ics 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
ics 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
ics 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
ics 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
ics Building a Fantasy Army — Recruitment & Logistics By mythicscribes.com Published On :: Sat, 19 Jun 2021 23:42:51 +0000 This article is by Toni Šušnjar. Recruitment and Numbers The most basic style of recruitment is that of a local militia – rural or urban – where a portion or all of the free men take up arms. Militiamen are usually not highly trained, but they make up for lack of training with motivation: fleeing not only carries social stigma, but is also harshly punished. As such, militias were more effective than what would be expected of “civilians in arms”. Militias almost always depended on relatively cheap and easy to use weapons, though urban militias might have access to more expensive weapons – such as hoplite panoply or crossbows. Tribal militias typically used weapons that were also used for hunting and sport. Peasant levy however was only ever used in a support and harassment role, and often had weapons modified from agricultural implements. Only urban militias could have heavy equipment. A common disadvantage of militia armies is the inability to deploy over long distances and time-frames due to soldiers having a day job; thus, focus on long-term warfare (be it conquest or defence) typically brings about the professionalization of the army. This also means that militias are best used in cases with high political fragmentation – such as city-states. Continue reading Building a Fantasy Army — Recruitment & Logistics at Mythic Scribes. Full Article World Building Building a Fantasy Army
ics Building a Fantasy Army — Weapons & Tactics By mythicscribes.com Published On :: Thu, 01 Jul 2021 21:47:58 +0000 This article is by Toni Šušnjar. In Antiquity and early the Middle Ages, the main weapon was the spear. Only a few exceptions appeared: Roman legions, which used javelins instead, and Macedonian pike phalanx with its sarissa. In the later Middle Ages, the main weapon could be a pike or a polearm (such as polehammer, poleaxe, halberd etc.), before the pike made its return in early modernity. Ranged weapons were not used to cause casualties, but rather to inconvenience the enemies and break up their formation. Weapons and tactics will adapt to each other, as well as to the terrain and the enemies faced – but adaptations will be done within the boundaries of the society. A society without a significant tradition of horse archery will not counter horse archers with their own, but rather with foot archers. Horse archery was important for nomadic societies, because they could not afford the casualties which resulted from the shock and attrition tactics of the settled societies. Weapons and armour likewise have a relationship, but since armour is the more difficult to produce of the two, it is developments in armour which typically drive the adaptation of weapons, rather than the other way around. Continue reading Building a Fantasy Army — Weapons & Tactics at Mythic Scribes. Full Article World Building Building a Fantasy Army
ics Egypt’s purchase of a Chinese fighter jet is a reminder Cold War tactics are back in the Middle East By www.chathamhouse.org Published On :: Fri, 18 Oct 2024 09:03:13 +0000 Egypt’s purchase of a Chinese fighter jet is a reminder Cold War tactics are back in the Middle East Expert comment LJefferson 18 October 2024 The Egyptian army is a formidable force lacking air superiority capabilities to match its size and ambitions. China understood this predicament and offered to help. The reported agreement for Egypt to buy the Chinese Chengdu J-10C 4.5 generation fighter jets is part of a broader shift from focusing on modernizing ground troops to bolstering the air force. The details of the deal have not yet been published. Nonetheless, it reveals Egypt has two motivations beyond backing its arsenal with another fighter jet.Elusive Western technologyThe most important motivation for Egypt’s military diversification strategy (and the biggest source of frustration) is the perceived Western technology starvation. A quick examination of the map around Egypt shows that the most significant perceived threats to its national security are located in remote places where Egypt doesn’t traditionally enjoy ground troops’ presence. These include Ethiopia, the Southern Red Sea, Libya and the vulnerability a potential Israel–Iran regional war would create. From the generals’ perspective in Cairo, this list is more than a catalyst to build a modern and capable long arm.The race started in 2015 after the Obama administration paused an arms transfer to Cairo in 2013 that included four F-16C Block 52 fighter jets amid toppling the Muslim Brotherhood government. The psychological effect of Washington’s decision in Cairo increased Egypt’s risk tolerance towards challenging its military ties with the US by diversifying away from it. Egypt ordered the MiG-29M2 fighter jets from Russia and the French Rafales this same year. In 2018, Egypt negotiated a $2 billion deal with Russia to purchase the Su-35 fighter jet, seen in Washington as crossing a red line and triggering a warning to Egypt that it would impose sanctions under the Countering America’s Adversaries Through Sanctions Act (CAATSA). This caused the deal to collapse. Related content The Fatah–Hamas agreement increases Chinese influence in Palestinian affairs. But the road to unity is rocky The main factor of the US military sales in the Middle East is the upholding of the Israel Military Qualitative Edge principle over its neighbours. This principle requires the US to ensure Israel is superior over other regional countries’ strategic military capabilities, especially in air power.For Egypt, this has long been a strategic vulnerability. The US turned down multiple requests by Egypt to purchase the active radar long-range AIM-120 AMRAAM fire-and-forget missile that can be launched from the F-16 fighter jets, the main striking force in Egypt’s arsenal. Unlike the Gulf and other states (such as Jordan and Turkey), Egypt was only allowed the old AIM-7 Sparrow and the AIM-9 Sidewinders, which are shorter in range and technologically inferior. Israel also allegedly pressured the Trump administration to refuse Egypt’s request to buy the F-35 stealth fight jets in 2019.The US and Israel reportedly pressured France to not sell to Egypt the MBDA’s Meteor 100 km air-to-air missile with the Rafale fighters. Instead, Egypt received the 80 km MICA missile as part of the deal to buy 30 Rafales in 2021. Acquiring this advanced radar system and long-range missiles was likely behind Cairo’s deal to purchase 24 Eurofighter Typhoon aircraft from Italy in 2022. However, it is unlikely that they will come with the full package.Egypt thought the Chinese J-10C Vigorous Dragon fighter may solve this predicament. The Chinese fighter has a beyond-visual range AESA radar and can carry the PL-15 200 km air-to-air missile, similar to the Rafale’s Meteor. The J-10C’s price tag is attractive for Egypt at $40-50 million, much less than the F-16 and Rafales.The Chinese fighters are also a hedge against Russia’s sanctioned fighter jets, traditionally a second choice for the Egyptian air force.Risky manoeuvres This doesn’t mean Egypt is on a path to abandon its weapons purchases from its Western partners. Egyptian weapons procurement policy is not only motivated by technical considerations. It also serves political objectives. Egypt still receives $1.3 billion every year in military and economic aid from Washington. Regime security and backing are two objectives that will likely encourage Cairo to rely on Western weapons systems for decades. However, from Egypt’s military perspective, the time may have come to resort to the Cold War tactics of diversification and counterbalancing. Being forced to accept old technology during the significant modernization of its air force creates a technical and operational necessity to seek this technology elsewhere. Egyptian weapons procurement policy is not only motivated by technical considerations. It also serves political objectives. The regional uncertainty since Hamas’s 7 October attack on Israel and the war that followed in Gaza, southern Lebanon, and Israel’s intermittent confrontations with Iran makes make it imperative for the Egyptian strategic planners to take risky manoeuvres while targeting specific capabilities they seem desperate to acquire. The threat to deploy CAATSA sanctions against Egypt in 2019 makes the J-10C deal with China an interesting case study for all Middle Eastern allies of the West. It shows an uptick in Egypt’s risk tolerance to overcome its technological dilemma. It allows other countries considering the Chinese fighters (mainly Saudi Arabia) to gauge Washington’s reaction and design their future approach accordingly. Another motivation is to pressure the US, UK, and their allies to reconsider their implicit embargo on certain advanced technology by showing that Cairo now has alternatives. This tactic seems to work. General Frank McKenzie, the former head of US Central Command, said during a congressional hearing in 2022 that Washington will finally provide Egypt with the F-15 heavy-weight air superiority fighter, a longstanding demand by Cairo.Building favoursThe J-10C fighter jet ticks all the boxes: It satisfies Cairo’s diversity strategy and technological needs. It is under the sanctions threshold since it is less technologically savvy than the most controversial J-20 5th generation fighters, the equivalent to Russia’s SU-35. And it takes Egypt’s military partnership with China to a new level. A heavyweight military power like Egypt relying on Chinese fighters would almost certainly boost China’s share in the regional weapons market. The rumour that the Chinese fighters are bought to replace the ageing versions of Egypt’s significant F-16 fleet is a source of pride for Beijing since its military technology started to be seen as a competitor to Western technology. A heavyweight military power like Egypt relying on Chinese fighters would almost certainly boost China’s share in the regional weapons market, just like Cairo’s purchase of the Rafale boosted its popularity globally. Full Article
Related content The Fatah–Hamas agreement increases Chinese influence in Palestinian affairs. But the road to unity is rocky
ics Following its snap election, Japanese politics has entered uncharted waters By www.chathamhouse.org Published On :: Tue, 05 Nov 2024 15:19:00 +0000 Following its snap election, Japanese politics has entered uncharted waters Expert comment LToremark 5 November 2024 Prime Minister Ishiba’s election gamble has failed. Japan now faces another period of political uncertainty, which could affect its international standing. In Japan’s snap election on 27 October, the ruling coalition of the Liberal Democratic Party (LDP) and New Komeito lost the overwhelming majority it had held since the 2012 general election. The ruling coalition now has 215 seats, leaving it 18 seats short of a majority. The largest opposition party is the Constitutional Democratic Party of Japan (CDP), which gained 50 seats to 148. The second largest opposition party is the Japan Innovation Party (Ishin), which lost six seats to 38, and the third largest opposition party is the National Democratic Party (NDP), which gained 21 seats to 28.But the opposition is divided and there is no real appetite to form a coalition government. This will likely result in a hung parliament, which will further destabilize Japan’s government.The election results reveal three key things about the state of Japanese politics and what comes next. Related content Japan’s snap election: Why Ishiba’s gamble might pay off First, that Prime Minister Ishiba’s snap election gamble has failed. The aim was for Ishiba, a non-mainstream member of the LDP, to strengthen the party base and stabilize his administration. But with the ruling coalition losing its majority, the party base has been further weakened and the Ishiba administration is now more likely to be short-lived. LDP voters as well as the public in general had hoped that Ishiba, as the ‘opposition within the party’, would change the LDP’s structure and government policies, eliminate the uncertainty surrounding party funding and increase transparency on how MPs use public funds to finance political activities.However, when Ishiba became LDP leader and prime minister, he abandoned his previously more critical stance and prioritized carrying on the policies of the mainstream LDP, leaving his supporters feeling betrayed.Second, while the ruling coalition has been punished, the people of Japan still did not vote for a change of government. The opposition is divided and, despite its gains in this election, the CDP is not fully committed to take the lead and consolidate the opposition to form a coalition. The CDP also suffers from internal division. The left wing of the party would prefer a coalition with the Communist Party, while the right wing of the party does not want to form a coalition with the LDP or the Communist Party, preferring a partner such as the NDP. The NDP is in a position to control the fate of Ishiba administration. Third, the NDP has become the key to future Japanese politics. By becoming the minority ruling party, the NDP is in a position to control the fate of Ishiba administration. While the CDP has no intention of cooperating with the LDP, the NDP is more willing to do so in order to implement its own policies. As the budget cannot be passed without the NDP’s cooperation, the ruling coalition will have no choice but to accept the NDP’s policy of substantial tax cuts through the expansion of tax credits. It will also likely have to accept an option for married couples to decide their family names, which requires a change of civil codes and is something it has been reluctant to do so far. If the NDP’s demands are rejected, a no-confidence motion will likely be submitted and passed, leaving the Ishiba cabinet with no choice but to resign or dissolve the House of Representatives (the lower house of Japan’s parliament).But the NDP has chosen to not form a coalition with the ruling party and enter government. Why? From the NDP’s point of view, forming a coalition with the LDP, would mean getting involved in the LDP’s internal turmoil – something it wishes to avoid. In addition, elections to the House of Councillors (upper house of parliament) will be held in the summer of 2025. The NDP may have judged that it will have a better chance of implementing its policies by cooperating with the government on a case-by-case basis, rather than forming a coalition with a party that is losing public support and risk following suit. Related content Democracy in Japan The minority ruling system that has emerged after the election is extremely rare in Japan’s political history and is likely to make its politics even more unstable in the years ahead. The Ishiba administration will probably be able to survive until the budget is passed in March next year by cooperating with the NDP, but beyond that its prospects are unclear.As the House of Councillors elections get closer, some in the LDP may say that they cannot fight the election with Ishiba as prime minister. If so, they may choose the option of a same-day election for the lower and the upper house. The cost of an election campaign is significant, and the LDP’s financial strength gives it an advantage in the case of a same-day election. There is also a strong possibility that the public will choose the LDP to regain stability in government. However, this election has shown that public distrust of the LDP is high, and if Ishiba continues to be pushed around by the NDP, his party’s chances of winning would be reduced.Japanese politics has entered uncharted waters, where the patterns and customs of the past do not apply. There are now doubts both at home and abroad as to whether Ishiba, who has a weak party base, will be able to stay on and steer the government. Over the past decade, the Abe and Kishida administrations have provided Japan with political stability, which has in turn enhanced its international presence. An unstable political system, with frequent changes of government, will likely lead to a decline in Japan’s international influence. Although Trump might be open to Ishiba’s demand for parity with the US, he could become irritated with Ishiba’s weak domestic position. There is also a risk that US–Japan relations could become unstable. Although the NDP does not have a strong agenda to change the course of this relationship, Ishiba may struggle to keep the promise made by his predecessors to increase defence spending. Ishiba’s nationalist posture could also create a confrontational relationship with the United States, while his weak leadership means he may not seek to invest in strengthening the US–Japan alliance. Donald Trump’s win in the US presidential election could pose a further risk. Although Trump might be open to Ishiba’s demand for parity with the US, he could become irritated with Ishiba’s weak domestic position. Ishiba may not be able to make decisions – or a deal with Trump – unless the NDP agrees to it. Full Article
ics The Politics of Personality in the Middle East By f1.media.brightcove.com Published On :: Mon, 21 May 2018 00:00:00 +0100 Full Article
ics Jordan: Regime Survival and Politics Beyond the State By f1.media.brightcove.com Published On :: Tue, 26 Jun 2018 00:00:00 +0100 Full Article
ics China, Russia and Iran: Power Politics of a New World Order? By f1.media.brightcove.com Published On :: Tue, 10 Jul 2018 00:00:00 +0100 Full Article
ics The Belt and Road Initiative: Modernity, Geopolitics and the Global Order By f1.media.brightcove.com Published On :: Fri, 28 Sep 2018 00:00:00 +0100 Full Article
ics Stacey Abrams: Democracy and the Politics of Identity By f1.media.brightcove.com Published On :: Wed, 06 Mar 2019 00:00:00 +0000 Full Article
ics Tectonic Politics: Navigating New Geopolitical Risks By f1.media.brightcove.com Published On :: Wed, 05 Jun 2019 00:00:00 +0100 Full Article
ics A Path Forward for US Politics By f1.media.brightcove.com Published On :: Mon, 17 Jun 2019 00:00:00 +0100 Full Article
ics Iran, Islam and Democracy: The Politics of Managing Change 20 Years On By f1.media.brightcove.com Published On :: Tue, 02 Jul 2019 00:00:00 +0100 Full Article
ics Undercurrents: Summer Special - Andrés Rozental on Mexican Politics By f1.media.brightcove.com Published On :: Thu, 01 Aug 2019 00:00:00 +0100 Full Article
ics Undercurrents: Episode 40 - Illicit Financial Flows, and Geopolitics in the Indo-Pacific By f1.media.brightcove.com Published On :: Thu, 14 Nov 2019 00:00:00 +0000 Full Article
ics Young and Male: Identity and Politics in Saudi Arabia By f1.media.brightcove.com Published On :: Fri, 29 Nov 2019 00:00:00 +0000 Full Article
ics Undercurrents: Episode 44 - The Iran Crisis, and Politics in Iraq By f1.media.brightcove.com Published On :: Thu, 23 Jan 2020 00:00:00 +0000 Full Article
ics Undercurrents: Episode 45 - Politics in Kazakhstan, and Youth Engagement in Politics By f1.media.brightcove.com Published On :: Mon, 10 Feb 2020 00:00:00 +0000 Full Article
ics Undercurrents: Episode 49 - EU Responses to COVID-19, and the Politics of Celebrity By brightcove.hs.llnwd.net Published On :: Thu, 16 Apr 2020 00:00:00 +0100 Full Article
ics Undercurrents: Episode 51 - Preparing for Pandemics, and Gandhi's Chatham House Speech By brightcove.hs.llnwd.net Published On :: Thu, 30 Apr 2020 00:00:00 +0100 Full Article
ics Undercurrents: Episode 52 - Defining Pandemics, and Mikheil Saakashvili's Ukrainian Comeback By brightcove.hs.llnwd.net Published On :: Thu, 07 May 2020 00:00:00 +0100 Full Article
ics Undercurrents: Episode 55 - Benjamin Netanyahu's Trial, and the Identity Politics of Eurovision By brightcove.hs.llnwd.net Published On :: Thu, 28 May 2020 00:00:00 +0100 Full Article
ics Undercurrents: Episode 63 - The Politics of Violent Images By brightcove.hs.llnwd.net Published On :: Thu, 16 Jul 2020 00:00:00 +0100 Full Article
ics Lipidomics reveals a remarkable diversity of lipids in human plasma By www.jlr.org Published On :: 2010-11-01 Oswald QuehenbergerNov 1, 2010; 51:3299-3305Research Articles Full Article
ics Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics By www.jlr.org Published On :: 2008-05-01 Vitali MatyashMay 1, 2008; 49:1137-1146Methods Full Article
ics Trump’s Strikes Risk Upending Iraqi Politics By www.chathamhouse.org Published On :: Fri, 06 Mar 2020 16:26:01 +0000 Source Foreign Affairs URL https://www.foreignaffairs.com/articles/iran/2020-01-27/trumps-strikes-risk-upen... Release date 27 March 2020 Expert Dr Renad Mansour In the news type Op-ed Hide date on homepage Full Article
ics Regional politics of Kazakhstan in Central Asia By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:21:20 +0000 Source Central Asia Analytical Network URL https://caa-network.org/archives/18673 Release date 03 December 2019 Expert Annette Bohr In the news type Op-ed Hide date on homepage Full Article
ics Why democracies do better at surviving pandemics By www.chathamhouse.org Published On :: Wed, 27 May 2020 11:59:28 +0000 Source Los Angeles Times URL https://www.latimes.com/opinion/story/2020-05-26/democracies-autocracies-coronav... Release date 26 May 2020 Expert Robin Niblett Dr Leslie Vinjamuri In the news type Op-ed Hide date on homepage Full Article
ics Coupled intra- and interdomain dynamics support domain cross-talk in Pin1 [Signal Transduction] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well. Full Article
ics Functional and structural characterization of allosteric activation of phospholipase Cϵ by Rap1A [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Phospholipase Cε (PLCε) is activated downstream of G protein–coupled receptors and receptor tyrosine kinases through direct interactions with small GTPases, including Rap1A and Ras. Although Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors, translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation and identified hydrophobic residues on the surface of the RA2 domain that are also necessary. Small-angle X-ray scattering showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. These data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLCε core. Full Article
ics Biochemical and biophysical analyses of hypoxia sensing prolyl hydroxylases from Dictyostelium discoideum and Toxoplasma gondii [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles. Full Article
ics Building better polymerases: Engineering the replication of expanded genetic alphabets [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases. Full Article
ics Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization. Full Article
ics Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation. Full Article
ics Mapping invisible epitopes by NMR spectroscopy [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens. Hydrogen/deuterium exchange monitored by NMR can be used to map epitopes onto folded protein surfaces, but only if the complex rapidly dissociates. Modifying the standard NMR-exchange measurement to detect substoichiometric complexes overcomes this time scale limitation and provides new insights into recognition of lipid transfer polyprotein by antibodies. In the future, this new and exciting development should see broad application to a range of tight macromolecular interactions. Full Article
ics Co-crystal structures of HIV TAR RNA bound to lab-evolved proteins show key roles for arginine relevant to the design of cyclic peptide TAR inhibitors [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 RNA-protein interfaces control key replication events during the HIV-1 life cycle. The viral trans-activator of transcription (Tat) protein uses an archetypal arginine-rich motif (ARM) to recruit the host positive transcription elongation factor b (pTEFb) complex onto the viral trans-activation response (TAR) RNA, leading to activation of HIV transcription. Efforts to block this interaction have stimulated production of biologics designed to disrupt this essential RNA-protein interface. Here, we present four co-crystal structures of lab-evolved TAR-binding proteins (TBPs) in complex with HIV-1 TAR. Our results reveal that high-affinity binding requires a distinct sequence and spacing of arginines within a specific β2-β3 hairpin loop that arose during selection. Although loops with as many as five arginines were analyzed, only three arginines could bind simultaneously with major-groove guanines. Amino acids that promote backbone interactions within the β2-β3 loop were also observed to be important for high-affinity interactions. Based on structural and affinity analyses, we designed two cyclic peptide mimics of the TAR-binding β2-β3 loop sequences present in two high-affinity TBPs (KD values of 4.2 ± 0.3 and 3.0 ± 0.3 nm). Our efforts yielded low-molecular weight compounds that bind TAR with low micromolar affinity (KD values ranging from 3.6 to 22 μm). Significantly, one cyclic compound within this series blocked binding of the Tat-ARM peptide to TAR in solution assays, whereas its linear counterpart did not. Overall, this work provides insight into protein-mediated TAR recognition and lays the ground for the development of cyclic peptide inhibitors of a vital HIV-1 RNA-protein interaction. Full Article
ics Existence and uniqueness result for reaction-diffusion model of diffusive population dynamics By www.ams.org Published On :: Tue, 01 Oct 2024 14:21 EDT A. Kh. Khachatryan, Kh. A. Khachatryan and A. Zh. Narimanyan Trans. Moscow Math. Soc. 83 (), 183-200. Abstract, references and article information Full Article
ics Power Sector Transformation, New Market Dynamics and Geopolitical Implications By www.chathamhouse.org Published On :: Thu, 06 Dec 2018 13:45:01 +0000 Power Sector Transformation, New Market Dynamics and Geopolitical Implications 7 November 2018 — 8:00AM TO 9:30AM Anonymous (not verified) 6 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE The global electricity sector is experiencing profound change due to a confluence of technological innovation, environmental policies and regulatory reform. The effect is most obvious in the EU28, Australia and parts of North America.However, this is just the beginning and the success of the next phase of electricity sector transformations hinges on enhancing system flexibility to facilitate unhindered low-cost deployment of renewables. It remains to be seen how utilities will seek to navigate this second phase of electricity transformations.This session starts with a presentation and discussion that focuses on:Public and private sector risks of the transformation of the power sector, changes in generation mix and their implications for supply chain, employments and investment patterns.The role of government and the regulatory framework in light of changing market structure, new entrants and big data.Wider geopolitical issues including the implication for fossil fuel producers and the rise in demand for new materials and changes in land use. The possible implications on the power sector on the electrification of heat and transport.The discussion then moves to the speed of transformation and what this means for existing and new market actors. Full Article
ics Impact of the US Election on Global Climate Politics By www.chathamhouse.org Published On :: Mon, 16 Nov 2020 16:19:46 +0000 Impact of the US Election on Global Climate Politics 25 November 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 16 November 2020 Online Panellists discuss how Joe Biden’s victory will impact international efforts to tackle climate change. Will climate finally become a common area for global cooperation? Joe Biden’s victory over Donald Trump is already having a positive impact on international efforts to tackle climate change. Leaders from across the world, including the UK, Canada, Australia and Fiji, have used their first messages to the President-elect to draw attention to the climate crisis. Biden has promised to re-join the global community in its commitment to the Paris Agreement – but this could be the easy part. More difficult will be whether and how Biden is able to deliver his ambitious climate plan, and how effectively he is able to integrate climate change into foreign policy efforts and national security strategies. Global climate action has also moved forward in the last four years. The European Union recently pledged to become climate neutral by 2050, and China, Japan and South Korea have committed to achieving carbon neutral economies. How will the US re-enter this global landscape of distributed leadership and what difficulties does it face? Will the US be willing to work within a competitive partnership with the EU and China? How will Biden’s win change the dynamic of COP26 next year? Full Article
ics Climate finance and conflict dynamics on the road to COP27 By www.chathamhouse.org Published On :: Fri, 09 Sep 2022 07:37:13 +0000 Climate finance and conflict dynamics on the road to COP27 21 September 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 9 September 2022 Online Stakeholders discuss the role of conflict and conflict sensitivity in climate finance and action. With climate change, fragility and conflict challenges worsening, the role of international climate finance is more urgent than ever. From the implementation of climate finance and who it reaches to the rush for renewable energy, the inclusion of conflict analysis and conflict sensitivity principles often remain absent from climate finance discussions and planning. With COP27 around the corner and for the occasion of International Peace Day, stakeholders ranging from government representatives to climate activists discuss their perspectives on the role of conflict and conflict sensitivity as part of climate finance and action. This event was organized in partnership with International Alert. Full Article
ics Demographics and politics By www.chathamhouse.org Published On :: Thu, 16 Jan 2020 13:17:30 +0000 Demographics and politics Analysing political trends based on demographics is growing as the global population changes and traditional political affiliations are replaced. nfaulds-adams… 16 January 2020 Major issues for Chatham House research include the impact of the growth of young people in the developing world, significant increases in population aging in the developed world, and the impact of increasing urbanization on political engagement. Gender and diversity also play an important part in changing political attitudes, while predicting voting behaviour is becoming ever harder to do accurately, as the methods and technology used by younger generations to engage with politics differ hugely from more traditional approaches. Full Article
ics Exploring Thermodynamics with Billiards By www.ams.org Published On :: Mon, 14 Feb 2022 14:38:14 -0400 Tim Chumley explains the connections between random billiards and the science of heat and energy transfer. If you've ever played billiards or pool, you've used your intuition and some mental geometry to plan your shots. Mathematicians have gone a step further, using these games as inspiration for new mathematical problems. Starting from the simple theoretical setup of a single ball bouncing around in an enclosed region, the possibilities are endless. For instance, if the region is shaped like a stadium (a rectangle with semicircles on opposite sides), and several balls start moving with nearly the same velocity and position, their paths in the region soon differ wildly: chaos. Mathematical billiards even have connections to thermodynamics, the branch of physics dealing with heat, temperature, and energy transfer. Full Article
ics Giving Health Care Policy a Dose of Mathematics By www.ams.org Published On :: Wed, 5 Apr 2023 10:49:14 -0400 Imelda Flores Vazquez from Econometrica, Inc. explains how economists use mathematics to evaluate the efficacy of health care policies. When a hospital or government wants to adjust their health policies — for instance, by encouraging more frequent screenings for certain diseases — how do they know whether their program will work or not? If the service has already been implemented elsewhere, researchers can use that data to estimate its effects. But if the idea is brand-new, or has only been used in very different settings, then it's harder to predict how well the new program will work. Luckily, a tool called a microsimulation can help researchers make an educated guess. Full Article
ics Supporting Wildlife with Statistics By www.ams.org Published On :: Thu, 16 Feb 2024 10:33:14 -0400 Dr. Outi Tervo of Greenland Institute for Natural Resources, shares how mathematics helps recommend speed limits for marine vessels, which benefits narwhals and Inuit culture. Narwhals "can only be found in the Arctic," said Outi Tervo, a senior scientist at GINR. "These species are going to be threatened by climate change more than other species that can live in a bigger geographical area." The collaboration has already lobbied on behalf of the narwhals to reduce the level of sea traffic in their habitat, after using mathematical analysis to identify how noise from passing boats changes the narwhals' foraging behavior. Full Article
ics Smashing Particles up Against Mathematics By www.ams.org Published On :: Fri, 8 Mar 2024 14:33:14 -0400 Dr. Abiy Tasissa of Tufts University, discusses the mathematics he and colleagues used to study particle collider data, including optimal transport and optimization. Collider physics often result in distributions referred to as jets. Dr. Tasissa and his team used "Earth Mover's Distance" and other mathematical tools to study the shape of jets. "It is interesting for me to see how mathematics can be applied to study these fundamental problems answering fundamental equations in physics, not only at the level of formulating new ideas, which is, in this particular case, a notion of distance, but also how the importance of designing fast optimization algorithms to be able to actually compute these distances," says Dr. Tasissa. Full Article
ics Higher Structures in Topology, Geometry, and Physics By www.ams.org Published On :: Mon, 01 Jul 2024 10:29 EDT Ralph M. Kaufmann, Martin Markl and Alexander A. Voronov, editors. American Mathematical Society, 2024, CONM, volume 802, approx. 330 pp. ISBN: 978-1-4704-7142-2 (print), 978-1-4704-7642-7 (online). This volume contains the proceedings of the AMS Special Session on Higher Structures in Topology, Geometry, and Physics, held virtually on March... Full Article
ics Topics in Multiple Time Scale Dynamics By www.ams.org Published On :: Tue, 01 Oct 2024 10:00 EDT Maximilian Engel, Hildeberto Jardón-Kojakhmetov and Cinzia Soresina, editors. American Mathematical Society, 2024, CONM, volume 806, approx. 232 pp. ISBN: 978-1-4704-7327-3 (print), 978-1-4704-7684-7 (online). This volume contains the proceedings of the BIRS Workshop "Topics in Multiple Time Scale Dynamics," held from November 27– December 2, 2022, at... Full Article