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{alpha}2-Macroglobulin-like protein 1 can conȷugate and inhibit proteases through their hydroxyl groups, because of an enhanced reactivity of its thiol ester [Protein Structure and Folding]

By www.jbc.org
Published On :: 2020-12-04T00:06:05-08:00

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.


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Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site [Protein Structure and Folding]

By www.jbc.org
Published On :: 2020-12-11T00:06:20-08:00

Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response.


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Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing [Molecular Bases of Disease]

By www.jbc.org
Published On :: 2020-12-11T00:06:20-08:00

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.


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Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator [Gene Regulation]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.


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Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins [Molecular Biophysics]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.


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Evolving the naturally compromised chorismate mutase from Mycobacterium tuberculosis to top performance [Protein Structure and Folding]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity.


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Why the Corrupt President of Belarus Deserves Sanctions

By www.chathamhouse.org
Published On :: Mon, 10 Aug 2020 19:31:05 +0000

10 August 2020

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Sanctions would be a wake-up call for those who oversaw this brutal and dirty election campaign.

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People protest at a rally of solidarity with political prisoners in Belarus. Photo by Beata Zawrzel/NurPhoto via Getty Images.

Belarusian president Aliaksandr Lukashenka deserves sanctions. This election campaign in Belarus, which culminated in a vote on Sunday is the most brutal and dirty in its history. But, so far, the EU, the UK and the US have only issued familiar-sounding and futile appeals to the Belarusian authorities condemning their actions. Not imposing sanctions is a de facto licence to continue with repression.

Despite all this, the West is unlikely to impose significant sanctions afterwards. There are several questionable reasons for this. First, Western policymakers fear sanctions against Lukashenko will make him more likely to genuflect to Russia. However, relations with Russia have already deteriorated as Belarus accuses Russia of trying to interfere with its domestic affairs.

Sanctions serve as a wake-up call. The Belarusian authorities then might seek - once again - to repair relations with the West and reduce repression for greater assistance in any direct confrontation with Russia.

Second, the West is reluctant to implement sanctions because it has already invested somewhat in warming relations with Belarusian authorities. Punishing Lukashenko could mean burying the - admittedly modest - achievements of a Belarus-West dialogue that started in 2014 after the conflict in Ukraine began.

Even US secretary of state Mike Pompeo met with Lukashenko in Minsk this year, after which Belarus replaced a small but symbolic amount of Russian oil for American. All the same, the West has its conscience to answer to if dialogue is won but repressions continue.

The third reason why the West may not resort to targeted economic sanctions and visa restrictions is a latent concern whether such measures have any effect on democratization processes at all. They may be appropriate punishment, but there is little evidence they ever change the nature of a regime.

According to this logic, if the West imposes sanctions, the Belarusian authorities will continue to crack down with repression because they will have nothing to lose. That said, in previous years, the Belarusian authorities have released political prisoners in response to sticks and carrots brandished by the West. If Belarusian political prisoners did not have a price tag, the authorities would most likely keep everyone in jail.

To be fair, there are reasonable arguments in favour of and against sanctions. But if the West fails to impose them - be it through lack of political will or out of genuine concern about their effectiveness - at least it should focus on helping ordinary Belarusians withstand Lukashenko’s repressions. After the vote, arrested and jailed Belarusian citizens might lack money for lawyers and arbitrarily imposed fines.

If repression spreads further, independent media and human rights organizations will need funds to keep their structures running in the heat of the crackdown. Many entrepreneurs might lose their companies for openly supporting free elections. Thus, if the West will not sanction Lukashenko, it should at least show solidarity with these Belarusians in peril.

This article was originally published in The Telegraph.


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Balancing Demands on the World’s Forests

By www.chathamhouse.org
Published On :: Wed, 19 Aug 2020 14:58:15 +0000

19 August 2020

Alison Hoare

Senior Research Fellow, Energy, Environment and Resources Programme
Finding equitable solutions to balancing the myriad demands on forests requires meaningful engagement with local actors, writes Alison Hoare.

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An aerial view of forest area in the Ternei District in Primorye Territory in the far east of Russia located along the country's border with Asia. Photo: Getty Images.

Healthy forests have always been a vital resource for the communities living in, and around, them. Offering food, clothing, fuel and medicine, forests also stabilize the water table and guard against soil erosion. Timber from forests also serves local, national and international markets, generates jobs and is an important revenue stream for many governments around the world.

Forests have also increasingly been tasked with combatting the double threats of climate change and biodiversity loss. Furthermore, the COVID-19 pandemic has put a spotlight on the role of forests in preventing diseases which has further added to the need to preserve the world’s forest area.

However, at the same time, pressure on forest lands is increasing, particularly for agriculture and also for mining, infrastructure and urbanization. But, with myriad demands placed on forests, and impacts that transcend political boundaries, achieving a balance requires a reckoning of local and global priorities.

International forest initiatives until now have, quite rationally, prioritized a globalized conceptualization of forests – privileging their place in global supply chains and global crises. International regulations around timber, for instance, are primarily aimed at securing a long-term source of timber by reducing illegality in the system while national plans under the Paris Agreement focus on forests primarily as a global carbon sink.

Within these initiatives, local impacts are often dealt with as flanking measures. Community benefit-sharing agreements, compensation schemes and incentive programmes are aimed at mitigating impacts and modifying behaviour at the local level so that these align with international goals.

Meanwhile, and despite intense international attention, it has been found that globally natural forest cover declined in the six years since the New York Declaration of Forests set a goal to halve deforestation. Greenhouse gas emissions have continued to rise and, although there have been successes, illegal timber continues to be traded internationally.

To halt these trends, it is important to reflect on the demands being placed on forests and to achieve a better balance between them. But this will require radical change. That’s why, in July, Chatham House convened an online Global Forum on Forest Governance at which these issues were explored.

One issue that was discussed is why it remains vital to listen to, and learn from, a wide range of voices. Single perspectives fail to acknowledge or respond to the full range of pressures exerted on forests therefore it is important to have a range of perspectives including those from the global north and south, economists and agronomists, social scientists and climate scientists.

But beyond the research community, all those who have a stake in forests must be included in the discussion too: women and men, young and old people, those living in urban and rural areas as well as people from the government and private sectors.

This lesson has often been repeated but rarely enacted perhaps because it is not easy to do and takes time. Nevertheless, broadening participation can help deliver the deep-rooted changes that are needed to the way forests are governed and managed.

Considerable evidence exists to show that improvements to governance can facilitate a more equitable approach to forests that better balances the needs and priorities of these different groups. Legal and institutional reforms, for example, that are sensitive to the needs of local populations have precipitated change. Successes in improving transparency have also been a key factor in holding both the private sector and governments to account.

Thus, creating radical change may not mean brand new ideas. Lessons can be learnt from the successes and failures of the past. It will be important that, as new and increasing demands are placed on already overburdened forests, these lessons are not forgotten and previous mistakes are not repeated.

What will matter over the next few years will be which ideas are acted upon and who gets to decide. As more than 100 countries announce plans to increase the ambition of their nationally determined contributions on emission reductions, and as the EU and the US move forward with plans to legislate deforestation out of commodity supply chains, a clear message that has emerged is that local actors need to be in the driving seat. This needs to go beyond listening and consultation to meaningful engagement that gives due weight to local priorities, perspectives and experience.


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US-Cuba Sanctions: Are They Working Yet?

By www.chathamhouse.org
Published On :: Thu, 20 Aug 2020 11:48:37 +0000

20 August 2020

Dr Christopher Sabatini

Senior Research Fellow for Latin America, US and the Americas Programme
The recent spate of sanctions limiting US travel to Cuba announced by the White House and the news that the Cuban regime has re-opened US dollar stores have sharpened the question: do sanctions work and when? Central to that question is how would they work?

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A taxi driver wears a face mask while driving tourists around Havana on 19 March 2020. Photo: Getty Images.

It’s easy to take a look at the array of economic and diplomatic punitive policies that the sanctions-happy Trump administration has slapped on individuals and countries from Argentina to Iran and conclude that they have failed to achieve their objectives. With US oil sanctions on Venezuela, trade sanctions on select Argentine, Brazilian and Canadian exports and the tightening of the US embargo on Cuba, sanctions have become a go-to tool of the current administration.

Have they worked so far? Some have. Some haven’t. All of this leads to a legitimate question: when do they? The most extreme example, the US embargo on Cuba – first imposed by executive order under the Trading with the Enemy Act in 1961 and then codified into law by the Cuba Democracy Act (1992) and Libertad Act (1996) passed by Congress – has failed miserably, but remains an article of faith among its advocates, the bulk of them in southern Florida. The 1992 Democracy Act and 1996 Libertad Act have failed to produce either democracy or liberty in Cuba… yet their potential efficacy persists in the collective imaginations of their supporters. Why?

Conditions on Cuba

Any policy needs to have an explicit goal and with it an implicit or explicit theory of change. Whether it’s advertising that smoking kills on cigarette packages or trade negotiations, these efforts have behind them an explicit idea of the change they seek to foster and the causal relationships to achieve them. These are testable and, in theory, subject to course correction if they are not meeting their intended goals. Has advertising reduced the incidence of smoking?  Are workers better paid and receiving better health benefits and labour protections under the trade agreement several years on?

None of those has applied on the US’s embargo on Cuba. First, the policy goals have changed. In some cases, it has been stated that the limitations on US commerce and travel to the island is to reduce the regime’s international support for autocratic regimes. But Cuba’s to-the-death support of the Nicolas Maduro government in Venezuela has demonstrated this isn’t working. 

Arguably it has had the opposite effect: by impoverishing the state-centered Cuban economy, the embargo has made the regime more dependent on the decreasing oil that Venezuela supplies the island nation. In other cases, the stated goal has been regime change as the titles of the 1992 and 1996 act titles reveal.

The latter even lays out a set of conditions that must be present in Cuba before the Congress can lift the trade and diplomatic isolation the US has imposed on the island unilaterally. Those include the release of political prisoners, the absence of any Castro family members from decision-making, and credible steps toward free and fair elections. 24 years after the passage of the Libertad Act, Cuba is no closer to achieving not just one but any of those goals despite the putative incentive of a full and complete lifting of the embargo.   

The question here is the implicit theory of change for the embargo. Here, embargo supporters have never been clear about this link. First, there is the implied hope that sanctions will impose such costs and suffering on the general population that the masses will rise up and shake off autocratic rule of their overlords.

There are several problems with this. One is that general sanctions that reduce access to foodstuffs and finances – as has been the case in the US embargo on Cuba and sanctions on Venezuela – lowers the incentives for protest. It concentrates the government’s political and economic control over the population rather than weakening it. More, people who are hungry living under a repressive government simply aren’t that likely to rise up; they are often more concerned with the day-to-day struggles of getting by.

Second, there is a naïve notion that either those in power or those around them will see the light of day and decide to step down. Promoters of sanctions often have a cold-eyed reality of the nature of evil of autocratic governments. So why do they believe in some hidden decency among its inner circles? In truth, the purveyors of this view deny the basic and laudable basis for their hatred of autocrats: their bottomless cruelty and disregard for their own people. 

Do sanctions work? 

There is also a growing body of research on the efficacy of sanctions. Comparative research has revealed a number of conclusions, none of which appear to have been considered by current policymakers in the White House or State Department.  

The first of these is that sanctions work when they are implemented broadly by a wide coalition of governments. Most of the sanctions that have succeeded in their intentions have been along those lines including the UN sanctions on Iran to push the country to a nuclear deal.  

The second is that the goals of sanctions should be narrow and clearly defined. Successful cases, as Daniel Drezner who wrote a book on the topic has detailed, have been tied to specific goals. Regime change is not one of those. It is too broad and amorphous – though as I say above also unrealistic in its logic between intended effect and the targeted individual. 

A third element of successful sanctions is keeping them flexible and credible. As detailed in a Council on Foreign Relations backgrounder ‘the target must believe that sanctions will be increased or reduced based on its behaviour.’ 

That’s never been the case with Cuba sanctions under the Democracy or Libertad acts. Instead, sanctions relief is presented as a binary choice: democracy or nothing. There are no provisions for intermediate steps that could potentially incentivize changes of behaviour toward loosening state control and reducing human rights abuses.  

The recent tightening of the US embargo that included restrictions on US travel to Cuba and financial transactions under the Trump White House has been disconnected from any specific policy changes in the island. In this case, human rights conditions that the changes were linked to or intended to punish had not taken a dramatic turn for the worse. They were instead intended to simply ratchet up pressure for an embargo which advocates felt was too leaky and hope for a collapse that would weaken the Maduro regime.

That is precisely the problem for many of the most strident advocates of the US-Cuba embargo: the policy has become the objective, divorced from on-the-ground realities and incentives to move them forward.  There is the legitimate concern that the sanctions hurt the very people that the policy claims to defend. They also serve as a rallying point for the Castro regime and a way to cover up for its own economic failures.  But the most damning indictment of the embargo is that in its almost 50-year history it has failed to achieve its objectives.

If the matter is the efficacy of sanctions, then the US embargo on Cuba does not meet the test. It’s not limited to Cuba. None of the cases of regime change that many of the embargo advocates love to cite, communist Eastern Europe, the Soviet Union and South Africa had embargos as tight or isolating as those imposed on Cuba for nearly half a century. There’s a reason for that. It’s basic logic.

A version of this article will also appear in Spanish in the journal Foro Cubano in September.  


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Lessons from COVID-19: A Catalyst for Improving Sanctions?

By www.chathamhouse.org
Published On :: Tue, 25 Aug 2020 23:00:00 +0000

26 August 2020

Emanuela-Chiara Gillard

Associate Fellow, International Law Programme
As the COVID-19 pandemic continues, efforts by states and humanitarian actors to stop its spread and to treat the sick are being hindered by existing sanctions and counterterrorism measures.

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Syrians walk past a mural painted as part of an awareness campaign by UNICEF and WHO, bearing instructions on protection from COVID-19, in the Kurdish-majority city of Qamishli, Syria, on 16 August 2020. Photo by Delil Souleiman/AFP via Getty Images.

If sanctions imposed by the UN Security Council, the EU, or states unilaterally, are not sufficiently targeted, and do not include adequate safeguards for humanitarian action, they can adversely affect the very populations for whose well-being they were imposed in the first place.  This is not a new concern, but one brought starkly to the fore by their impact on responses to COVID-19.

The detrimental impact of sanctions, which can prevent the supply of medical or personal protective equipment (PPE), or the provision of technical support or training to local health authorities is evident. Sanctions can also affect remote learning if support cannot be provided to local education authorities, export licences cannot be obtained for the necessary equipment and software, or if the companies providing reliable internet coverage are designated under the sanctions.

A comparison of US and EU sanctions on Syria reveals key challenges, but also opportunities for improving current arrangements for the imposition and implementation of sanctions so as to minimize adverse consequences in Syria and more generally.

The US has imposed broad sanctions, such as restrictions on the provision of funds, goods or services – even charitable contributions – to the Syrian government, including the health and education ministries, now playing a central role in the COVID-19 response.

UN agencies are exempted from these restrictions. A general license authorizes NGOs to conduct activities to meet basic needs, but it excludes those involving the government. So NGOs wishing to provide medical devices, PPE, training or other support to ministry of health staff have to apply for a specific licence.

But procedures for applying for licences are complicated, and the approval process notoriously slow.  No accommodation has been made to facilitate the COVID-19 response: no interpretative guidance – that would be valuable for all NGOs – has been issued, and no procedures established for reviewing applications more quickly.  There is no statement of policy indicating the circumstances under which specific licences might be granted.

Transactions with designated entities other than the government, such as internet providers whose services are necessary for remote learning, remain prohibited, and regulations expressly preclude applying for specific licences.

US sanctions frequently have a broad scope, both in direct and indirect application.  NGOs registered in the US, and staff who are US nationals, are directly bound by them, and grant agreements between the US government and non-US NGOs require the latter to comply with US sanctions.

This leaves the non-US NGOs in a Catch-22 situation – as they are not ‘US persons’ they cannot apply for specific licenses, but if they operate without such licences they may be violating grant requirements. This lack of clarity contributes to banks’ unwillingness to provide services, and may lead NGOs to curtail their activities.  This situation is regrettable in Syria, where the US is the first donor to humanitarian action, and also arises in other contexts where the US has imposed similar sanctions.

The EU’s sanctions for Syria are far more targeted. Of relevance to the COVID-19 response, they do not include prohibitions on the provision of support to the government that could impede assistance in the medical field.  There are, however, restrictions on the provision of certain types of PPE or substances used for disinfection, and also on transactions with designated telecommunications providers that affect continuity of education during lockdowns.  Although not prohibited, these activities must be authorized by member states’ competent authorities. Similar concerns arise about the complexity and delays of the processes.

The EU sanctions framework is complex, so the recent European Commission Guidance Note on Syria providing official clarification of how it applies to humanitarian action is welcome.  Although the note only explains the existing rules rather than amending them to facilitate the COVID-19 response, it does include a number of important elements relevant not just to Syria, but to the interplay between sanctions and humanitarian action more broadly.

First, it notes that ‘in accordance with International Humanitarian Law where no other option is available, the provision of humanitarian aid should not be prevented by EU restrictive measures’.  This recognizes that humanitarian assistance takes priority over any inconsistent restrictions in sanctions, and it also applies both to UN sanctions and unilateral measures. It is a starting premise that is frequently overlooked in discussions of whether sanctions should include exceptions for humanitarian action.  Its reaffirmation is timely, and it must guide states in drawing up future sanctions.

Second, the note states that sanctions do not require the screening of final beneficiaries of humanitarian programmes.  This means that once someone has been identified as an individual in need on the basis of humanitarian principles, no further screening is required.  This is extremely important to COVID-19 responses as it reflects a foundational principle of IHL that, to the fullest extent practicable, everyone is entitled to the medical care required by their condition without distinction.

Third, while responsibility for the implementation of sanctions, including the granting of authorizations, lies with member states, the note nudges them to adopt a number of measures to expedite and streamline such processes.  These include the suggestion that states could issue a single authorization for the provision of humanitarian aid in response to the pandemic.

The European Commission is to be commended for this initiative, which should be replicated for other contexts where the COVID-19 response may be undermined by sanctions.  These include Gaza, where it would be important to highlight that the designation of Hamas under EU counterterrorism sanctions must not prevent the provision of assistance to relevant ministries.

Failing to draw a distinction between the designated political party and the structures of civil administration risks turning targeted financial sanctions into measures akin to comprehensive sanctions.

The pandemic should serve as a catalyst for improving the system for the adoption and implementation of sanctions by the UN, the EU and individual states, including the UK as it elaborates its sanctions policy post-Brexit. The principles are clear: without prejudicing the aims for which sanctions have been imposed, humanitarian needs must always be prioritized, and met.


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Formal Representation for Young People Enhances Politics for All

By www.chathamhouse.org
Published On :: Thu, 10 Sep 2020 11:38:51 +0000

10 September 2020

Ben Horton

Communications Manager, Communications and Publishing

Michel Alimasi

Member, Common Futures Conversations, Italy

Gift Jedida

Member, Common Futures Conversations, Kenya

Sanne Thijssen

Member, Common Futures Conversations, Netherlands

Mondher Tounsi

Member, Common Futures Conversations, Tunisia
Despite grassroots associations, community organizing and online groups offering pathways for political engagement, the room for youth representation in international politics remains narrow, with many young people still left feeling they are passive participants in policymaking.

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Youth protests at Parliament square against a new exam rating system which has been introduced in British education system - London, England on August 16, 2020. Photo by Dominika Zarzycka/NurPhoto via Getty Images.

According to UN Youth, people aged 15-24 make up one-sixth of the world’s population but, in roughly one-third of countries, the eligibility for parliamentarians begins at 25 years old and only 1.6% of parliamentarians are in their twenties. Young people are largely being excluded and overlooked, both as political candidates and even as participants in political processes, giving them limited political control over their own futures. 

If politics continues to be regarded as a space for older, more politically experienced individuals from particular backgrounds, young people will continue to be left systematically marginalized, and overall disengagement with politics within societies will continue to grow. Global leaders may increasingly point out the importance of youth representation in national and international fora, but the reality is their real policymaking impact still comes mainly from self-organized and informal activities.

And yet, despite this continued exclusion, huge numbers of young people are interested in political and civic engagement, and they have been driven to create new spaces. Youth networks, movements, and constituencies have emerged which provide the opportunity for younger voices to express political stances, and thus enhance the diversity and inclusivity of political debate. 

From the global Extinction Rebellion protests, to the student-led Rhodes Must Fall movement in South Africa and the UK, there are numerous examples of the power of informal youth networks and movements pushing for change. In certain cases, such as Sudan’s political revolution in 2019, we can see how direct action by young people creates major impact, but unfortunately these successes are few as most informal initiatives remain overlooked and undervalued. 

Putting youth representation into government

Creating diverse representation requires the linking of vital informal networks to formal political processes. In response to a recent Common Futures Conversations challenge, one mechanism with the potential to achieve this aim that emerged is creating dedicated youth representatives within government departments, so that qualified young people with relevant expertise are formally appointed to act as the link between government and informal youth movements. 

These individuals should be hired as employees rather than volunteers and take up the responsibilities of a government employee, supported by a large network of youth-led movements and initiatives as well as a smaller, voluntary advisory board of young people. 

This network then acts as a sounding board for the representative, gathering the opinions in their local communities and bringing forward crucial concerns so the youth representatives can confidently feed into policymaking processes with a clear sense of the substance of youth opinion. Alongside the network, a voluntary board of young people could provide additional support to the representatives when required to consult a broader range of youth organizations.

Both in the youth network and the board, a key priority is to involve different movements and initiatives reflecting diversities such as geographic spread, people who are marginalized due to ethnicity, gender or sexuality, educational and professional backgrounds, and other factors. 

Implementing such a structure would ensure more diversity in youth representation, something which is missing in many existing youth participation and formal political structures. Representation needs to move away from only highly-educated youth living in cities to ensure more influence for those young people usually left on the sidelines. 

Youth involvement in politics leads to better civic engagement overall. It improves the influence and access of young people, and supports governments becoming more inclusive and responsive to the plurality of voices they are representing. It also has the potential of encouraging millions more people to become properly engaged with politics. 

In order to gain support from parliamentarians and policymakers, it is crucial to highlight these benefits and demonstrate how the support of young people helps shift the political landscape for the better. All the necessary parties already exist in most countries, so all that is required is to drive a collective initiative and for both governments and the youth to take responsibility for making it work.

As the former president of Ireland Mary Robinson said during a recent Chatham House Centenary event: ‘We need to make space for young people so we can hear their voices, their imagination, their commitment to question and speak truth to power. We need young people to feel that they are part of the solution.’ 

Building formal structures is a necessary step to achieving this vision, as it provides practical solutions to realize a more diverse, inclusive and meaningful participation of the youth in politics, and also creates more representative and responsive governments.


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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance [Immunology]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.


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Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting [Protein Synthesis and Degradation]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

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.


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Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells [Enzymology]

By www.jbc.org
Published On :: 2020-12-25T00:06:30-08:00

Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.


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Towards just transition in Africa: Green financing for urban energy solutions and job creation

By www.chathamhouse.org
Published On :: Wed, 18 May 2022 10:37:13 +0000

Towards just transition in Africa: Green financing for urban energy solutions and job creation 9 June 2022 — 7:30AM TO 11:00AM Anonymous (not verified) 18 May 2022 Nairobi and online

This event explores the major openings and potential impediments to the development of a just transition policy in Africa.

Global climate policies towards a ‘just transition’ under the Paris Agreement should also align with and support African states’ national sustainable development priorities. In particular, the need for decent and fair job creation and the establishment of sufficient, resilient and sustainable power supply, accessible to all, and efficient energy use.

Achieving green growth requires innovative and more accessible financing models, especially as wealthy nations’ financial pledges have fallen short. Ahead of the ‘African COP27’ set to take place in Egypt in November 2022, there is a need for transformational strategic thinking and context-specific action from African governments, civil society, businesses and financiers in their green financing demands and national implementation plans.

Sustainable urban energy solutions represent a critical zone of opportunity for the development of new and more reliable green finance pathways. Africa’s rapidly expanding cities present a significant economic opportunity and source of growth. However, urban centres are also where income and energy inequalities are at their starkest. The acceleration of sustainable energy generation and use could have a transformative impact on SMEs and livelihoods across value chains.

At this event, participants will discuss the major openings and potential impediments to the development of a credible ‘just transition’ policy in Africa towards net zero goals, with a particular focus on establishing and enhancing links between green financing innovation, employment creation, sustainable power supply and generation, and sustainable energy usage and consumption in an urban environment.

This event is held in partnership with the Pan African Climate Justice Alliance (PACJA). It is part of a series on Towards Just Transition: Connecting Green Financing and Sustainable Job Creation in Africa, supported by the Chatham House Sustainability Accelerator.

This event will be held in English and French with simultaneous interpretation.

[English] Agenda- Towards Just Transition in Africa (PDF)
[French] Agenda - Towards Just Transition in Africa (PDF)

 


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Enhancing the role of women in peacebuilding and politics in Ethiopia

By www.chathamhouse.org
Published On :: Thu, 16 Jun 2022 16:47:14 +0000

Enhancing the role of women in peacebuilding and politics in Ethiopia 29 June 2022 — 1:00PM TO 2:30PM Anonymous (not verified) 16 June 2022 Online

Panellists discuss the priorities for promoting the agency of women in politics and peacebuilding in Ethiopia and approaches for combatting gender-based discrimination and violence.

The war in northern Ethiopia and conflicts elsewhere have disproportionately affected women and girls – including through the infliction of physical and sexual violence, the heightened impacts of displacement and disruptions to education, and the co-option of women’s experiences in narratives by aggressors of conflict.

Hard-won political gains in women’s rights have been undermined and deep-rooted gender inequalities exacerbated. Despite this, women remain central actors in politics, as well as in conflict resolution and mediation efforts. However, more needs to be done to promote the security and inclusion of women in finding sustainable solutions for Ethiopia’s long-term recovery and to institutionalize reforms for gender equity and development.

At this public event, panellists will discuss the priorities for improving women’s participation and equality in public decision-making in Ethiopia and how to strengthen the implementation of legislation on women’s rights. They will also discuss what societal shifts and approaches are needed to combat gender-based discrimination and violence and to promote the agency of women in peacebuilding.

This webinar is part of a series of events and outputs on Ethiopia’s political transition.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.


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Towards just transition in Africa: Green financing for nature-based solutions and rural resilience

By www.chathamhouse.org
Published On :: Thu, 30 Jun 2022 10:52:13 +0000

Towards just transition in Africa: Green financing for nature-based solutions and rural resilience 21 July 2022 — 9:30AM TO 1:00PM Anonymous (not verified) 30 June 2022 Libreville and online

This hybrid event in Libreville explores just transition policy and green financing for nature-based solutions, with a particular focus on the integration of job creation priorities in conservation and rural resilience.

Global climate policies towards a ‘just transition’ under the Paris Agreement should align with and support African states’ national sustainable development priorities – in particular, the need for decent and fair job creation, as well as resilient and sustainable land, environment, and ecosystem management policies.

Achieving green growth requires innovative and more accessible financing models, especially as wealthy nations’ financial pledges have fallen short. Ahead of the ‘African COP27’ set to take place in Egypt in November 2022, there is a need for transformational strategic thinking and context-specific action from African governments, civil society, businesses and financiers, in their green financing demands and national implementation plans.

Preservation of biodiversity and nature is not only critical in the global fight against climate change but is also vital for conservation-based economic development. Natural capital stocks, such as terrestrial and marine ecosystems and biodiversity, produce benefits that support societal and individual well-being and economic prosperity, such as clean air, fresh water, regulation of water flows and pollination of crops – while also acting as important carbon sinks. Financing environmental protection must go beyond compensation and contribute to creating fair social and economic conditions for incentivizing conservation.

At this hybrid event in Libreville, participants will discuss green financing for nature-based solutions, particularly the integration of plans for job creation in conservation and rural resilience within just transition planning.

This event is part of a series on Towards Just Transition: Connecting Green Financing and Sustainable Job Creation in Africa, supported by the Chatham House Sustainability Accelerator.

This event will be held in French and English with simultaneous interpretation.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.

Green financing for nature-based solutions and rural resilience - English agenda (PDF)
Green financing for nature-based solutions and rural resilience - French agenda (PDF)


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Towards just transition in Africa: Continental coordination on green financing and job creation

By www.chathamhouse.org
Published On :: Thu, 08 Sep 2022 14:07:13 +0000

Towards just transition in Africa: Continental coordination on green financing and job creation 6 October 2022 — 7:00AM TO 3:30PM Anonymous (not verified) 8 September 2022 Addis Ababa and online

At this hybrid conference in Addis Ababa, speakers take stock of preparations ahead of the ‘African COP27’ in November and discuss the key priorities for streamlining continental cooperation on policy approaches to just transition.

At this hybrid conference in Addis Ababa, speakers will take stock of policy efforts and preparations ahead of the ‘African COP27’ in November and discuss the key priorities for streamlining continental cooperation on policy approaches to just transition.

Global climate policies towards a ‘just transition’ under the Paris Agreement should align with and support African states’ national sustainable development priorities – in particular, the need for decent and fair job creation, as well as resilient and sustainable land, environment and ecosystem management policies.

They must also be cognizant of African nations’ urgent requirements for sustainable and accessible energy to underpin economic development. Achieving green growth requires innovative and more accessible financing models, especially as wealthy nations’ financial pledges have fallen short. It also requires clarity and cooperation to unlock investment in both renewable and transitional energy.

African countries face collective climate and employment-related challenges. However, policymaking often remains regionally siloed according to differing political, energy sector and ecological realities. There is a need for transformational strategic thinking and context-specific action from African governments, civil society, businesses and financiers, in their green financing demands and national implementation plans.

At this hybrid conference in Addis Ababa, speakers will take stock of policy efforts and preparations ahead of the ‘African COP27’ in November and discuss the key priorities for streamlining continental cooperation on policy approaches to just transition, job creation and green financing.

This event is the third in a series on Towards just transition: Connecting green financing and sustainable job creation in Africa, supported by the Chatham House Sustainability Accelerator.

Agenda: Towards a just transition in Africa (English) (PDF)
Agenda: Towards a just transition in Africa (French) (PDF)


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Guidance and best practices for nuclear cardiology laboratories during the coronavirus disease 2019 (COVID-19) pandemic: An Information Statement from ASNC and SNMMI

By jnm.snmjournals.org
Published On :: 2020-05-15T05:25:22-07:00


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The added value of 18F-FDG PET/CT compared to 68Ga-PSMA PET/CT in patients with castration-resistant prostate cancer

By jnm.snmjournals.org
Published On :: 2021-04-23T13:46:28-07:00

Purpose: The 68Ga-PSMA PET/CT is a commonly used imaging modality in prostate cancers. However, few studies have compared the diagnostic efficiency between 68Ga-PSMA and 18F-FDG PET/CT and evaluated whether a heterogeneous metabolic phenotype (especially PSMA-FDG+ lesions) exists in patients with castration-resistant prostate cancer (CRPC). We determined the added value of 18F-FDG PET/CT compared to 68Ga-PSMA PET/CT in CRPC patients and identified CRPC patients who may benefit from additional 18F-FDG PET/CT. Methods: Data of 56 patients with CRPC who underwent both 68Ga-PSMA and 18F-FDG PET/CT from May 2018 to February 2021 were retrospectively analysed. Patients were classified into two groups with or without PSMA-FDG+ lesions. The differences in patient characteristics between the two groups and predictors of patients who having at least one PSMA-FDG+ lesion were analysed. Results: Although both the detection rate (75.0% vs. 51.8%, P = 0.004) and positive lesion number (135 vs. 95) of 68Ga-PSMA PET/CT were higher than 18F-FDG PET/CT, there were still 13/56 (23.2%) patients with at least one PSMA-FDG+ lesion. The prostate-specific antigen (PSA) and Gleason score were both higher in the patients with PSMA-FDG+ lesions than in those without PSMA-FDG+ lesions (P = 0.04 and P<0.001, respectively). Multivariate regression analysis showed that the Gleason score (≥8) and PSA (≥7.9 ng/mL) were associated with the detection rate of patients who had PSMA-FDG+ lesions (P = 0.01 and P = 0.04, respectively). The incidences of having PSMA-FDG+ lesions in low-probability (Gleason score<8 and PSA<7.9 ng/mL), medium-probability (Gleason score≥8 and PSA<7.9 ng/mL or Gleason score<8 and PSA≥7.9 ng/mL), and high-probability (Gleason score≥8 and PSA≥7.9 ng/mL) groups were 0%, 21.7%, and 61.5%, respectively (P<0.001). Conclusion: Gleason score and PSA are significant predictors for PSMA-FDG+ lesions, and CRPC patients with high Gleason score and PSA may benefit from additional 18F-FDG PET/CT.


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Impact of 18F-FDG PET/MRI on Therapeutic Management of Women with Newly Diagnosed Breast Cancer: Results from a Prospective Double-Center Trial

By jnm.snmjournals.org
Published On :: 2024-10-10T08:33:38-07:00

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[18F]F-AraG Uptake in Vertebral Bone Marrow May Predict Survival in Patients with Non-Small Cell Lung Cancer Treated with Anti-PD-(L)1 Immunotherapy

By jnm.snmjournals.org
Published On :: 2024-10-24T11:58:48-07:00

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Intraarterial Administration of Peptide Receptor Radionuclide Therapy in Patients with Advanced Meningioma: Initial Safety and Efficacy

By jnm.snmjournals.org
Published On :: 2024-10-24T11:58:49-07:00

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Comparison of Posttherapy 4- and 24-Hour [177Lu]Lu-PSMA SPECT/CT and Pretherapy PSMA PET/CT in Assessment of Disease in Men with Metastatic Castration-Resistant Prostate Cancer

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:16-07:00

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Outcomes for Patients with Metastatic Castration-Resistant Prostate Cancer and Liver Metastasis Receiving [177Lu]Lu-PSMA-617

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:14-07:00

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Clinical, Pathologic, and Imaging Variables Associated with Prostate Cancer Detection by PSMA PET/CT and Multiparametric MRI

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:14-07:00

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CT Enhancement of a Nasal Leech After Thrombectomy

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:14-07:00


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FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:15-07:00

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Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET in Breast Cancer

By jnm.snmjournals.org
Published On :: 2024-10-30T08:04:15-07:00

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Performance Characteristics of a New Generation 148-cm Axial Field-of-View uMI Panorama GS PET/CT System with Extended NEMA NU 2-2018 and EARL Standards

By jnm.snmjournals.org
Published On :: 2024-11-07T04:28:32-08:00

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SPECT/CT in Early Response Assessment of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving 177Lu-PSMA-617

By jnm.snmjournals.org
Published On :: 2024-11-07T04:28:32-08:00

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Feasibility of 177Lu-PSMA Administration as Outpatient Procedure for Prostate Cancer

By jnm.snmjournals.org
Published On :: 2024-11-07T04:28:31-08:00


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Changed Regulation Enables Pragmatic Solution for Cancer Patients

By jnm.snmjournals.org
Published On :: 2024-11-07T04:28:32-08:00


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A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia

By www.mcponline.org
Published On :: 2020-11-30

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
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Imaging Mass Spectrometry and Lectin Analysis of N-linked Glycans in Carbohydrate Antigen Defined Pancreatic Cancer Tissues

By www.mcponline.org
Published On :: 2020-11-24

Colin T. McDowell
Nov 24, 2020; 0:RA120.002256v1-mcp.RA120.002256
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Peptidomics-driven strategy reveals peptides and predicted proteases associated with oral cancer prognosis

By www.mcponline.org
Published On :: 2020-11-11

Leandro Xavier Neves
Nov 11, 2020; 0:RA120.002227v1-mcp.RA120.002227
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Human pancreatic cancer cells under nutrient deprivation are vulnerable to redox system inhibition [Cell Biology]

By www.jbc.org
Published On :: 2020-12-04T00:06:05-08:00

Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.


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Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer [Cell Biology]

By www.jbc.org
Published On :: 2020-12-11T00:06:20-08:00

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.


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Clearance of intracellular tau protein from neuronal cells via VAMP8-induced secretion [Cell Biology]

By www.jbc.org
Published On :: 2020-12-18T00:06:18-08:00

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.


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PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells [Signal Transduction]

By www.jbc.org
Published On :: 2020-12-25T00:06:31-08:00

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.


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Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1-JNK axis [Cell Biology]

By www.jbc.org
Published On :: 2020-12-25T00:06:31-08:00

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.


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Lipid signature of advanced human carotid atherosclerosis assessed by mass spectrometry imaging

By www.jlr.org
Published On :: 2020-12-23

Astrid M. Moerman
Dec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974
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Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

By www.jlr.org
Published On :: 2020-12-01

Genta Kakiyama
Dec 1, 2020; 61:1629-1644
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Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice

By www.jlr.org
Published On :: 2020-12-01

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
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rHDL modelling and the anchoring mechanism of LCAT activation

By www.jlr.org
Published On :: 2020-12-02

Tommaso Laurenzi
Dec 2, 2020; 0:jlr.RA120000843v1-jlr.RA120000843
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Problem Notes for SAS®9 - 66095: The message "ERROR: Could not move and link one or more files to..." occurs while running a job-flow instance

By
Published On :: Fri, 21 Aug 2020 15:33:44 EST

In SAS Infrastructure for Risk Management, the message "ERROR: Could not move and link one or more files to..." occurs while running a job-flow instance if an orphaned folder exists in the persistent area.


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Problem Notes for SAS®9 - 66500: A content release on the SAS Risk Governance Framework fails to load when you use SAS 9.4M7 (TS1M7) on the Microsoft Windows operating system

By
Published On :: Wed, 19 Aug 2020 17:45:15 EST

When you log on to the SAS Risk Governance Framework and choose a solution, the web application might fail to load the solution content. When the problem occurs, you continue to see "Loading..." on the screen, an


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WITHDRAWN: Structural and mechanistic studies of hydroperoxide conversions catalyzed by a CYP74 clan epoxy alcohol synthase from amphioxus (Branchiostoma floridae) [Research Articles]

By www.jlr.org
Published On :: 2014-03-04T09:59:12-08:00

This manuscript has been withdrawn by the Author.


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WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins [Thematic Reviews]

By www.jlr.org
Published On :: 2018-10-15T08:42:37-07:00

This article has been withdrawn by the authors as part of this review overlapped with the contents of Pietrangelo A and Ridgway ND. 2018. Cellular and Molecular Life Sciences. 75; 3079-98.


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rHDL modelling and the anchoring mechanism of LCAT activation [Research Articles]

By www.jlr.org
Published On :: 2020-12-02T13:30:37-08:00

Lecithin:cholesterol-acyl-transferase (LCAT) plays a major role in cholesterol metabolism as it is the only extracellular enzyme able to esterify cholesterol. LCAT activity is required for lipoprotein remodelling and, most specifically, for the growth and maturation of HDLs. In fact, genetic alterations affecting LCAT func- tionality may cause a severe reduction in plasma levels of HDL-cholesterol with important clinical consequences. Although several hypotheses were formulated, the exact molecular recognition mechanism between LCAT and HDLs is still unknown. We employed a combination of structural bioinformatics procedures to deepen the insights into the HDL-LCAT interplay that promotes LCAT activation and cholesterol esterification. We have generated a data-driven model of reconstituted HDL (rHDL) and studied the dynamics of an assembled rHDL::LCAT supramolecular complex, pinpointing the conformational changes originating from the interaction between LCAT and apolipoprotein A-I (apoA-I) that are necessary for LCAT activation. Specifically, we propose a mechanism in which the anchoring of LCAT lid to apoA-I helices allows the formation of a hydrophobic hood that expands LCAT active site and shields it from the solvent, allowing the enzyme to process large hydrophobic substrates.


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