Visual Abstract

What our incident responders know from five years of fighting an octopus

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.

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.

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

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

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and the enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (Lipin^NLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic but not nuclear gene regulatory activity of Lipin is essential for survival. Notably, adult Lipin^NLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were misregulated in Lipin^NLS flies. Altogether, our data suggest that the nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal Cell Carcinoma (ccRCC), we interrogated the immune infiltrate in patient-matched ccRCC tumor samples, benign normal adjacent tissue (NAT) and peripheral blood mononuclear cells (PBMCs isolated from whole blood, focusing our attention on the myeloid cell infiltrate. Using flow cytometric, MS, and ExCYT analysis, we discovered unique myeloid populations in PBMCs across patient samples. Furthermore, normal adjacent tissues and ccRCC tissues contained numerous myeloid populations with a unique signature for both tissues. Enrichment of the immune cell (CD45⁺) fraction and subsequent gene expression analysis revealed a number of myeloid-related genes that were differentially expressed. These data provide evidence, for the first time, of an immunosuppressive and pro-tumorigenic role of myeloid cells in early, clinically localized ccRCC. The identification of a number of immune proteins for therapeutic targeting provides a rationale for investigation into the potential efficacy of earlier intervention with single-agent or combination immunotherapy for ccRCC.

Nuclear Disarmament and the Protection of Cultural Heritage Research paper sysadmin 6 October 2017

States possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear-weapons doctrines and policies.

Summary

• Renewed risk assessments for nuclear weapons and policies are taking place around the world in light of nuclear modernization and the changing geostrategic environment that is making the use of nuclear weapons more likely. As such the humanitarian impacts of nuclear weapons and tests have received increased attention. However, the effect on cultural heritage has so far been neglected.
• The potential for armed conflict to destroy cultural heritage has been recognized in international law since 1954. There is significant evidence on the impact of nuclear weapons on cultural heritage including the consequences of their use in Hiroshima and Nagasaki and the effect of nuclear-testing programmes in places of cultural significance since 1945. States that possess nuclear weapons have increased liabilities and responsibilities to protect cultural heritage and cultural rights. The need to protect cultural heritage should strengthen the case for reducing and eliminating nuclear weapons.
• Failure to take into account the protection of heritage in the development of nuclear weapons policies – including disarmament, non-proliferation and arms-control negotiations – significantly undermines states’ existing commitments to protecting heritage threatened by conflict.
• Risk assessments of the impact of nuclear weapons on cultural heritage and important cultural artefacts – and methods of preventing such catastrophic damage – should be part of protecting cultural heritage in every country and the subject of informed public debate. A new body of knowledge on the full range of nuclear weapons impacts would introduce a fresh perspective to inform decision-makers, international organizations and the public in thinking about nuclear weapons policies and practices.
• Risk and resilience frameworks, which provide sets of solutions for risk assessments, would allow assessments of nuclear weapons threats to heritage and highlight vulnerabilities that need to be addressed. Such frameworks would provide a basis for policymakers to identify the world’s cultural heritage most at risk and help develop mitigation strategies to ensure that it is protected. In particular, states possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear weapons doctrines and policies, as a contribution to transparency and confidence-building, and as a responsibility to the world’s shared heritage. International organizations, such as the UN Educational, Scientific, and Cultural Organization (UNESCO), have a role to play in bridging security perspectives with protecting cultural heritage.

Moving Energy Initiative Learning Briefs Research paper sysadmin 29 March 2019

Drawing on experiences from Phase II of the MEI in Burkina Faso, Kenya and Jordan, these learning briefs highlight MEI’s approach to innovation, engagement with the private-sector and host communities, and gender-sensitive energy projects. The four learning papers are intended for practitioners and policymakers working in the humanitarian sector and host-country governments.

Findings from Phase I of the Moving Energy Initiative (MEI) in 2015, published in the Chatham House research paper Heat, Light and Power for Refugees: Saving Lives, Reducing Costs, highlight the negative impacts of limited sustainable energy provision on the security of displaced populations. The paper also identified some of the challenges for energy programmes in this sector, such as the lack of robust data on energy access and the priorities of refugee populations.

In Phase II of the MEI, Practical Action led detailed research into the energy needs of refugees in Burkina Faso and Kenya. Chatham House analysed data on global refugee energy use in displacement contexts and produced an interactive map. Energy 4 Impact explored sustainable funding options, private-sector contract models and non-wood cooking concessions. The market development and low-carbon energy initiatives in Burkina Faso, Jordan and Kenya were managed by Practical Action and Energy 4 Impact, with the support of local partners. These partners represented the MEI at multiple conferences and events to share findings and advocate for the inclusion of displaced people in the sustainable energy agenda.

Drawing on experiences from Phase II of the MEI in Burkina Faso, Kenya and Jordan, these learning briefs highlight MEI’s approach to innovation, engagement with the private-sector and host communities, and gender-sensitive energy projects. The four learning papers are intended for practitioners and policymakers working in the humanitarian sector and host-country governments.

Mine Action in Angola: Clearing the Legacies of Conflict to Harness the Potential of Peace Other resource sysadmin 14 June 2019

This publication draws on and updates the briefing note published following a meeting of the All- Party Parliamentary Group (APPG) on Angola on 26 April 2017. It also incorporates insights from a Chatham House Africa Programme conference session on the legacies of the Angolan Civil War, held on 23 March 2018; and draws on the Africa Programme’s research into conservation-driven development models in Southern Africa.

Almost two decades after the end of its civil war, Angola remains one of the most heavily landmine-contaminated countries in the world. The Angolan government has committed to clearing its landmines by 2025, and there is constructive collaboration between the government and mine clearing agencies in this endeavour, but the target will be achievable only if a decline in funding from international donors is reversed. International funding for mine clearance in Angola fell by more than 80 per cent between 2005 and 2017, and this sharp drop in external support has compounded the impact on domestic funding for national clearance efforts as a result of the downturn in prices for Angola’s main export commodities.

The national mine action agency, the Comissão Nacional Intersectorial de Desminagem e Assistência Humanitária (CNIDAH), is supported by the Mines Advisory Group (MAG), Norwegian People’s Aid (NPA) and the HALO Trust. By 2017, 15 years after the end of the civil war, these organizations had collectively helped clear 56 per cent of known landmine-contaminated land. State-led demining has focused principally on clearing areas designated for infrastructure projects. Now, it is critical that humanitarian demining in largely agricultural and conservation areas is prioritized to bring to an end the daily threat to Angola’s rural poor – as well as to the country’s livestock and wildlife – of injury or death as a result of landmine accidents.

Angola has some of the world’s most important remaining wilderness, including the tributary system for the unique Okavango Delta, and the country has the potential to host one of the most diverse wildlife populations on the continent. However, the presence of landmines and other remnants of the civil war render large areas of the country unsafe both for wildlife and for the local people, whose ability to derive a sustainable livelihood from their natural environment is fundamental to its protection.

Wildlife and tourism provide important economic opportunities for diversification beyond an oil-dominated economy. Critically, Angola’s economic diversification and development objectives can only be achieved if the landmines that prohibit access to land for agriculture, mining, tourism and wildlife are cleared.

There are economic opportunities for released land in the most heavily mined provinces of Cuando Cubango and Moxico. Already, some new funding for mine action in Angola, if upscaled or matched by international donors, could be transformative for its people, and for the conservation of the region’s vital biodiversity.

A new nuclear order 7 February 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 26 January 2023 Chatham House and Online

In conversation with Rafael Mariano Grossi.

For more than half a century, the global nuclear non-proliferation framework has supported international security and facilitated the expansion of the many peaceful applications of nuclear science and technology. 

What is happening today in Ukraine, Iran and North Korea, not only challenges the way we deal with the existential threat of nuclear weapons, but also the impact it could have on addressing another existential threat – climate change.

Russia’s invasion of Ukraine is the biggest test to global resolve both in avoiding nuclear conflict and in ensuring the safety of one of the biggest nuclear power programmes in Europe.

Rafael Mariano Grossi of the International Atomic Energy Agency discusses key questions on global nuclear cooperation including:

• The impact of the war in Ukraine and issues with Iran and North Korea on countries’ risk assessment with regards to nuclear non-proliferation.

• What the IAEA’s on-the-ground presence and the director general’s missions to Ukraine, particularly the Zaporizhzhia Nuclear Power Plant, tells us about what is necessary – now and in the long term – to ensure the safety and security of nuclear material under all circumstances.

• The role of ensuring nuclear energy can play its vital part in mitigating climate change now and in the future.

As with all member events, questions from the audience drive the conversation.

Read the transcript.

From Iraq to Ukraine: What did governments learn? 20 March 2023 — 12:00PM TO 1:00PM Anonymous (not verified) 6 March 2023 Chatham House and Online

What were the main lessons for today’s conflicts from the way in which the war in Iraq played out?

This March marks the 20th anniversary of the US and UK-led invasion of Iraq to oust Saddam Hussein. Based primarily on unfounded fears Iraq’s WMD (weapons of mass destruction) capability was buidling up in the absence of UN inspection and constraints on the IAEA (International Atomic Energy Agency) safeguards, the decision to go to war has reverberated throughout the Middle East, the intelligence communities, and Western political decision-making ever since.

In the 2002–03 period when UN inspectors were allowed back into Iraq, Hans Blix, chairman of UNMOVIC (UN Monitoring, Verification and Inspection Commission) and Mohamed ElBaradei, director general of the IAEA, were at the centre of a storm in which they were put under huge pressure to agree with the US/UK narrative on the ‘missing’ WMD.

Their problem was that the evidence they were uncovering did not support the claims, but the war went ahead – and Saddam was overthrown – despite these UN findings.

Much has changed since 2003. As the geopolitical landscape has shifted, so have geopolitics and capabilities. Today’s Russia’s war against Ukraine which includes WMD threats, cyberattacks, and an assertive disinformation campaign has opened up new ways of thinking about communicating information from open source and government intelligence analysis.

This panel explores the experiences of people involved with decision-making at the UN and in the UK in 2003 and how things have changed today.

• What were the lessons from the way in which the war in Iraq played out?
• How has that influenced the way in which NATO has responded to Russia’s wars against Ukraine?
• How should information be communicated within governments and to the public?
• How to deal with disinformation campaigns in the days of open source information and social media?

As with all member events, questions from the audience drive the conversation.

Bispecific antibodies (bsAbs) are engineered to target 2 different epitopes simultaneously. About 75% of the 16 clinically approved bsAbs have entered the clinic internationally since 2022. Hence, research on biomedical imaging of various radiolabeled bsAb scaffolds may serve to improve patient selection for bsAb therapy. Here, we provide a comprehensive overview of recent advances in radiolabeled bsAbs for imaging via PET or SPECT. We compare direct targeting and pretargeting approaches in preclinical and clinical studies in oncologic research. Furthermore, we show preclinical applications of imaging bsAbs in neurodegenerative diseases. Finally, we offer perspectives on the future directions of imaging bsAbs based on their challenges and opportunities.

Earlier this month, the United States and the Republic of Korea reached an agreement on greater cooperation on civil nuclear energy projects, the U.S. Department of Energy said this week.

A grassroots online movement has helped shift the way scientists think about asexuality. But much is still unknown.

NEW YORK, Nov. 1, 2024 — NANO Nuclear Energy Inc. has announced the October 29, 2024 closing of the sale of an additional 317,646 shares of its common stock at […]

The post NANO Nuclear Energy Raises Over $40M from Recent Underwritten Follow-On Offering appeared first on HPCwire.

A simple 8-minute exercise can free up your brain and make you more efficient under stress.

“Being on a voyage forces you to unplug,” says TED Fellow and third-generation captain Lehua Kamalu. Sharing ancient knowledge from traditional Hawaiian ocean voyaging, she reflects on the transformational power of seafaring journeys — and what it means to travel mindfully, no matter where you are.

The rapid shift to tech-driven, remote learning this spring has infused more technology into K-12 education, but AI tools still remain on the fringe.

The Chan-Zuckerberg Initiative and other funders are supporting Rhode Island's efforts to define and research personalized learning in traditional public schools.

The Rhode Island Department of Education and the nonprofit Learning Accelerator are teaming to develop a strategic plan and a communications strategy aimed at expanding blended learning.

Lisa Duty of The Learning Accelerator, a Rhode Island Department of Education (RIDE) and Highlander Institute funding partner, outlines the Rhode Islands's commitment to a blended learning future. She describes how the state is developing its new five-year strategic plan that's engaging RIDE's Ambas

In this fourth installment on the growth in dual-language learning, the director of dual-language education in Portland, Ore., says schools must have a clear reason for why they are offering dual-language instruction.

Chief technology officers are facing an unprecedented test of digital preparedness due to the coronavirus pandemic, struggling with shortfalls of available learning devices and huge Wi-Fi access challenges.

Several states already offer a state-sanctioned LMS option to their schools, with some encouraging results in their efforts to cut costs and improve technical capabilities.

More schools are trying to shift to some in-person learning for students, but many teachers don’t believe it’s safe.

The mix of hybrid learning approaches is dizzying, but schools are learning valuable lessons about what is worth replicating.

Researchers interviewed scores of principals in 19 states on how they’ve coped and the lessons they’re taking away from the pandemic’s disruption.

Chief technology officers are facing an unprecedented test of digital preparedness due to the coronavirus pandemic, struggling with shortfalls of available learning devices and huge Wi-Fi access challenges.

Too often, teachers are asked to use SEL practices without enough training and ongoing support, tanking the effectiveness.

School districts are competing against each other for purchases of digital devices as remote learning expands to schools across the country.

A strategy that gives more learning time in small groups of students without taking time away from core instruction.

Watch a discussion between three educators who ran for their state legislatures about their experiences on the campaign trail.

In five northern U.S. states, black students comprise more than a fifth of ELL enrollment.

The rocky shift to remote learning has exacerbated inequities for the nation's 5 million English-learners. An army of multilingual liaisons work round the clock to plug widening gaps.