Saverio Cinti
Nov 1, 2005; 46:2347-2355
Research Articles

Influence of soft law grows in international governance Expert comment NCapeling 17 June 2021

Soft law is increasingly being used by policymakers to enable greater cooperation and inclusivity, and its role is here to stay in creating effective regimes.

As the UK government’s recent Integrated Review points out, international law-making in a fragmented international order is becoming increasingly difficult.

Geopolitical tensions, and the length of time required to agree multilateral treaties – typically decades – make it challenging to reach binding agreements in complex and fast-evolving policy areas such as climate change and technology governance.

As a result, the regulation of international behaviour through soft law – meaning non-binding instruments such as principles, codes of conduct or declarations – is starting to assume greater significance. And states increasingly find soft law-making attractive because there are relatively fewer decision costs involved.

Soft law also lays the ground for the possibility of transforming into hard law if, over time, its principles become widely accepted and it is evident states are treating them as legal obligations. And the emergence of a hybrid of both soft and hard law components in treaties has started to develop in recent years, such as the Paris Agreement on Climate Change.

Opening access to global governance

A major attraction of soft law-making is that it provides for non-traditional, non-state actors to take part in the process of global governance. Non-governmental organizations (NGOs), social movements, corporate sector, and individuals are more easily drawn into soft law-making compared to treaties, to which only states can be party.

This holds out the promise for greater inclusiveness in global rulemaking and governance, but soft law processes also pose many challenges. Soft law provides an avenue for states to avoid legal obligations on important subjects and developing rules in such an informal manner can lead to fragmentation and a lack of coherence in the international system.

As noted in dialogues held under Chatham House’s Inclusive Governance Initiative, some areas of international interaction require hard law, such as economic competition, certain international security issues, and aspects of the global commons. In these areas, soft law is just not appropriate or enough.

Soft law measures such as codes of conduct may be useful in rapidly developing areas such as technology, as they are more flexible and adaptable than hard law. And they may be particularly effective if used in conjunction with binding regulation, and subject to monitoring and enforcement by a regulator, as in recent proposals by the European Union (EU) for a Digital Services Act.

The Chatham House Inclusive Governance Initiative report highlights that the proliferation of soft law does not necessarily have to compete with the existing system of hard law, so long as soft law solutions do not conflict with, or undermine, hard law such as existing treaty provisions.

Case study: Business and human rights

The UN Guiding Principles on Business and Human Rights (UNGPs) are an interesting example of both the promise of soft law-making, and its challenges. Officially adopted by the UN General Assembly in 2011, the UNGPs set out the global standard of what is expected of companies as regards human rights due diligence (HRDD) to prevent and address business-related human rights harms.

The sections on HRDD in the UNGPs have been constructed as a non-binding ‘social’ standard of conduct, though with the expectation that this would eventually be reinforced through a “smart mix” of both soft law and hard law initiatives. Arguments in favour of the predominantly soft law approach at the time – subsequently borne out in practice – were that this would encourage a higher level of participation, by states and businesses in particular, and better foster creativity and innovation in a still-developing field.

The UNGPs recognize and reinforce the importance of meaningful and inclusive stakeholder engagement for both the credibility and legitimacy of processes, and for the quality of substantive outcomes. The Ruggie process which led to the UNGPs, drew extensively from a wide range of stakeholder engagement processes covering many different jurisdictions and all UN regional groupings. The importance of deep and inclusive stakeholder engagement is also recognized in the mandate of the UN Working Group on Business and Human Rights.

The annual UN Forum on Business and Human Rights is one of the largest and most vibrant multi-stakeholder events in the UN calendar. Now in its tenth year, the forum provides an opportunity for an annual review by stakeholders – government, business and civil society – of past achievements in implementing the UNGPs and knowledge sharing on ways to address more persistent, underlying challenges.

Its relatively informal approach to agenda setting has, year on year, enabled an increasingly diverse array of stakeholder-organized sessions, supporting a ‘bottom up’ approach which raises awareness of under-reported issues and undervalued solutions.

In addition, while the UNGPs provide the substantive framework for discussion, flexible governance arrangements allow for rapid reorientation to respond to present and emerging crises, such as COVID-19 pandemic and climate change.

However, the sluggish responses of many companies, coupled with revulsion at reports of serious abuses in the value chains of many well-known brands, have prompted some governments to seek ways of translating some aspects of HRDD methodologies into binding legal standards. France passed a Corporate Duty of Vigilance Law in 2017 and Germany adopted a new law on supply chain due diligence in June 2021 which is to enter into effect on 1 January 2023. The European Commission is also working up proposals for an EU-wide regime to be unveiled in mid-2021.

Soft law versus hard law

At the international level, there are signs of divergence between those states which see value in persevering with the soft law route towards better regulation and corporate standards, and those which want to move as rapidly as possible to a hard law framework for business and human rights, enshrined in treaty, to improve domestic-level regulation and access to effective remedies.

Those supporting the hard law route – largely less industrialized states – received a boost in 2016 when the UN Human Rights Council mandated an Intergovernmental Working Group to explore options for a new treaty on business and human rights.

This initiative, known as the ‘treaty process’, has completed six rounds of negotiations. Despite the necessarily greater formality, these treaty negotiation sessions continue to emphasize the importance of stakeholder consultation. NGOs with ECOSOC status are invited to contribute views on the framing and content of draft treaty provisions immediately following the interventions by states, intergovernmental organizations and national human rights institutions, in that order.

The key question is whether this dynamism and inclusivity can be preserved as the transition is made from soft law to more binding approaches. Translating soft law standards into binding regimes inevitably means making hard choices, and different stakeholder groups have different views as to where legal lines should be drawn, how key concepts should be defined, and where the balance between legal certainty and flexibility should be struck.

The negotiations needed to strike an effective balance between competing objectives and needs can be challenging and time-consuming, as experiences with the treaty process have shown. But stakeholder demand for inclusive processes to help shape the law remains strong. Stakeholder groups clearly want a say in how the new EU-wide regime for ‘mandatory human rights due diligence’ will work in practice. A recent online ‘stakeholder survey’ garnered more than 400,000 responses.

Ultimately, the most effective domestic regimes are likely to be a mix of hard law standards supported by more flexible standards and guidance. Civil society organizations and trade unions will continue to have a multi-faceted role to play. Not only are they vital sources of expertise on human rights challenges connected to business activities, at home and abroad, they can also act as private enforcers of standards and advocates for affected people and communities.

Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? 9 September 2021 — 2:00PM TO 3:30PM Anonymous (not verified) 21 July 2021 Online

Exploring current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

Counter-terrorism measures  address broad forms of support to terrorist acts. Their expansion, internationally and domestically, has given rise to new points of friction with international humanitarian law. Unless the measures include adequate safeguards, they  can impede humanitarian action. Country-specific sanctions imposed for other objectives, such as ending conflicts or protecting civilians, raise similar challenges for humanitarian action. 

These problems are not new, but solutions at international and national level remain elusive. 

At this panel event, which marks the launch of a new Chatham House research paper, panellists explore current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

• What are the current dynamics and developments at Security Council level?  
• What are the opportunities now that the UK is developing its independent sanctions strategy? 
• What challenges do counter-terrorism requirements in funding agreements for humanitarian action  pose? 
• What is necessary to make progress?

How can the investor community address the ‘S’ in ESG? – the role of social purpose values 16 November 2021 — 1:30PM TO 2:30PM Anonymous (not verified) 18 October 2021 Online

This webinar highlights the crucial relationship between an open civic space and a profitable business environment.

2020 was a tipping point for investors to think and act more responsibly, galvanized by catalysts like the killing of George Floyd and the pandemic. There is increasing investor support for social and environmental causes. Younger investors are placing increasing emphasis on values and social issues in their investment decisions.

The ‘S’ in the Environment Social and Governance (ESG) agenda is clearly gaining traction, but how far does it extend to civil and political liberties i.e. the right of citizens, NGOs and journalists to speak freely, assemble and associate which are increasingly shrinking around the world?

While there is increasing focus on human rights issues such as modern slavery and supply chains, civil society space issues often fall between the cracks when investors consider ESG.

This webinar also explores opportunities and challenges that arise for the investor community in terms of factoring civic space issues into their political risk and ESG analysis.

• To what extent are civic space issues being factored into ESG social purpose values, especially by younger investors?
• What is the best methodology for assessing these issues in order to ensure a common and coherent set of global standards in this area?
• And how can investors mitigate the risks of their activities to civic space in practice?

Elizabeth Wilmshurst CMG appointed Honorary Queen’s Counsel News release jon.wallace 14 January 2022

Founder of the International Law Programme at Chatham House recognized for her major contribution to the law of England and Wales.

Elizabeth Wilmshurst CMG, distinguished fellow of Chatham House’s International Law Programme, has been awarded the title of Honorary Queen’s Counsel (QC Honoris Causa), recognizing her major contribution to the law of England and Wales, outside practice in the courts. The Lord Chancellor will preside over an appointment ceremony at Westminster Hall on 21 March 2022.

Elizabeth founded the International Law Programme at Chatham House and is an academic expert member of Doughty Street Chambers. She was a legal adviser in the United Kingdom diplomatic service between 1974 and 2003. Between 1994 and 1997 she was the Legal Adviser to the United Kingdom mission to the United Nations in New York. She also took part in the negotiations for the establishment of the International Criminal Court.

Throughout her career, Elizabeth has worked to strengthen the role of international law in reducing global tensions, addressing cross-border challenges and promoting individual liberty, including through influential publications at the Institute such as The Chatham House Principles of International Law on the Use of Force in Self-Defence. 

Robin Niblett CMG, Director and Chief Executive of Chatham House said:

‘We are delighted by this award which recognizes Elizabeth’s outstanding contribution to the field of international law, both in government and – on a continuing basis – through the International Law Programme at Chatham House.’

Expert

Expert

Erythromycin-resistance methyltransferases are SAM dependent Rossmann fold methyltransferases that convert A2058 of 23S rRNA to m6 2A2058. This modification sterically blocks binding of several classes of antibiotics to 23S rRNA, resulting in a multidrug-resistant phenotype in bacteria expressing the enzyme. ErmC is an erythromycin resistance methyltransferase found in many Gram-positive pathogens, whereas ErmE is found in the soil bacterium that biosynthesizes erythromycin. Whether ErmC and ErmE, which possess only 24% sequence identity, use similar structural elements for rRNA substrate recognition and positioning is not known. To investigate this question, we used structural data from related proteins to guide site-saturation mutagenesis of key residues and characterized selected variants by antibiotic susceptibility testing, single turnover kinetics, and RNA affinity–binding assays. We demonstrate that residues in α4, α5, and the α5-α6 linker are essential for methyltransferase function, including an aromatic residue on α4 that likely forms stacking interactions with the substrate adenosine and basic residues in α5 and the α5-α6 linker that likely mediate conformational rearrangements in the protein and cognate rRNA upon interaction. The functional studies led us to a new structural model for the ErmC or ErmE-rRNA complex.

E. A. Rakhmanov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 269-290.
Abstract, references and article information

A. I. Aptekarev and M. L. Yattselev
Trans. Moscow Math. Soc. 83 (), 251-268.
Abstract, references and article information

A. Kh. Khachatryan, Kh. A. Khachatryan and A. Zh. Narimanyan
Trans. Moscow Math. Soc. 83 (), 183-200.
Abstract, references and article information

Z. A. Kasumov and N. R. Akhmedzade
Trans. Moscow Math. Soc. 83 (), 67-74.
Abstract, references and article information

Fossil Fuels Expert Roundtable: Forecasting Forum 2018 12 February 2018 — 2:00PM TO 5:30PM Anonymous (not verified) 18 December 2017 Chatham House, London

This forum will present the latest thinking from senior researchers on the dynamics that will affect fossil fuels investment and markets in the year ahead. The first session will assess the various factors keeping oil and gas prices from bouncing back and will consider conditions and political developments that could influence markets in the year ahead. The second session will assess the future of the power sector and what this means for the fossil fuels industry.

Attendance at this event is by invitation only.

Fossil Fuels Expert Roundtable: How Solar is Shaping the Energy Transition 1 June 2018 — 9:00AM TO 10:30AM Anonymous (not verified) 22 May 2018 Chatham House, London

As global temperatures rise and extreme weather events multiply, doubts over the reality and imminence of climate change have dissipated. Despite this, there is a clear lack of urgency by governments to the approaching crisis. At this event, Prem Shankar Jha will set out what he believes are the three main causes for this inaction.

Furthermore, he will argue that catastrophic climate change is imminent, but even if it weren’t, the risk is too great to ignore. Only a complete shift from fossil fuels by 2070 at the latest would provide reasonable certainty of avoiding irreversible consequences. This transition is not only possible but the technologies to enable it were harnessed four to nine decades ago – and all of them draw their primary energy from the sun. These technologies are already capable of delivering electricity, transport fuels, and petrochemicals at prices that are competitive with the current delivered cost of electricity in the US and Western Europe. So what is holding up the energy shift?

Attendance at this event is by invitation only.

Zhaonan Wang and Yingpu Deng
Math. Comp. 93 (), 2921-2942.
Abstract, references and article information

Haiyong Wang
Math. Comp. 93 (), 2861-2884.
Abstract, references and article information

Denise Uwamariya and Xiangfeng Yang
Theor. Probability and Math. Statist. 111 (), 167-179.
Abstract, references and article information

Abdessamad Dehaj and Mohamed Guessous
Theor. Probability and Math. Statist. 111 (), 1-8.
Abstract, references and article information

P. Lochak
St. Petersburg Math. J. 35 (), 477-535.
Abstract, references and article information

When using the distinct count function in SAS Visual Analytics reports, you might find that a negative value is displayed instead of the actual distinct count: imgalt="distinct_count" src="{fusion_66562_1_disti

If you connect to a FTP/TLS server that is configured to use implicit FTP/TLS, FILENAME FTP/TLS might fail with the following error:

Arabinogalactan proteins (AGPs) are plant proteoglycans with functions in growth and development. However, these functions are largely unexplored, mainly because of the complexity of the sugar moieties. These carbohydrate sequences are generally analyzed with the aid of glycoside hydrolases. The exo-β-1,3-galactanase is a glycoside hydrolase from the basidiomycete Phanerochaete chrysosporium (Pc1,3Gal43A), which specifically cleaves AGPs. However, its structure is not known in relation to its mechanism bypassing side chains. In this study, we solved the apo and liganded structures of Pc1,3Gal43A, which reveal a glycoside hydrolase family 43 subfamily 24 (GH43_sub24) catalytic domain together with a carbohydrate-binding module family 35 (CBM35) binding domain. GH43_sub24 is known to lack the catalytic base Asp conserved among other GH43 subfamilies. Our structure in combination with kinetic analyses reveals that the tautomerized imidic acid group of Gln263 serves as the catalytic base residue instead. Pc1,3Gal43A has three subsites that continue from the bottom of the catalytic pocket to the solvent. Subsite −1 contains a space that can accommodate the C-6 methylol of Gal, enabling the enzyme to bypass the β-1,6–linked galactan side chains of AGPs. Furthermore, the galactan-binding domain in CBM35 has a different ligand interaction mechanism from other sugar-binding CBM35s, including those that bind galactomannan. Specifically, we noted a Gly → Trp substitution, which affects pyranose stacking, and an Asp → Asn substitution in the binding pocket, which recognizes β-linked rather than α-linked Gal residues. These findings should facilitate further structural analysis of AGPs and may also be helpful in engineering designer enzymes for efficient biomass utilization.

Members of the B-cell lymphoma (BCL-2) protein family regulate mitochondrial outer membrane permeabilization (MOMP), a phenomenon in which mitochondria become porous and release death-propagating complexes during the early stages of apoptosis. Pro-apoptotic BCL-2 proteins oligomerize at the mitochondrial outer membrane during MOMP, inducing pore formation. Of current interest are endogenous factors that can inhibit pro-apoptotic BCL-2 mitochondrial outer membrane translocation and oligomerization. A mitochondrial-derived peptide, Humanin (HN), was reported being expressed from an alternate ORF in the mitochondrial genome and inhibiting apoptosis through interactions with the pro-apoptotic BCL-2 proteins. Specifically, it is known to complex with BAX and BID. We recently reported the fibrillation of HN and BAX into β-sheets. Here, we detail the fibrillation between HN and BID. These fibers were characterized using several spectroscopic techniques, protease fragmentation with mass analysis, and EM. Enhanced fibrillation rates were detected with rising temperatures or pH values and the presence of a detergent. BID fibers are similar to those produced using BAX; however, the structures differ in final conformations of the BCL-2 proteins. BID fibers display both types of secondary structure in the fiber, whereas BAX was converted entirely to β-sheets. The data show that two distinct segments of BID are incorporated into the fiber structure, whereas other portions of BID remain solvent-exposed and retain helical structure. Similar analyses show that anti-apoptotic BCL-xL does not form fibers with humanin. These results support a general mechanism of sequestration of pro-apoptotic BCL-2 proteins into fibers by HN to inhibit MOMP.

30 September 2020

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.

Priorities for implementing Ethiopia's national dialogue 11 May 2022 — 1:00PM TO 3:00PM Anonymous (not verified) 3 May 2022 Online

Experts discuss challenges and priorities in shaping an inclusive and effective national dialogue in Ethiopia.

Ethiopia is grappling with numerous contentious national issues – not least persistent conflict in several parts of the country – which underscore the need for large-scale dialogue and reconciliation efforts to address the country’s deep-rooted societal and political divisions. Ethiopia’s newly established National Dialogue Commission – whose 11 commissioners were appointed in February 2022 – has begun a four-phased process of preparations for a dialogue, with its initial stage focused on stakeholder engagement and local knowledge mobilization.

There are major challenges, however, in ensuring inclusivity amidst ongoing conflict and questions on how a country-wide process will sit alongside local dialogue initiatives and wider mediation and peacebuilding efforts. Linking the process to constitutional bodies will also be an important priority to ensure dialogue outcomes are effectively implemented.

At this public event, panellists will exchange perspectives on how to shape an effective national dialogue in Ethiopia, including priorities for building a credible National Dialogue Commission and the roles and responsibilities of other national, regional and local-level actors. They will also discuss key implementation mechanisms and long-term priorities for trust-building and cultivating a conducive environment for inclusive dialogue.

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.

Silencing the Guns in Africa by 2030: Lessons from Mozambique 17 February 2023 — 7:00AM TO 9:00AM Anonymous (not verified) 7 February 2023 Addis Ababa and online

A hybrid event in Addis Ababa reflecting on Mozambique’s 2019 peace agreement and the lessons it offers for the African Union’s ‘Silencing the Guns’ agenda by 2030.

This event will explore opportunities for furthering the AU’s Silencing the Guns agenda by 2030 to assist Africa’s transformative development, highlighting lessons learnt from Mozambique’s experience.

The ‘Silencing the Guns in Africa’ agenda, a flagship initiative of the African Union’s (AU) Agenda 2063, aspires to end all wars and conflict, prevent genocide, and stop gender-based violence.

The 2019 peace agreement in Mozambique and the subsequent disarmament, demobilization and reintegration process supported by the United Nations (UN) but implemented by Mozambique’s government and institutions, provides experience and learning for other continental conflicts that have recently ended or resumed.

Mozambique is seeking to break from the cyclical ‘conflict trap’ where once a country experiences one civil war, it is significantly more likely to experience additional episodes of violence.

Since the end of Mozambique’s civil war in 1992, targeted armed conflict by RENAMO resumed in 2013 and ended through the new agreement in August 2019. The final reintegration into civilian life of former Mozambican combatants of opposition RENAMO will be completed in 2023.

Mozambique and Switzerland – a key supporter of successive Mozambican peace processes – have become non-permanent members of the UN Security Council for the first time in their respective histories.

At a moment when old vulnerabilities and new threats are apparent on the African continent, this seminar, held by Chatham House in partnership with the United Nations Development Programme (UNDP), explores opportunities to furthering the AU’s Silencing the Guns agenda by 2030 to assist Africa’s transformative development, as outlined by the UNDP in a report published in February 2022.

This hybrid event is held in partnership with the African Union Commission and the United Nations Development Programme (UNDP).

This event will also be broadcast live via the Africa Programme Facebook page.

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.

Visual Abstract

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

Colin T. McDowell
Nov 24, 2020; 0:RA120.002256v1-mcp.RA120.002256
Research

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential, and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis, showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that, sildenafil, a phosphodiesterase 5 inhibitor, induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content, and voltage-dependent anion channel protein expression. Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil depends upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.

Montgomery Blencowe
Dec 23, 2020; 0:jlr.RA120000713v1-jlr.RA120000713
Research Articles

Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles

Amanda D.V. MacCannell
Nov 18, 2020; 0:jlr.ILR120001204v1-jlr.ILR120001204
Images in Lipid Research

For data that is being loaded from a SAS Stored Process Server, an insertion process might fail to a MySQL database with a warning, as well as an error message that says "During insert: Incorrect datetime value…"

In SAS Customer Intelligence Studio, you might notice that the user interface becomes unresponsive, as shown below: imgalt="SAS Customer Intelligence Studio UI becomes unresponsive" src="{fusion_66537

In SAS Customer Intelligence Studio, you can choose to create a new calculated variable in the Edit Value dialog box when you populate a treatment custom detail. Following creation of the new calculated

If the OBSMARGINS= or OM= option is specified in an LSMEANS, LSMESTIMATE, or SLICE statement and a user-defined format is applied to any of the effect variables in the OM-data-set , PROC PLM incorrectly stops proce

In SAS Customer Intelligence Studio,  when you add  Reply- node variable values in the Define Value dialog box, you might notice that two identically labeled data-grid variables are

SAS Web Report Studio enables you to link reports based on a group break value. However, when you click the link, it might fail with an HTTP 400 error. The exact message you see depends on which browser you are u