsibility for delivering global goods. The G20 failed to endorse the G7’s pledge to achieve net zero emissions by 2050 or to accelerate the mobilization of previously agreed climate financing. Success at Glasgow – and beyond – will depend on the extent to which these fault lines can be bridged. Communique’s language was weak Professor Tim Benton A positive outcome on climate from the G20 summit was the commitment to end international financing for coal projects by the end of 2021. This is a win for the climate and for the G20-host, Italy. The G20 might seem disappointing to some, but a lot will depend on expectations The references to 1.5 degrees and the commitment to taking further action this decade were also important, and help lay the groundwork for COP26. On the downside, the communique’s language on phasing out fossil fuel subsidies and coal domestically was very weak. The G20 summit should be regarded as the next step – it is crucial world leaders accelerate their efforts at COP26 in Glasgow to avert climate catastrophe and keep 1.5 degrees alive. Platitudes and vague plans on pandemic preparedness Robert Yates As G20 leaders head to Glasgow to tackle the evolving climate crisis, they leave Rome having failed, yet again, to take serious action to end the ongoing COVID-19 crisis. Despite the obvious urgency to achieve universal vaccine coverage, their communique contains little more than platitudes and vague plans to prepare better for future pandemics. It is not as if they had not been briefed. This year’s G20 leaders’ summit marks a stark contrast with the past four years when much of the group’s energy was exhausted simply trying to maintain a consensus In the run up to the G20, the leaders of the WHO, WTO, IMF, World Bank, former world leaders, Nobel laureates and the Pope, all highlighted the costs of ongoing vaccine inequity: five million deaths next year and $5.3 trillion dollars in lost economic output by 2026. The ask was also straightforward: launch a massive airlift of unneeded vaccines from rich countries through COVAX, ramp up financing of the multilateral response and accelerate technology transfers to developing countries. But on all these issues the wording of the communique is weak, with no numbers on vaccines or funding, no hard timescales and no urgency. This does not augur well for the COP-26 summit. G20 communique is a launching pad Dr Leslie Vinjamuri The G20 might seem disappointing to some, but a lot will depend on expectations. If your starting point is a pandemic that has so far taken five million lives and driven a global economic crisis, and that both these crises are marked by deep inequality, then the measures adopted are bound to look insufficient. But if your starting point is 16 years of democracy in decline, rampant disinformation on issues of climate and public health, four years of failed international leadership during the Donald Trump presidency and, especially today, heightened tensions between the US and China, the world’s two greatest powers, then the fact that the G20 communique achieved as much as it has is remarkable. Any written document that requires agreement between the US, UK, China, Russia, India, Saudi Arabia and the EU is necessarily going to be watered down. But the principles are in the document, and mostly everyone turned up – if some by video. That is a good outcome for this kind of multilateralism in 2021. The G20 communique is a floor not a ceiling, and it’s a launching pad for activism and mobilisation by individual states, but also by corporates, civil society, and subnational actors. Now we need to hope that those on the right side of progress, whether on climate, health, or development, will use this language to drive forward concrete actions towards net zero, climate finance, vaccine distribution, and debt relief. Specifics are for the most part missing Creon Butler This year’s G20 leaders’ summit marks a stark contrast with the past four years when much of the group’s energy was exhausted simply trying to maintain a consensus – in the face of opposition by a President Trump-led United States – on such issues as the importance of tackling climate change, the benefits of the rules-based multilateral trade system and the centrality of the International Monetary Fund (IMF) in the global financial safety net. By contrast, today’s G20 Rome Leaders’ declaration early on underlines ‘the crucial role of multilateralism in finding shared, effective solutions’. In two critical areas for the world economy – the global boost to liquidity from the general allocation of $650bn in Special Drawing Rights and the global tax deal focused on addressing challenges arising from digitalisation – this outlook has been translated into very substantial and concrete achievements announced earlier in the year. Full Article
pro Professor Sir Laurence Martin (1928-2022) By www.chathamhouse.org Published On :: Tue, 03 May 2022 09:50:13 +0000 Professor Sir Laurence Martin (1928-2022) News release NCapeling 3 May 2022 Professor Sir Laurence Martin, director of Chatham House from 1991-96, has died aged 93. — Professor Sir Laurence Martin, director of Chatham House from 1991-96. Professor Sir Laurence Martin was one of the UK’s leading experts on international security with a particular interest in nuclear strategy. Before joining Chatham House, he was Professor of War Studies at King’s College, London and Vice Chancellor of Newcastle University. He was also appointed Deputy Lieutenant of Tyne and Wear as well as holding several distinguished professorships. His most well-known work was Two-Edged Sword: Armed Forces in the Modern World which was also the subject of the BBC’s Reith Lectures he gave in 1981. Sir Laurence led Chatham House as the world was entering the post-Cold War era, a time when international relations were in a state of flux which, as he wrote in International Affairs, provided grounds for optimism that ‘the objective conditions exist to eliminate violent and mutually harmful conflict at least between the major powers’. Professor Martin worked hard to ensure the financial sustainability of the institute following the loss of core funding from the UK government in the 1980s. By modernizing its approach to fundraising, he was able to invest in a much-needed refurbishment of the House, as well as the institute’s first foray onto the internet. This enabled Chatham House to communicate with new audiences beyond its members, event attendees, and readers of printed reports, The World Today magazine, and International Affairs journal. He paid particular attention to the need for the institute to communicate its ideas to those making policy as well as wider audiences. In addition to strengthening the institute’s research, he was keen to continue engaging its members in discussions to develop a well- informed understanding of international affairs. On the 75th anniversary of Chatham House in 1995, he wrote that its role was ’providing the evidence and, above all, encouraging the habit of mind, to facilitate prudent, if possible optimistic, but never utopian judgements about world affairs’. Today’s staff would agree this role remains at the heart of delivering the institute’s mission. Selected works Two-Edged Sword: Armed Forces in the Modern World The Reith Lectures: The Two-Edged Sword British Foreign Policy: Challenges and Choices for the 21st Century Full Article
pro Independent Thinking: Iran protests, Iraq's invasion legacy By www.chathamhouse.org Published On :: Thu, 17 Nov 2022 17:04:55 +0000 Independent Thinking: Iran protests, Iraq's invasion legacy Audio NCapeling 17 November 2022 Episode five of our new weekly podcast has a Middle East focus with insights into what is driving the ongoing protests in Iran, and the progress of Iraq in the years since the fall of Saddam Hussein. Since September, Iran has been swept by thousands of women-led protests, demanding an end to the morality police and the even calling for the fall of the Islamic Republic. Meanwhile at Chatham House this week saw our Iraq Initiative conference 2022, which delved heavily into the multiple challenges facing Iraq two decades on from the invasion which toppled Saddam Hussein. Joining Bronwen Maddox on the podcast this week are the Chatham House Middle East and North Africa programme deputy director Dr Sanam Vakil and senior research fellow Dr Renad Mansour, who is also project director of the Iraq Initiative. They are joined by Sanya Burgess, digital investigations journalist with Sky News. Full Article
pro Independent Thinking: China protests, North Korea missile tests By www.chathamhouse.org Published On :: Thu, 01 Dec 2022 13:25:51 +0000 Independent Thinking: China protests, North Korea missile tests Audio NCapeling 1 December 2022 Episode seven of our new weekly podcast examines the civil unrest in China and the ongoing development of North Korea’s nuclear weapons programme. Anti-lockdown protests are sweeping the cities of Beijing, Shanghai, and Guangzhou. What does the unrest say about China’s response to COVID-19? How serious a challenge is it to Xi Jinping’s legitimacy so soon after the Party Congress? Meanwhile, 2022 has been a record year for Pyongyang’s ballistic missile launches. How far has North Korea’s nuclear programme and its missile systems developed, and what does it mean for the country’s neighbours? Joining Bronwen Maddox in the studio this week from the Chatham House Asia-Pacific programme are its director Ben Bland and senior research fellow Dr Yu Jie. Joining the panel is special guest Ankit Panda, the Stanton senior fellow at the Carnegie Endowment for International Peace, and editor-at-large for The Diplomat magazine. About Independent Thinking A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues. Full Article
pro Independent Thinking: UK Integrated Review, Georgia protests By www.chathamhouse.org Published On :: Thu, 16 Mar 2023 19:26:37 +0000 Independent Thinking: UK Integrated Review, Georgia protests Audio NCapeling 16 March 2023 Episode 19 of our weekly podcast examines the AUKUS deal, UK defence priorities, and the state of Georgia’s democracy following anti-government protests. The UK and Australia will soon be building nuclear submarines together, but is the UK’s tilt to the Indo-Pacific sustainable? Two years on from the last Integrated Review, has the UK finally clarified its foreign policy priorities on Russia, China, and on defence? And is the money there to do it all? Also on the show, the panel discusses Georgia following recent anti-government protests in Tbilisi. Following the Rose revolution in 2003, Georgia seemed to be on a path towards closer ties with NATO and the European Union (EU). But the country’s government has recently moved closer to Russia and Vladimir Putin. What is the state of Georgia’s democracy and where is the country heading? Joining Bronwen Maddox from Chatham House is Creon Butler, director of our Global Economy and Finance programme, Professor Andrew Dorman, editor of the International Affairs journal, and Alice Billon-Galland, research fellow in our Europe Programme. They are joined by Natia Seskuria, associate fellow with the Royal United Services Institute (RUSI) and Arthur Snell, former diplomat and host of the podcast Doomsday Watch. About Independent Thinking A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues. Full Article
pro Microtubule affinity-regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration [Neurobiology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis. Full Article
pro Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function. Full Article
pro High temperature promotes amyloid {beta}-protein production and {gamma}-secretase complex formation via Hsp90 [Neurobiology] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1. Full Article
pro The UK needs to address growth and debt problems if it is to match resources to ambitions on international priorities By www.chathamhouse.org Published On :: Tue, 05 Nov 2024 09:34:10 +0000 The UK needs to address growth and debt problems if it is to match resources to ambitions on international priorities Expert comment LJefferson 5 November 2024 The budget marks the lowest amount in decades the country has spent on development, and it is struggling to fund other international priorities too. The UK’s Chancellor Rachel Reeves unveiled her much-anticipated budget last week, the first of the new Labour government. Labour is in a difficult place. There are numerous calls on the public purse and public services are not performing well. Meanwhile, public debt remains close to 100 per cent of GDP, and there has been a long run of sluggish growth. Reeves argues with some justification that the previous government left her a challenging inheritance – gaps in this year’s spending plans, and persistent debt questions left unresolved. More importantly, there are longer-term concerns about the sustainability of UK public spending – the country’s Office for Budget Responsibility has warned public debt could triple by the 2070s due to an ageing population, the climate crisis, and security risks. The focus has understandably been on kitchen table questions about tax rises and funding public services. But this picture also has longstanding implications for international policy – on whether the UK can afford to invest in its foreign policy. The Chancellor did announce an increase of £2.9bn for defence. But the question of whether the UK can get on a sustainable path to spending 2.5 per cent of GDP on defence is still being worked through in the ongoing Strategic Review, and remains challenging despite increasingly urgent warnings from parliamentary committees about the UK’s defence readiness. Related content Independent Thinking: Will debt constrain Western foreign policy? The budget also marks one of the lowest amounts in recent years the UK will spend on development overseas, despite setting an ambition to reset relations with the Global South and recover the UK’s role as a leader in international development. The UK needs to either match resources to ambition, spend much more efficiently, or, in the case of the aid budget, it could seek to focus on priorities that are less dependent on spending. But even this will still require consistent resources, alongside significant diplomatic attention, intellectual leadership, and focus.Longer-term, the UK may need to consider larger questions: addressing broader problems with its lack of growth and productivity will be critical to fund an expansive international role.With this budget, UK aid spent overseas is at a historic lowIn 2020 the UK government cut its goal for spending on international development to 0.5 per cent of Gross National Income (GNI), ending a longstanding policy of spending 0.7 per cent. Labour have echoed this, promising to only return to previous levels when fiscal circumstances allow. But this masks a bigger issue. Since 2022, significant amounts of the UK’s aid budget have been spent on accommodation for asylum seekers in the UK. This is within the rules governing aid, but reduces the amount spent on reducing poverty overseas. In 2023 this spending was 28 per cent of the £15.4bn aid budget. In 2016, it was 3.2 per cent. Previous Chancellor Jeremy Hunt quietly allowed a top-up of aid spending over the last two fiscal years to offset how much is being spent at home on asylum seeker accommodation. That provided an additional £2.5 billion for 2022–23 and 2023–24. Related content In conversation with the Rt Hon Anneliese Dodds But Rachel Reeves declined to provide extra funding this time, meaning the amount being spent overseas is likely the lowest its been since 2007 – an effective cut – under a Labour government.The Minister for Development, Anneliese Dodds, speaking at Chatham House last month, said the government is working on clearing the backlog of asylum claims, which should free up more to spend overseas.But beyond this there has been little clarity on plans to address the issue. And costs for asylum seeker accommodation have increased significantly – the UK appears to spend much more than comparator countries per head, according to the Center for Global Development, raising questions about how this spending is managed.Development is not just about money – but money is importantThe UK debate about development has often focused on the 0.7 per cent figure, which can distract from larger questions about what development policy is intended to achieve. As many experts have argued, development aid is about more than spending, and the wider, complex process by which the UK contributes to broad-based growth and stability for poorer countries is not about hitting a specific number. There are things the UK can do that aren’t about spending more directly. This might include focusing on priorities like reforming multilateral development banks so they provide more low-cost public finance, and more flexible and agile loans to poorer countries – a priority echoed by Dodds. It might also incorporate focusing more broadly on helping developing countries attract more investment to bolster growth. The UK debate about development has often focused on the 0.7 per cent figure, which can distract from larger questions about what development policy is intended to achieve. There is also the issue of developing country debt, much of which is held by the private sector. Dodds previously said, when she was shadow chancellor, she might consider changing the law to address this issue. However, she declined to recommit to this when questioned at Chatham House. None of this can be done unilaterally – on debt, for example, the UK has spearheaded some creative policies. Its UK Export Finance body developed climate-resilient debt clauses – agreements that countries can pause debt repayments in the event of a climate shock – but the UK holds limited amounts of developing country debt. Impact will only come by galvanizing and coordinating others to adopt similar approaches. Full Article
pro Trump and his growing number of European allies threaten the European project By www.chathamhouse.org Published On :: Fri, 08 Nov 2024 14:03:05 +0000 Trump and his growing number of European allies threaten the European project Expert comment LToremark 8 November 2024 With Trump in the White House, a key challenge for Europe will be the growing transatlantic illiberal ties which risk undermining European unity. As the US presidential election result became clear, European leaders followed a similar formula when congratulating President-elect Trump. They offered their congratulations, mentioned previous good working relations with the US (special points for a nod to long-standing relations), and – most importantly – emphasized the need for this to continue for the benefit of the citizens of both their country and the US.The formula was a telling sign of the political bartering most European heads of state expect with Trump back in the White House. The exception, of course, were Trump’s European allies who were simply ecstatic.Transatlantic illiberalismTrump’s growing number of European allies and the increase of illiberalism and populism is perhaps the most worrying development for Europe. In 2016, some of Trump’s counterparts in Europe were Angela Merkel in Germany, Emmanuel Macron in France, Mark Rutte in the Netherlands, and Giuseppe Conte in Italy. Regardless of their record, they were moderates. What European populist leaders have in common is a deep-seated scepticism of the EU and a desire to erode it from within. The picture looks very different today. Anti-war extremist parties Alternative for Germany and the Sahra Wagenknecht Alliance are on the rise in Germany. In France, pro-Russia Marine le Pen has been able to reduce support for Ukraine from €3 billion to €2 billion in the draft French budget. In the Netherlands, the far-right Freedom Party is the biggest coalition partner. In Italy, Prime Minister Georgia Meloni hails from a neo-fascist party. Hungarian Prime Minister Viktor Orbán’s populist and illiberal playbook is being replicated across Europe. Related content Independent Thinking: Is the far-right a threat to the European Union? Meanwhile in Poland, moderate prime minister, Donald Tusk, is experiencing the difficulties of reversing damage done by the previous populist government.What European populist leaders have in common is a deep-seated scepticism of the EU and a desire to erode it from within. And many of these leaders also welcome the return of Trump.It is no coincidence that Orbán scheduled the European Political Community Summit, hosted by Hungary, to take place just days after the US election. The Trump win was an added bonus. This meant European heads of state travelled to Budapest for the summit still reeling from – or rejoicing at – the election result. Orbán would like to position himself as Trump’s man in Europe. He has spent the past four years building ties with the president-elect and the MAGA wing of the Republican party. Trump even namechecked Orbán – a Eurosceptic Putin-supporter – during the presidential debate.Italy’s Meloni, meanwhile, has so far worked with EU institutions and NATO rather than against them: she has supported EU and NATO resolutions for Ukraine and demonstrated opposition to Russia. But this may have been a strategic calculation. She likely looked at her country’s balance sheet and realized she needed the European Commission’s COVID-19 recovery funds. But with the fund coming to an end and given her history of Euroscepticism and pro-Russian views, the transatlantic illiberal ties mean she may now feel emboldened to revise her positions. She is already deploying the illiberal playbook domestically.Policy implications for Europe of a second Trump term Despite some ideological similarities, Trump’s policies will not be good for his European allies. He has threatened to impose 10 to 20 per cent tariffs on all EU imports. For Italy and the Netherlands, the second and fifth largest EU exporters to the US, this would have direct negative impacts on their economies. Despite some ideological similarities, Trump’s policies will not be good for his European allies. Increased tariffs on Chinese goods – Trump has threatened up to 60 per cent – would also have an impact on Europe’s economies. Rerouting of Chinese goods could see China dump overproduction in Europe, one of the few remaining relatively open markets, and make European products compete with cheaper Chinese goods in Europe and on the global market. Neither of these developments are positive for export-led European countries. In France, the EU’s fourth largest exporter to the US, Marine le Pen – previously a strong supporter of Trump – had a notably muted response to his victory due to concerns over a trade war. Related content Independent Thinking: What does Donald Trump’s re-election mean for the world? Even European leaders who might have hoped for a different election outcome may seek to hedge their bets. There are two things that are clear about Trump: he is unpredictable and transactional. It is quite possible that some European states, in particular frontline states with genuine fears over Russia’s imperialist ambitions, will seek to buy Trump’s support through bilateral arms deals – despite their distaste for Trump’s position vis-à-vis Russia. These countries already have some of the highest defence spending in NATO, with Poland, Estonia and Latvia leading the way, so this will not irk Trump – arms deals would simply be an additional insurance premium.Countries rushing to make bilateral deals with the US risks a similar uncoordinated race for American arms deals as during Trump’s first term. This would in turn undermine much-needed European defence industrial cooperation efforts. As the need to reduce dependencies on third countries – even for defence equipment from historically close allies – has become increasingly clear, this would be a problematic development.The silver lining may be that it could galvanize the UK and the EU just enough to take action on UK-EU security and defence cooperation, of which the defence industrial piece is the most essential.Europe disunitedThe transatlantic link between populist, illiberal leaders should be a concern. Trump is no longer isolated in Europe, he is rapidly accumulating allies among European heads of state. These leaders agree on the perceived existential threat posed by migration, the need for so-called ‘traditional family values’ and ‘anti-wokeism’. But beyond that, they share and want to advance an illiberal view of the world, with ramifications from security and global trade to human rights – and directly threatening the European project. Full Article
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