Lars Jønson
May 1, 2007; 6:798-811
Research

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research

Jesper V. Olsen
Jun 1, 2004; 3:608-614
Technology

Can the world avoid a new nuclear arms race? 18 November 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 16 October 2024 Chatham House and Online

Leading experts discuss how states are expanding nuclear arsenals amid rising geopolitical challenges.

Leading experts discuss how states are expanding nuclear arsenals amid rising geopolitical challenges.

The Doomsday Clock stands at 90 seconds to midnight – the closest to global catastrophe it has ever been. As geopolitical competition intensifies, nuclear risks are resurging at an alarming rate. The collapse of key arms control agreements, such as the Intermediate-Range Nuclear Forces (INF) Treaty, has removed crucial safeguards against arms races. Efforts to extend or replace existing treaties face significant hurdles in the current geopolitical climate.

Nuclear rhetoric has become more aggressive, as evidenced by Russian and North Korean nuclear threats. Several nuclear-armed states are also engaging in extensive modernization programmes of their nuclear arsenals, potentially fuelling a new arms race.

Despite these pressures, the number of nuclear possessor states has held steady so far. The ongoing Iranian efforts to build nuclear weapons is the closest attempt by a new state to acquire nuclear weapons. As the global security environment becomes more and more tense, existing nuclear possessor states increasingly rely on their nuclear weapons. This might threaten the global consensus against nuclear proliferation.

This session examines these competing pressures and propose strategies to reduce the risks of nuclear weapons use and proliferation. Our expert panel explores diplomatic initiatives, technical measures, and policy innovations to address these critical challenges.

This expert panel discusses key questions including:

• Are we already in the middle of a global nuclear arms race?
• How can international arms control treaties be negotiated in the current geopolitical environment?
• Does a new US president change the nuclear calculus? Is the US still able to reassure allies of its ‘extended deterrence’?
• How can we reduce the risk of additional proliferation? Which states might want to acquire nuclear weapons and what can we do about it?

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

RK Tangirala
Nov 1, 1995; 36:2320-2328
Articles

JE Hixson
Mar 1, 1990; 31:545-548
Articles

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

The Electric Vehicle Revolution: Impacts on Oil Economies and Industry 24 January 2019 — 8:15AM TO 9:45AM Anonymous (not verified) 3 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Electric vehicle (EV) deployment is gathering pace: the Norwegian government thinks that EV subsidies will be unnecessary by 2025 as they reach parity with diesel and petrol vehicles.

China has stipulated that EVs comprise 12 per cent of vehicle sales by 2020 while more governments are committing to banning diesel and petrol vehicles.

These developments are expected to be replicated as urban air pollution rises up the political agenda while technological developments and falling costs have given rise to ambitious forecasts on the increase in the deployment of EVs and the demise of the internal combustion engine.

Considering this, the presentations and initial discussion focus on:

• The influence of new technologies on the automotive landscape, including autonomous vehicles.
• How the automotive and oil companies are adjusting their business models to accommodate and encourage the rise in EVs.
• The risks and opportunities for the deployment of EVs for incumbents and new market actors.
• The role of government for example in public procurement and infrastructure development.
• The potential for modal shift and its impact on oil demand.

The discussion then seeks to explore the need for benchmarks of change including data and metrics to understand the changing risk landscape and the implications for different actors.

Finally, the discussion focuses on the speed of transformation and what this means for existing and new market actors.

Nuclear Energy in a Post-Brexit Europe 11 October 2019 — 8:30AM TO 10:00AM Anonymous (not verified) 18 September 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

Brexit will significantly change the balance within the EU in relation to nuclear energy. Apart from France and Finland, both of whose nuclear development programmes are behind schedule, the UK is the only member state in northern or western Europe currently investing in new nuclear capacity. Brexit will therefore leave the supporters of nuclear energy within the EU27 and the European Commission in a weaker position.

The speaker will argue that at a time when the energy industry needs to accelerate its shift away from fossil fuels, and when the electricity generation industry must cut its carbon emissions faster than it has ever managed to do in the past, this change is unhelpful.

The workshop will also address the need for additional interconnector capacity and the future of carbon-trading outside the EU emission trading system and how this relates to potential nuclear energy capacity.

Attendance at this event is by invitation only.

Nuclear, gas and green finance taxonomies in the EU and UK 23 February 2022 — 10:00AM TO 11:00AM Anonymous (not verified) 20 January 2022 Online

Experts discuss EU, UK, and international perspectives on green taxonomy.

This event will address the controversial additions to the EU green finance taxonomy, including the labelling of some nuclear and gas power sources as “green”. Hear perspectives from the UK, EU and international experts.

The UK has committed to creating a green taxonomy to provide a shared understanding of which economic activities count as sustainable. It should be robust and evidence-based, taking an objective and science-based approach to assessing sustainability.

Technical Screening Criteria (TSCs) for the climate change mitigation, and climate change adaptation objectives within the UK green taxonomy will be based on those in the EU Taxonomy. The Government is currently reviewing these and expects to consult on UK draft TSCs in the first quarter of 2022, ahead of legislating by the end of 2022.

In recent weeks the European Commission has proposed controversial additional TSCs for the EU taxonomy, most notably the inclusion of nuclear and natural gas in power generation, which are currently being discussed by Member States and the European Parliament.

The inclusion of controversial power sources not only risks affecting investment and deployment patterns in the net-zero transition, but may also be a threat to the authority of the taxonomy as a whole

Key questions for the UK now include whether and how to address these issues in its own taxonomy, and how to promote a science-based ‘race to the top’ between jurisdictions that can lead to robust international standards.

This Environment and Society Discussion Series event brings expert voices together to discuss EU, UK, and international perspectives, and is co-organized with E3G.

Jan Goedgebeur, Jorik Jooken, On-Hei Solomon Lo, Ben Seamone and Carol T. Zamfirescu
Math. Comp. 93 (), 3059-3082.
Abstract, references and article information

Dr. Stan Wagon of Macalester College discusses the mathematics behind rolling a square smoothly. In 1997, inspired by a square wheel exhibit at The Exploratorium museum in San Francsico, Dr. Stan Wagon enlisted his neighbor Loren Kellen in building a square-wheeled tricycle and accompanying catenary track. For years, you could ride the tricycle at Macalester College in St. Paul, Minnesota. The National Museum of Mathematics in New York now also has square-wheeled tricycles that can be ridden around a circular track. And more recently, the impressive Cody Dock Rolling Bridge was built using rolling square mathematics by Thomas Randall-Page in London.

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.

Guido De Philippis, Nicola Fusco and Massimiliano Morini
Trans. Amer. Math. Soc. 377 (), 5787-5835.
Abstract, references and article information

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The police have arrested an individual in the probe surrounding two bags of cash that allegedly fell from a Beryllium security vehicle en route to the Norman Manley International Airport in Kingston last week. 

A growing number of motor vehicle crashes across Jamaica has been attributed to drivers operating the vehicles under the influence of marijuana, according to Health Minister Dr Christopher Tufton. "The data is clear, we are seeing more people...

Carnosine (β-alanyl-l-histidine) and anserine (β-alanyl-3-methyl-l-histidine) are abundant peptides in the nervous system and skeletal muscle of many vertebrates. Many in vitro and in vivo studies demonstrated that exogenously added carnosine can improve muscle contraction, has antioxidant activity, and can quench various reactive aldehydes. Some of these functions likely contribute to the proposed anti-aging activity of carnosine. However, the physiological role of carnosine and related histidine-containing dipeptides (HCDs) is not clear. In this study, we generated a mouse line deficient in carnosine synthase (Carns1). HCDs were undetectable in the primary olfactory system and skeletal muscle of Carns1-deficient mice. Skeletal muscle contraction in these mice, however, was unaltered, and there was no evidence for reduced pH-buffering capacity in the skeletal muscle. Olfactory tests did not reveal any deterioration in 8-month-old mice lacking carnosine. In contrast, aging (18–24-month-old) Carns1-deficient mice exhibited olfactory sensitivity impairments that correlated with an age-dependent reduction in the number of olfactory receptor neurons. Whereas we found no evidence for elevated levels of lipoxidation and glycation end products in the primary olfactory system, protein carbonylation was increased in the olfactory bulb of aged Carns1-deficient mice. Taken together, these results suggest that carnosine in the olfactory system is not essential for information processing in the olfactory signaling pathway but does have a role in the long-term protection of olfactory receptor neurons, possibly through its antioxidant activity.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

3 July 2020

6 July 2020

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.

Visual Abstract

Tricia Rowlison
Dec 1, 2020; 19:2090-2103
Research

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

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using total internal reflection fluorescence (TIRF) microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism and α-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and α-synuclein clearance to prevent their intracellular accumulation.

Neurodegeneration in Parkinson's disease (PD) can be recapitulated in animals by administration of α-synuclein preformed fibrils (PFFs) into the brain. However, the mechanism by which these PFFs induce toxicity is unknown. Iron is implicated in PD pathophysiology, so we investigated whether α-synuclein PFFs induce ferroptosis, an iron-dependent cell death pathway. A range of ferroptosis inhibitors were added to a striatal neuron-derived cell line (STHdhQ7/7 cells), a dopaminergic neuron–derived cell line (SN4741 cells), and WT primary cortical neurons, all of which had been intoxicated with α-synuclein PFFs. Viability was not recovered by these inhibitors except for liproxstatin-1, a best-in-class ferroptosis inhibitor, when used at high doses. High-dose liproxstatin-1 visibly enlarged the area of a cell that contained acidic vesicles and elevated the expression of several proteins associated with the autophagy-lysosomal pathway similarly to the known lysosomal inhibitors, chloroquine and bafilomycin A1. Consistent with high-dose liproxstatin-1 protecting via a lysosomal mechanism, we further de-monstrated that loss of viability induced by α-synuclein PFFs was attenuated by chloroquine and bafilomycin A1 as well as the lysosomal cysteine protease inhibitors, leupeptin, E-64D, and Ca-074-Me, but not other autophagy or lysosomal enzyme inhibitors. We confirmed using immunofluorescence microscopy that heparin prevented uptake of α-synuclein PFFs into cells but that chloroquine did not stop α-synuclein uptake into lysosomes despite impairing lysosomal function and inhibiting α-synuclein toxicity. Together, these data suggested that α-synuclein PFFs are toxic in functional lysosomes in vitro. Therapeutic strategies that prevent α-synuclein fibril uptake into lysosomes may be of benefit in PD.

Type I and III interferons induce expression of the “myxovirus resistance proteins” MxA in human cells and its ortholog Mx1 in murine cells. Human MxA forms cytoplasmic structures, whereas murine Mx1 forms nuclear bodies. Whereas both HuMxA and MuMx1 are antiviral toward influenza A virus (FLUAV) (an orthomyxovirus), only HuMxA is considered antiviral toward vesicular stomatitis virus (VSV) (a rhabdovirus). We previously reported that the cytoplasmic human GFP-MxA structures were phase-separated membraneless organelles (“biomolecular condensates”). In the present study, we investigated whether nuclear murine Mx1 structures might also represent phase-separated biomolecular condensates. The transient expression of murine GFP-Mx1 in human Huh7 hepatoma, human Mich-2H6 melanoma, and murine NIH 3T3 cells led to the appearance of Mx1 nuclear bodies. These GFP-MuMx1 nuclear bodies were rapidly disassembled by exposing cells to 1,6-hexanediol (5%, w/v), or to hypotonic buffer (40–50 mosm), consistent with properties of membraneless phase-separated condensates. Fluorescence recovery after photobleaching (FRAP) assays revealed that the GFP-MuMx1 nuclear bodies upon photobleaching showed a slow partial recovery (mobile fraction: ∼18%) suggestive of a gel-like consistency. Surprisingly, expression of GFP-MuMx1 in Huh7 cells also led to the appearance of GFP-MuMx1 in 20–30% of transfected cells in a novel cytoplasmic giantin-based intermediate filament meshwork and in cytoplasmic bodies. Remarkably, Huh7 cells with cytoplasmic murine GFP-MuMx1 filaments, but not those with only nuclear bodies, showed antiviral activity toward VSV. Thus, GFP-MuMx1 nuclear bodies comprised phase-separated condensates. Unexpectedly, GFP-MuMx1 in Huh7 cells also associated with cytoplasmic giantin-based intermediate filaments, and such cells showed antiviral activity toward VSV.

The kinesin-3 family contains the fastest and most processive motors of the three neuronal transport kinesin families, yet the sequence of states and rates of kinetic transitions that comprise the chemomechanical cycle and give rise to their unique properties are poorly understood. We used stopped-flow fluorescence spectroscopy and single-molecule motility assays to delineate the chemomechanical cycle of the kinesin-3, KIF1A. Our bacterially expressed KIF1A construct, dimerized via a kinesin-1 coiled-coil, exhibits fast velocity and superprocessivity behavior similar to WT KIF1A. We established that the KIF1A forward step is triggered by hydrolysis of ATP and not by ATP binding, meaning that KIF1A follows the same chemomechanical cycle as established for kinesin-1 and -2. The ATP-triggered half-site release rate of KIF1A was similar to the stepping rate, indicating that during stepping, rear-head detachment is an order of magnitude faster than in kinesin-1 and kinesin-2. Thus, KIF1A spends the majority of its hydrolysis cycle in a one-head-bound state. Both the ADP off-rate and the ATP on-rate at physiological ATP concentration were fast, eliminating these steps as possible rate-limiting transitions. Based on the measured run length and the relatively slow off-rate in ADP, we conclude that attachment of the tethered head is the rate-limiting transition in the KIF1A stepping cycle. Thus, KIF1A's activity can be explained by a fast rear-head detachment rate, a rate-limiting step of tethered-head attachment that follows ATP hydrolysis, and a relatively strong electrostatic interaction with the microtubule in the weakly bound post-hydrolysis state.

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles

Jiayan Guo
Dec 1, 2020; 61:1764-1775
Research Articles

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

Astrid M. Moerman
Dec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974
Research Articles

Carlota Oleaga
Nov 17, 2020; 0:jlr.RA120000964v1-jlr.RA120000964
Research Articles

Jenny E. Kanter
Dec 8, 2020; 0:jlr.ILR120001217v1-jlr.ILR120001217
Images in Lipid Research

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

In SAS Life Science Analytics Framework 4.6, group membership removal fails with an exception if a user is set as assignee, a candidate, or a notification recipient in a user task for a Process Flow . The Process