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MacOS Sonoma 14.7.1 & MacOS Ventura 13.7.1 with Security Updates Available

Apple has released macOS Sonoma 14.7.1 and MacOS Ventura 13.7.1 for Mac users who have not yet updated to MacOS Sequoia, of which MacOS Sequoia 15.1 with Apple Intelligence was just released. macOS Sonoma 14.7.1 and macOS Ventura 13.7.1 both contain many security fixes, making them important updates to install for Mac user who are ... Read More




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Fix the “Failed to Personalize Software Update” Error in MacOS

Though not common, some Mac users are encountering a strange error message that says “Failed to personalize the software update. Please try again.” when attempting to update their Mac to MacOS Sequoia, and sometimes even with other MacOS software updates too. This is a frustrating error since it prevents the installation of a major system ... Read More




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Apple Releases New Mac Mini, Revamped iMac, & M4 MacBook Pro

Apple has spent the last few days trickling releases of new Mac hardware, debuting a revamped iMac with an M4 chip and new colors, a redesigned Mac Mini that is smaller in size and now has an M4 chip, and the MacBook Pro lineup has been revamped with M4 processors as well. Each of the ... Read More




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How to Update ChatGPT on Mac

The ChatGPT app for Mac is a fantastic AI tool and LLM that makes for a great addition to many Mac users workflows, whether you’re extremely tech savvy, or just a novice. One thing that some users have wondered is how to keep the ChatGPT app for Mac updated, and how to install updates to ... Read More




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Got a PPC Mac in the Closet? Check Out the Aquafox Browser for Tiger & Leopard

If you have an old PowerPC Mac laying around collecting dust in a closet somewhere, you might be able to get some use out of it today by installing a functional modern web browser, like Aquafox. Since so much of what many of us do on computers is done in a web browser, you might ... Read More




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5 Helpful Uses for Apple Intelligence on Mac, iPhone, & iPad

Apple Intelligence is here on Mac, iPhone, and iPad, and while the system requirements are strict, the Apple devices that are new and powerful enough to use the AI tools now gain some really fantastic features. We’re going to show you six helpful Apple Intelligence features and uses that you’ll find beneficial to your workflow, ... Read More




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How to Change iPhone Used by iPhone Mirroring on Mac

If you have several iPhone’s, as many people do when they buy a new iPhone, upgrade, get a hand-me-down, develop iPhone software, or develop mobile sites or apps where you test things on multiple devices, you might be in a situation where iPhone Mirroring on the Mac is using an iPhone that you do not ... Read More




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Beta 2 of iOS 18.2, MacOS Sequoia 15.2, & iPadOS 18.2 Available for Testing

The second beta versions of iOS 18.2, MacOS Sequoia 15.2, and iPadOS 18.2 are now available for users participating in the beta testing programs for Apple system software. The new betas continue to focus on additional Apple Intelligence features, expanding beyond the writing tools, smart replies, and summary features what was initially introduced in iOS ... Read More




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How to Install Windows 11 on Mac with UTM

You can install and run Windows 11 on a Mac, without having to overwrite the MacOS operating system, by installing Windows 11 into a virtual machine. Virtual machines are self-contained installations of operating systems that can be used for a variety of purposes, from testing to demonstrations, to running software that runs on Windows but ... Read More




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How to Turn Off Find My Mac

Find My Mac is an incredibly valuable aspect of iCloud that allows you to find your Mac by using another Apple device’s Find My app, or through iCloud on the web. Aside from the obvious anti-theft aspects that make Find My Mac so important, the majority of users are more likely end up using Find ... Read More




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Deals: M2 MacBook Air with 16GB RAM for $749.99 ($250 Off!)

Amazon is selling the M2 MacBook Air 13″ model with 16GB RAM for just $749.99, taking $250 off the $999 retail price from Apple. Like many great Amazon deals, they tend to shift quickly, so if you’ve been thinking of getting a 16GB model MacBook Air now might be the time. To get the deal ... Read More




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Beta 3 of iOS 18.2, iPadOS 18.2, MacOS Sequoia 15.2, Available for Testing

The third betas of iOS 18.2, iPadOS 18.2, and MacOS Sequoia 15.2, are available for beta testers of Apple system software. The latest betas continue to emphasize on new Apple Intelligence features, including ChatGPT integration, Genmoji custom Emoji creation, Image Playground for AI image generation, and more. These new AI features are in addition to ... Read More




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How to Fix Spotlight Search Issues on MacOS Sequoia

A fair number of Mac users have discovered that Spotlight Search is not working well in MacOS Sequoia, either missing files, apps, and sometimes not working at all to find any local file. For some users the issues with Spotlight happens right after they update to MacOS Seqouia, and for others it may happen later ... Read More





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Coding for #AI and #machinelearning – online course/workshop

Coding for #AI and #machinelearning – online course/workshop We are exploring a new way to learning how to code for AI and Machine Learning by applying ideas of  deliberate practise Starting Oct 2018 – the workshop has limited places Please contact info@futuretext.com if you want to sign up for our online workshop (300 USD)   [...]




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News24 Business | Internet Archive, Wayback Machine hit by 'catastrophic' cyberattack, data breach

The Internet Archive, an online repository of web pages, was offline Thursday after its founder confirmed a major cyberattack that exposed the data of millions of users and left the site defaced.




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Enhanced enzyme kinetics of reverse transcriptase variants cloned from animals infected with SIVmac239 lacking viral protein X [Microbiology]

HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.




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Undercurrents: Episode 8 - Ronan Farrow on Diplomacy




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Unelected Power: Finding Legitimacy in Central Banking and the Regulatory State




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Securing Peace in the 21st Century: The Roles of Diplomacy and Statesmanship




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Une Nouvelle Révolution? Macron and the Gilets Jaunes




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American Diplomacy: Past, Present and Future




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Securing Our Climate Future: Risk, Resilience and Diplomacy




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Technology Diplomacy in the Digital Age




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Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

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





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COMAC says Air China is the first customer for C929 widebody jet




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Woman, 23, had a 'burning sensation' in her stomach. It was the first sign of a rare cancer




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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]

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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Nile Basin States Must Persist with Water Diplomacy

11 August 2020

Owen Grafham

Assistant Director, Energy, Environment and Resources Programme

Ahmed Soliman

Research Fellow, Horn of Africa, Africa Programme

Dr Nouar Shamout

Water Resources and Sustainability (Independent Researcher)
After multiple failed negotiations, any serious breakdown in current talks mediated by the African Union would be dangerous for regional stability. The international community must ramp up its support for this crucial diplomacy to ensure that an agreement is reached.

2020-08-12-Dam-Nile-Ethiopia

The Blue Nile river passes through the Grand Ethiopian Renaissance Dam (GERD) near Guba in Ethiopia. Photo by EDUARDO SOTERAS/AFP via Getty Images.

Ongoing talks between Egypt, Ethiopia and Sudan attempting to find a diplomatic and peaceful solution to the dispute over the Blue Nile Basin offer a unique opportunity for trans-boundary cooperation and have huge significance for a region dealing with multiple complex issues.

With trust clearly at a premium, the continuation of talks demonstrates good faith, but there is an urgent need to strengthen negotiations through all available diplomatic channels. The African Union (AU) is well-placed to continue mediating, but sustained high-level engagement is also needed from regional and international partners such as the EU and US, as well as multilateral support in terms of both financial and technical resources.

A tense history to overcome

At the heart of this dispute is the new Grand Ethiopian Renaissance Dam (GERD) – set to become Africa's biggest hydroelectric dam when complete. Egypt and Sudan, who lie downstream, fear that Ethiopia, as the dam builders, will effectively gain control of the flow of the Nile, a turn of events that radically changes the way that water resources have been shared in the region.

Egypt - widely described as a ‘gift of the Nile’ - is almost entirely dependent on the Nile to meet its various water needs, and is the major beneficiary of the 1929 and 1959 agreements on using the shared river’s water. The 1959 agreement gives Egypt a share of 55.5 billion cubic meters (BCM) annually out of 74 billion available, and a veto right over projects being developed upstream, while Sudan is allocated 18.5 BCM.

Crucially neither of these old agreements recognises the interests of other upstream countries on the Nile, some of which have asserted their own development ambitions on the river over the last two decades and pushed for a new agreement to enshrine equitable rights and harmonious use of the water.

One such country is Ethiopia where the Blue Nile River originates. The GERD is a central part of Ethiopia’s ambitions for economic prosperity. The dam, which is largely self-financed, will have a capacity of 74 BCM when completed, enough to provide abundant cheap energy to power both national and regional developments. Currently, more than half Ethiopia’s 110 million people do not have access to electricity, but demand is increasing by 30 per cent annually.

Unclear impacts

The unclear impact of the GERD – and lower volumes of water – on food security and agriculture complicate the negotiations. Egypt, Ethiopia and Sudan’s populations are set to increase significantly in the coming decades and each are already dealing with significant challenges around food insecurity and nutrition, which in Egypt and Sudan, are partly exacerbated by the colonial-era agricultural structures set up to exploit cash crops.

Any change in water quality would have a huge impact on the 67% of Egyptian farm holdings considered as ‘small’ – the majority of which are on the banks of the Nile. And changes in water volumes might increase desertification and loss of livelihoods, potentially causing civil unrest if not addressed properly.

The environmental impact of the GERD on the complex Nile River system also raises concerns about the river’s ecosystem, the surrounding environment, and the river’s downstream course. Despite talks in 2015 leading to an agreement on declaration of principles, thorough technical studies have not been implemented.

Although there is little evidence that overall water levels in the Nile Basin have reduced in recent years, climate change is causing more variation in the Nile’s flow which increases the risk of flooding and extended droughts. Downstream states are also concerned about impacts from any breaches, damage or failure of the dam, including possible seismic activity.

Of course, the GERD also offers some added value to the downstream states. The dam can help manage floods in Sudan, reduce the significant water loss to evaporation - as in the case of Lake Nasser - and lessen the effect of sediment on downstream dams. In Sudan, where less than one-quarter of the estimated 70 million hectares of arable land is currently cultivated, any reduction in seasonal flooding would boost agricultural output and aid economic recovery. The dam will offer Ethiopia significant opportunities for the trade of cheap renewable energy to Sudan and neighbouring states earning it a possible $1bn a year in revenues. And adopting a more ‘basin-integrated’ management approach can be a springboard for enhanced regional cooperation between the three states.

But geopolitical tensions between the three have escalated since satellite imagery revealed apparent significant filling of the dam prior to reaching any agreement. Ethiopia has long said it would begin filling the dam during its rainy season, but insists the filling occurred naturally through June-July from rainfall and runoff and its first-year target of 4.9 BCM was reached without needing to close the dam gates. Egypt and Sudan have restated their calls for a binding legal agreement on the rules for filling and management of disputes.

Security response not the answer

Internal pressures are particularly acute, with all three countries experiencing public uprisings and regime change in the last decade, and current leaders are under pressure not to appear weak from influential sections of society pushing a hard nationalist line.

Hawkish elements in Egypt have long supported a more securitized response to any potential threats from the GERD, and the recent request from President Sisi that Egyptian air forces be ready to handle targets inside and outside of the country was interpreted as a threat to Turkey in Libya, and Ethiopia.

Egypt has also asked for the GERD to be discussed at the UN Security Council but Ethiopia’s Nobel peace prize-winning prime minister Abiy Ahmed, facing significant internal unrest himself, has made it clear that a costly confrontation is not in anyone’s interests. Meanwhile, Sudan’s transitional government - being jointly run by civilians and the military - is keen to assert its own interests on the Nile but has also played a conciliatory role with its neighbours. Increased engagement of Gulf states in the Horn of Africa and the impacts of conflicts in Libya, Yemen and Syria add more complexity to the overall regional picture.

Certainly none of the major parties sharing the river would benefit from a hard security response to the dam. For Egypt, such a move would torpedo its re-engagement in Sub-Saharan Africa under President Sisi and likely lead to its expulsion from the AU. For Ethiopia, overt conflict would be a huge setback for its development and regional integration ambitions. And Sudan’s nascent transition can ill-afford to be part of another regional conflict.

Thankfully, such an outcome is both highly unlikely and historically rare, and behind the scenes there has been significant progress. Some reports suggest a provisional agreement has been reached on the volume of filling required and the timeframe for the filling to happen. If so, most dispute now revolves around what to do in the event of a drought, provisions for information exchange, and how to translate all this into a binding agreement.

A two-phase approach, consisting of a short-term deal on filling and operating the GERD followed by discussions on future developments and allocation, could be the best way to reach a lasting settlement and replace the extremely outdated existing water-sharing agreements.

Reaching a successful deal between the three countries is not easy as it requires brave leadership and political goodwill, a de-escalation of long-standing rhetoric and brinkmanship, and a willingness to compromise on all sides to ensure the gaps between the countries' positions are significantly narrowed.

What is required is a determined effort to keep the countries talking and provide the solutions which can bridge the parties’ differences, build confidence, and secure the vital diplomatic success so badly needed for wider stability and progress in the region.




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Economic Diplomacy in the Era of Great Powers

17 September 2020

Dr Linda Yueh

Associate Fellow, Global Economy and Finance Programme and US and the Americas Programme
The 21st-century global economy has different drivers from those in the previous century. Amid ever more politicized trade relations, economic diplomacy needs a more transparent framework.

2020-09-17-Trump-Economy-WEF-World-Economic-Forum-Davos

US president Donald Trump at the World Economic Forum in Davos, Switzerland, on January 22, 2020. Photo by JIM WATSON/AFP via Getty Images.

The emergence of a multipolar global economy in which the US is no longer the main engine of growth has boosted the role of economic diplomacy, the setting of foreign economic policy. While the EU remains the world’s biggest economic bloc and the US is still an economic powerhouse, it is Asia – China in particular – which has created hundreds of millions of new middle-class consumers, helping to drive global economic growth.

This shift has ignited an era of competition between the US and China and, by implication, a debate about the merits of different political and legal systems. The difficulty for the rest of the world is how best to navigate this highly polarized climate – in recent history, only the Cold War comes close to having matched the adversarial dynamics of such a divided international community.

In conducting economic diplomacy, governments should consider their economic strengths, the importance of transparency, and how best to operate in a fragmented international system.

First, the setting of trade and investment policy should take into account developments in the global economy. One trend worth noting is the rising importance of services – in particular digital services – in international trade. The expanding cross-border trade in intangibles such as business services and data means the negotiation, definition and enforcement of standards to regulate these are of growing importance for the global economy, and for policymakers in many countries.

In contrast, negotiations around merchandise trade are likely to take a somewhat lower profile. Under the World Trade Organization (WTO), tariffs on manufactured goods have dropped significantly in any case – though there is still scope to lower them. Contemporary diplomacy, as well as disputes, around the lowering or raising of barriers to international trade will increasingly concern non-tariff measures applicable to services rather than those, such as tariffs, that traditionally apply to goods.

For service-based economies, it is vital free-trade agreements (FTAs) encompass regulations and standards for intangibles. But this is difficult in a multipolar global economy where the US, China and the EU all have different legal and regulatory systems, and raises the prospect of a fragmented global trading system divided into blocs of countries adhering to different standards.

A pluralistic or mini-multilateral approach to trade such as the stalled Trade in Services Agreement (TiSA) could help resolve elements of this division. TiSA was launched in 2013 by a group of advanced economies, not the entirety of the WTO, to further opening up global services trade. However, talks have been on hold since 2016 and, in the current climate, it is near impossible to conclude negotiations when the major economies do not come to the table and instead promote their own standards with their closest trading partners.

Second, policymakers should consider that, in an era of heightened trade tensions, any framework for economic diplomacy needs to be transparent if it is to be trusted and credible. Such a framework could centre on commercial openness and consistency with a country’s foreign and intelligence policy aims. For example, clearly spelling out how a country reviews prospective foreign investment and applying this consistently would demonstrate that all projects are treated equally without singling out any individual country. This would be an improvement over an ad hoc and less transparent approach .

A major challenge in creating a ‘principle-based’ economic diplomacy framework of this kind is reconciling competing policy aims. To this end, several key questions need answering. Should trade agreements encompass non-economic elements, such as foreign policy aims? Do concerns over national security mean that trade and investment agreements should favour allies? Could such a framework assess a trading or investment partner in terms of national security as well as potential economic benefit?

A country should also re-think how to undertake a wider international role when embarking on economic diplomacy. The inability of the major powers to set new global rules has had a detrimental impact on an international system under significant strain. The stalling of multilateral trade talks and urgency of international coordinated action on global public goods, such as health and the environment, shows there is a pressing need for a new approach to international relations.

Economic diplomacy could, and should, bolster the rules-based multilateral system. The challenge is engaging the major powers without whom widespread adoption of global policies and standards is less likely. Yet the chances of wider adoption might actually be better if a proposal does not come from either the US or China. This opens up the opportunity for other countries to be ‘honest brokers’ and potentially improve their own international standing.

In an era of increasing tension between great powers, economic diplomacy requires re-tooling. It should consider not just economic considerations, but also broader foreign policy aims, greater transparency, and a pluralistic approach to global rules to strengthen the multilateral system.




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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]

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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Challenges with 177Lu-PSMA-617 Radiopharmaceutical Therapy in Clinical Practice




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Diagnostic Radiopharmaceuticals: A Sustainable Path to the Improvement of Patient Care




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MIRD Pamphlet No. 31: MIRDcell V4--Artificial Intelligence Tools to Formulate Optimized Radiopharmaceutical Cocktails for Therapy

Visual Abstract




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Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors

Visual Abstract




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Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology [Computational Biology]

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.




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Apolipoprotein C3 and apolipoprotein B colocalize in proximity to macrophages in atherosclerotic lesions in diabetes

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




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The emerging roles of the macular pigment carotenoids throughout the lifespan and in prenatal supplementation [Thematic Reviews]

Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies.




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Apolipoprotein C3 and apolipoprotein B colocalize in proximity to macrophages in atherosclerotic lesions in diabetes [Images in Lipid Research]




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Chronic insomnia: diagnosis and non-pharmacological management




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MacPhail: Phils are 'uniquely poised right now'

Phillies president Andy MacPhail opened a 28-minute press conference on Friday afternoon at Spectrum Field with facts and figures about investments the organization made the past few seasons as the team wallowed at the bottom of the National League. Then MacPhail talked a lot about Bryce Harper and Manny Machado as well as manager Gabe Kapler.




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Can diplomacy advance human rights?

Can diplomacy advance human rights? 25 April 2023 — 4:00PM TO 5:00PM Anonymous (not verified) 7 March 2023 Chatham House and Online

How is diplomacy contributing to advancing human rights through the multilateral system?

The international human rights system has come under significant pressure in recent years. Russia’s invasion of Ukraine and the US-China rivalry have created difficult political pressures, while major global challenges including climate change and global inequality demand answers. Effective diplomacy on human rights has become increasingly difficult, with incentives stacked against bold action.

The relationship between diplomacy and human rights is an uneasy one. Diplomacy is an art of negotiation, persuasion and compromise. Human rights are tightly defined and universal. The relationship between the two may seem paradoxical, but in the context of an unstable world order, it has never been more important.

In the 75th anniversary year of the Universal Declaration of Human Rights, this discussion will explore the critical role of diplomacy in advancing human rights in the future.

  • What are the critical human rights challenges today? What is the role of diplomacy in addressing them?

  • What is the impact of intensifying competition between the US and China on the human rights system?

  • Is there an opening for more leadership emerging from the Global South?

  • What is the future of the human rights system in the context of this polarized world?

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




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Here we go again: Russia’s energy ‘diplomacy’ in Moldova

Here we go again: Russia’s energy ‘diplomacy’ in Moldova Expert comment LJefferson 6 December 2021

The gas crisis shows that while the new Moldovan government may wish for geopolitics to go away, they are a weapon Russia will deploy at will.

In October, Moldova came under the spotlight when Russia, its primary provider of gas, slashed supplies by a third and refused to extend the existing contract.

The crisis was resolved at the end of October when Russia and Moldova signed a new contract, in which Moscow has used Moldova’s gas dependence to extract geopolitical concessions, weaken the new pro-western Chisinau government and drive a wedge between the EU and Moldova.

A chronic failure to reform

Moldova became a classic case of state capture when political elites – including nominally pro-European political elites – engaged in massive rent-extraction.

Up until 2020, when pro-reform forces came to power, Moldovan politics offered rapid route to riches for both the nominally pro-European parties and the pro-Russian Socialist Party; each was responsible for playing up ethnic and geopolitical cleavages in the country to mobilize votes and shore up legitimacy.

These predatory elites hollowed out Moldova economically and politically by a chronic failure to reform, in particular the energy sector which became a major source of rent.

However, this started to change when the pro-reform forces came to power as a result of the 2020 presidential and then 2021 parliament elections. The pro-reformist Maia Sandu defeated the incumbent president Igor Dodon (58 per cent to 42 per cent) in November of that year. And then her party got 58 per cent of the vote in the parliamentary elections which followed in July 2021.

The Party of Action’s winning formula was to focus on corruption and domestic reforms – rather than playing the ‘geopolitical’ card, a favourite strategy of their predecessors.

Her Party of Action’s (PAS) winning formula was to focus on corruption and domestic reforms – rather than playing the ‘geopolitical’ card, a favourite strategy of their predecessors. As Sandu put it, the elections marked ‘the end of the reign of thieves in Moldova’.

A gas crisis is initiated  

Russia’s response to these results was to initiate a gas crisis. Up until the victory of the pro-reform forces, Russia had annually renewed a gas contract signed in 2007. However, in September 2021, Russia refused to renew the contract as it had done many times before and instead insisted on a new contract, which allowed Russia to create linkages between energy prices, debt settlement, a halt on energy market reforms and, it can be logically inferred, further integration with the EU.

Moldova’s national energy company, Moldovgaz, is 63.5 per cent de facto owned by Gazprom with the Moldovan government owning the remaining 35.5 per cent. (Moldova was forced to give Gazprom a controlling stake when faced with a cut in supplies in January 2006). It is therefore hardly surprising that no efforts were made to de-monopolise the sector and diversify energy supplies.

This lack of modernization can be explained by the somewhat surreal fact that in any negotiations and planning, Moldovagaz – majority owned by Gazprom – represents the Moldovan side in negotiations with Gazprom. So, when it came to signing of the new five-year contract in October 2021, Russia, through Gazprom, was able to institute a contract which made gas prices conditional on various geopolitical conditions.

It is noteworthy that Moldova’s original 2007 gas contract had been renewed annually despite the supposed accrual of debt. However, the very nature of this debt is suspect. While Moldova’s debt is said to be approximately $700 million, the debt of the much smaller breakaway Transnistria was around $7.3 billion.

The exact level and source of the debt remain murky. Russia appears to be making Moldova liable to repay at least some of Transnistria’s debt while only demanding the debt settlement with Moldova, but not with Transnistria.

High stakes for Moscow

Moreover, the contract is used to derail liberalisation of the energy market in line with EU’s energy market rules (through the so-called unbundling of supplies and distribution) which Moldova had committed itself to since the country joined the Energy Community in 2010.

Referring to ‘the non-application of forced reorganization and sanctions against Moldovagaz’, the new gas contract forces Moldova to postpone implementing the unbundling of supplies and distribution by making it conditional on resolving the energy debt.

Furthermore, Moldova ominously agreed to create an ‘intergovernmental commission on economic cooperation’ with Russia, which effectively blocks Moldova’s economic integration with the EU. (This demand is hardly new as Russia previously requested, and was granted, a seat at the negotiating table on a bilateral trade agreement between the EU and Ukraine. The trilateral EU-Ukraine-Russia negotiations have made it clear that Russia is seeking a veto over European integration of all neighbouring countries.)  

Targeting Moldova’s new reformist government reflects high personal stakes for Moscow. Moldova’s caretaker (kurator) in the Kremlin is Dimitrii Kozak, who in 2003 masterminded the so-called ‘Kozak Memorandum’. This sought to reintegrate breakaway Transnistria into a Moldova-Transnistria federation.

It was thwarted at the last minute but the Russian leadership has not given up on its plan. Now using his position as the deputy head of Presidential Administration, Kozak is masterminding Russia’s rehashed policy towards Moldova and has attempted to bring back his Memorandum as a political blueprint for a ‘settlement’.

Russia’s heavy-handed energy ‘diplomacy’

The new Moldovan government is caught in a crossfire of domestic expectations and Russian geopolitical demands. The gas crisis shows that while the new government may wish for geopolitics to go away, they are a weapon Russia will deploy at will.

The new Moldovan government is caught in a crossfire of domestic expectations and Russian geopolitical demands.

The Moldovan government is brand new so it has relatively little experience of dealing with Russia’s heavy-handed ‘energy diplomacy’. But the EU has been on the receiving end of this before – this is a direct replica of Russia’s strategy toward Armenia and Ukraine – and neither ended well for the target countries or for the EU.

So, Russia’s plans for Moldova are likely to have similar consequences for the EU’s latest attempts to be a convincing foreign policy actor. 




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Preclinical Evaluation of 177Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide 177Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. 177Lu-OncoFAP and 177Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: 177Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of 177Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of 177Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.




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[68Ga]Ga-RAYZ-8009: A Glypican-3-Targeted Diagnostic Radiopharmaceutical for Hepatocellular Carcinoma Molecular Imaging--A First-in-Human Case Series

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [68Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [68Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with 68Ga from a 68Ge/68Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [68Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUVmax of these lesions was 19.6 (range, 2.7–95.3), and the mean SUVmean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUVmean, <1.6), with a continuous decline to 4 h after administration (mean SUVmean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUVmax of 31.3) and decreased gradually afterward. Conclusion: [68Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [68Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.




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Optimizing the Therapeutic Index of sdAb-Based Radiopharmaceuticals Using Pretargeting

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for 177Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP+) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [177Lu]Lu-DOTA-PEG7-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [177Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [177Lu]Lu-DOTA-PEG7-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([177Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.




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Boeing machinists agree to new contract, ending weeks-long strike

Tens of thousands of striking Boeing machinists voted Monday to ratify a new contract, ending their seven-week work stoppage.




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Starmer, Macron reaffirm 'ironclad' support for Ukraine amid uncertainty around Trump

French President Emmanuel Macron was joined in Paris on Monday by British Prime Minister Keir Starmer for Armistice Day commemorations after a meeting at which both leaders reaffirmed "unwavering" support for Ukraine.




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Nutritional supplements with curcumin could curb macular degeneration, study suggests

Nutritional supplements that contain curcumin -- a natural anti-inflammatory compound -- may protect the eyes from the development and progression of age-related macular degeneration, a new study suggests.