Apple today seeded the second public betas of upcoming iOS 18.2, iPadOS 18.2, and macOS Sequoia 15.2 updates, allowing the public to continue testing new features ahead of when the software launches. The public betas come a day after Apple provided developers with new betas.


Public beta testers can download the updates from the Settings app on each device after opting into the beta through Apple's public beta testing website. Note that Apple has also released public betas for watchOS 11.2, tvOS 18.2, and the latest HomePod software.

iOS 18.2, iPadOS 18.2, and ‌macOS Sequoia‌ introduce the next Apple Intelligence features, including the first image generation capabilities.

The update adds Image Playground, a new app for creating images based on text descriptions. You can enter anything you want, though Apple will suggest costumes, locations, items, and more to add to an image. There are options to create characters that resemble your friends and family, and you can choose a photo for ‌Image Playground‌ to use as inspiration to create a related image. Elements added to ‌Image Playground‌ creations are previewed, and there is a preview history so you can undo a change and go back to a prior version.

While ‌Image Playground‌ is a standalone app, it is also integrated into Messages, Notes, Freeform, and more. ‌Image Playground‌ does not make photorealistic images and is instead limited to animation or illustration styles.

The update also adds Genmoji, which are customizable emoji characters that you can create based on descriptions and phrases. Like ‌Image Playground‌ creations, you can base them on your friends and family, with the data pulled from the People album in Photos. You can also make characters using basic elements, and you'll get multiple ‌Genmoji‌ suggestions to choose from. You can create ‌Genmoji‌ using the emoji keyboard.

‌Genmoji‌ are limited to iOS 18.2 and iPadOS 18.2 right now, and will be coming to ‌macOS Sequoia‌ later.

Siri in iOS 18.2, iPadOS 18.2, and ‌macOS Sequoia‌ 15.2 has ChatGPT integration. If ‌Siri‌ is unable to provide an answer to a question, ‌Siri‌ will hand the request over to ChatGPT, though ‌Siri‌ will need user permission first. ChatGPT will answer the question and relay the information back through ‌Siri‌.

ChatGPT can be used to create content from scratch, including text and images. No account is required to use ChatGPT integration, and Apple and OpenAI do not store requests.

If you have an iPhone 16, there's a Visual Intelligence feature in iOS 18.2 that provides information about what's around you. Open up the camera and point it at a restaurant to get reviews, or point it at an item to search Google for it.

Some other Visual Intelligence capabilities include reading text out loud, detecting phone numbers and addresses to add them to Contacts, copying text, and summarizing text.

Apple added Writing Tools in iOS 18.1, but in iOS 18.2, you can more freely describe the tone or content change that you want to make, such as adding more action words, or turning an email into a poem.

‌Apple Intelligence‌ now supports localized English in Australia, Canada, New Zealand, South Africa, Ireland, and the UK in addition to U.S. English.

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Over the last several years, we have studied many examples of cost reduction initiatives to improve productivity and create economies of scale. In simplest terms, there are four actions that improve productivity and economies of scale. First, reduce the rate of cost you pay for an input. Second, reduce the inputs that do not produce output. Third, reduce unique activities or components in products and processes by redesigning the products and processes. Fourth, spread fixed cost activities over new product output. The cellular telephone carriers are introducing measures to reduce their costs by redesigning the product.

The wireless carriers use cellular towers to broadcast their signals. The cellular product design offers signals traveling long distances, primarily for voice and for relatively low data speeds. A cellular tower is expensive but capable of sending a signal for several miles.

This cellular technology worked well until the evolution of the smart phone. The growth of the smart phone has put very high demands on the cellular tower infrastructure because of the heavy data usage it brings to the market. Since 2010, data has taken over the majority of network traffic from voice communications. Now the carriers and, in particular, AT&T with its Apple iPhones, is having difficulty keeping up with the growth in demand.

AT&T today and, likely a few others in the future, has found a potential innovative solution, adding Wi Fi access points. These Wi Fi access points are ideal for heavy data traffic sent at high speeds over relatively short distances. Wi Fi access points transmit signals over a few hundred feet. The Wi Fi access points are smaller, easier and cheaper to install than are cellular towers. This low-cost approach appears to make sense in areas with high density of users. AT&T has placed them in New York’s Time Square and Rockefeller Center, in downtown Charlotte, North Carolina, in neighborhoods surrounding Chicago’s Wrigley Field and in San Francisco’s Embarcadero Center.

But there are some drawbacks to Wi Fi access points. Sometimes, a user has to take several steps to connect to a Wi Fi access point. Signals from the Wi Fi access points may interfere with one another, if signals come from multiple networks. Some smart phones do not have Wi Fi capability. These disadvantages have, so far, held back Verizon Wireless’s adoption of this apparently low-cost approach to providing service.

AT&T is leading this cost-saving innovation experiment. Their network strains force it to be creative and experimental. AT&T saves costs by redesigning the product itself using a less expensive technology with some shortcomings. If the AT&T experiment proves both cost effective and acceptable to cellular customers, every other wireless carrier will be forced to adopt it. And since a Wi Fi access point is largely a fixed cost, the wireless carriers with the highest density of membership within the Wi Fi area will have the lowest cost per unit. In most areas of the country that is likely to be either Verizon or AT&T. They will end up getting a unit cost advantage over their smaller competitors…if this works.

1. Brisbane Broncos star Ezra Mam charged over head-on collision, allegedly failing second drug test  ABC News
2. Brisbane news live: Broncos’ Ezra Mam charged over drug test result after crash | Stab victim’s widower wants knife checks in schools | Dog rescued near abandoned boat  Brisbane Times
3. Broncos player charged after car crash: 9News Latest Stories Season 2024, Short Video  9Now
4. Ezra Mam issued court notice after allegedly failing secondary drug test  Fox Sports
5. Club Statement: Ezra Mam  Broncos

The Planetary Society and Lerner Publishing Group have teamed up to bring young readers an engaging series of books that make space science fun and accessible.

White males make up the largest sector of the U.S. workforce and have, on average, always made the highest salaries. If we compare their salaries to those of women, ethnic minorities, the differently-abled, and LGBTQ+ persons, we see a large disparity between the wages of similarly-qualified candidates in the same fields. The gap is glaring, […]

The post Race, Gender, and LGBTQ+ wage gaps are real – and they end up costing us all appeared first on DiversityJobs.com.

Guest post by Dr. Melissa Betters Are you afraid of the deep, dark ocean? If so, you’re not alone. Thalassophobia (fear of deep water) seems…

The post  The Cost of Fear: How Perceptions of the Deep Sea Hurt Conservation first appeared on Deep Sea News.

It’ll go perfect with a tiny house. READ MORE...

Explores how the Institute for Research and Innovation in Social Services (IRISS) promotes the delivery of cost effective social services in Scotland that will support the achievement of positive outcomes for people accessing support. It identifies a number of principles that underpin the work of IRISS and suggests how these facilitate innovative evidence-informed practice. The approach to evidence-informed practice comprises four pillars of activity. The first pillar focuses on improving awareness and access to evidence and is exemplified by the Learning Exchange, the IRISS Insights series, and audio and video recording. The second pillar refers to strengthening the evidence base and is discussed in the context of work on self-directed support. Improving skills and confidence to use evidence forms the third pillar and is represented by work on data visualisation and peer support for self-evaluation. The final pillar is embedding evidence in organisations, through co-production, creating spaces to test and challenge evidence, and through the development of evidence-based products. Supporting people to share knowledge, learn from each other and to collectively produce new knowledge and solutions is an innovative approach but also one which should be cost-effective. Pre-print. Published in Evidence and Policy, 2014 (10)4 as Embedding research into practice through innovation and creativity: a case study from social services

I couldn’t believe my eyes as I wandered through IKEA’s soft toy section. There, perched among the bins was Hedwig from Harry Potter. It was then I realized I was staring at IKEA’s new SKOGSDUVA snowy owl hand puppet. The resemblance to Harry’s faithful feathered companion was uncanny. While it might not deliver Hogwarts acceptance letters, it certainly brought a touch of magic to my shopping trip. With its fluffy white feathers and expressive eyes, this soft, cuddly version of […]

The post This Must-Have IKEA Item Completes Your Kid’s Harry Potter Costume appeared first on IKEA Hackers.

The Housing NOW project addresses home insecurity in a variety of affordable, efficient and sustainable ways. Started by Blue Temple, an architecture design studio based in Myanmar, the structures are constructed using bamboo that is locally available and endlessly renewable.[...]

A threat actor with ties to the Democratic People's Republic of Korea (DPRK) has been observed targeting cryptocurrency-related businesses with a multi-stage malware capable of infecting Apple macOS devices. Cybersecurity company SentinelOne, which dubbed the campaign Hidden Risk, attributed it with high confidence to BlueNoroff, which has been previously linked to malware families such as

Cybersecurity researchers have discovered a new phishing campaign that spreads a new fileless variant of known commercial malware called Remcos RAT. Remcos RAT "provides purchases with a wide range of advanced features to remotely control computers belonging to the buyer," Fortinet FortiGuard Labs researcher Xiaopeng Zhang said in an analysis published last week. "However, threat actors have

Threat actors with ties to the Democratic People's Republic of Korea (DPRK aka North Korea) have been found embedding malware within Flutter applications, marking the first time this tactic has been adopted by the adversary to infect Apple macOS devices. Jamf Threat Labs, which made the discovery based on artifacts uploaded to the VirusTotal platform earlier this month, said the Flutter-built

The post Wives of Soviet Cosmonauts appeared first on English Russia.

A Princeton-led team of astrophysicists has measured a surprising value for the “clumpiness” of the universe’s dark matter.

Research by Princeton scholars at the Atacama Cosmology Telescope collaboration has culminated in a significant breakthrough in understanding the evolution of the universe.

Craig B. Arnold has been named Princeton’s first University Innovation Officer and heads the new office.

COSCON is Princeton's student-run computer science contest designed to encourage out-of-the-box thinking on the variety of topics arising in computer science and its applications. You can participate in teams comprised of at most three members, each of whom must be either an undergraduate or graduate student at Princeton. The best teams will win prizes, which include best freshman/sophomore team, best non-COS/MAT team, among others. Organized by the ACM Student Chapter of Princeton.

An alluring scent can restore unforgettable memories, evoke emotions, rejuvenate mood, and enhance one’s presence. Luxurious fragrances expressing your personality cost an extra penny. Out of curiosity, imagine why these exclusive perfumes are way more expensive. Premium perfumes are masterpieces of pleasant aromas, luxurious packaging, and exceptional quality. Dossier perfume is an exclusive scent inspired ... Read more

The post The Art of Fragrance: The Secrets Behind the High Cost of Exclusive Perfumes appeared first on Star Two.

Hyperbaric Oxygen Therapy (HBOT) is a medical treatment that involves breathing pure oxygen in a pressurized environment. This unique treatment method has shown effectiveness in healing various conditions, from complex wound healing to treating decompression sickness in divers. HBOT works on the principle of increasing oxygen concentration in the body, which can enhance the body’s ... Read more

The post How Much Does Hyperbaric Oxygen Therapy Cost? Price Tips appeared first on Star Two.

The oldest DNA ever retrieved, preserved in sediments in northern Greenland, reveals that Arctic and temperate species once commingled in an ecosystem unlike anything that exists today.

By Harold Hutchison Former Acting Secretary of Homeland Security Chad Wolf told CNN host Jim Acosta Tuesday that the incoming Trump administration would “initiate a pretty large program” to locate children the Biden-Harris administration lost track of. At least 85,000 children placed into the custody of the Office of Refugee Resettlement (ORR) are unaccounted for, […]

The post Former Trump Official Reminds Jim Acosta Of ‘Over 330,000 Children’ Biden-Harris Admin Lost Track Of At Border appeared first on Liberty Unyielding.

Jeannie Ambrose, one of about 1,000 affected patients, says the drug should be made available on the NHS

Trying to find the balance between pure engineering and entertainment has been a very difficult balancing act over the years in Formula 1, but many in the sport think we seeing the signs of change as the cost cap takes effect on track.

Honda and Alpine are fined by governing body the FIA after being found guilty of breaching Formula 1's cost-cap rules for engine manufacturers in 2023.

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

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

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

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

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

Donald Trump's proposed tariffs would hit the consumer tech sector, raising prices on US consumers' favorite gadgets, an October report found.

PORT LOUIS, Nov 10 - Mauritius was holding a parliamentary election on Sunday with Prime Minister Pravind Kumar Jugnauth and his main rivals all promising to tackle a cost of living crisis in the Indian Ocean archipelago.

A.F. Branco Cartoon – Mainstream leftist media, along with the Democrats (The Party of the KKK), are trying their best..

Water, Ecosystems and Energy in South Asia: Making Cross-Border Collaboration Work Research paper sysadmin 29 June 2016

A new paper sets out the factors that have made previous cross-border projects in South Asia successful, arguing that cooperation around water is feasible despite the region’s political differences and economic assymetries.

• The countries of South Asia share some of the world’s major river basins – the Ganga (or Ganges), the Brahmaputra and the Indus. These rivers and their tributaries flow through seven countries, support more than 1 billion people, irrigate millions of hectares of land and are of cultural importance to many of those who rely on them.
• River management presents common challenges across the region. These include physical factors such as droughts, flooding, cyclones and climate change, as well political and institutional factors impeding the development of solutions and policies to improve resource management and reduce vulnerability. Water is increasingly seen as a source of competition, with population growth, industrialization and urbanization exacerbating the pressures on supply.
• Although South Asian examples of regional cooperation in general are limited, there is a clear positive trend. In areas such as disaster response and cross-border power trading, regional and bilateral engagement is beginning to take place. Multilateral official arrangements exist for trade and other economic issues, but there is none on water or ecosystems. However, as the benefits from cooperation become proven, its desirability is likely to gradually enter mainstream policy thinking on water issues.
• This research paper sets out the factors that have enabled cooperation, and the processes adopted, in previous successful cross-border projects. It focuses on four categories of cooperation: development of early-warning systems for natural disasters, in particular floods; protection of cross-border ecosystems; sharing of learning, through the showcasing of innovative approaches in one country that can be adopted by others; and power trading, in particular the development of hydropower in Bhutan and its export to India.
• The paper argues that cooperation around water in South Asia is feasible despite political differences and economic asymmetries. Different forms of collective action, and common understanding of both the threats and the shared benefits from cooperation, are required to foster more partnerships within the river basin states.

Mobile Ecosystems as a Driver of Innovation and Growth in the Asia-Pacific 19 September 2018 — 12:30PM TO 3:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

How modular renewables can reduce the costs of relying on carbon capture Expert comment LToremark 10 October 2024

COP29 must raise countries’ ambitions to deploy vastly more low-cost modular renewable technologies to help meet the tripling of renewables target set at COP28 and reduce our reliance on expensive carbon capture systems.

The most important international climate conference is around the corner. COP29 in Baku, Azerbaijan will be especially important because next year countries will submit their five-yearly national climate plans – or Nationally Determined Contributions (NDCs) – as set out under the Paris Agreement.

At COP28 in Dubai last year, the final text was heralded as a last-minute success as – somewhat surprisingly – it was the first ever COP to commit to ‘transition away from fossil fuels in energy systems in a just, orderly and equitable manner’. To support this, over 200 countries also committed to triple renewable capacity by 2030.

Under current NDCs, even if all countries achieve their most ambitious decarbonization plans, the world would still fall 30 per cent short of tripling renewable capacity by 2030. 

At COP29 in November, hosted by a petrostate, additional agreement is needed to operationalize the removal of fossil fuels from the global energy system and set the ambition for those crucial NDCs in 2025. Failing to do so means the opportunity to triple renewables by 2030 will slip away. But the actions of oil producing nations, international oil companies, their associated supply chains and networks of lobbyists have in recent years done their best to disrupt and slow down the energy transition and water down key negotiations during COPs and elsewhere. 

During the final days of COP28, the Organization of the Petroleum Exporting Countries (OPEC) sent private letters to its 13 members – including COP28 host the United Arab Emirates (UAE) – urging them to ‘proactively reject any text or formula that targets energy, i.e. fossil fuels, rather than emissions’. OPEC members own 80 per cent of global oil reserves.

Due to the startling decline in the cost of renewables and electric vehicles, fossil fuel producers are increasingly concerned. To fight back they are turning to carbon capture and storage (CCS) technologies and carbon removal options, which would enable the continued burning of fossil fuels – and protect their assets and business models.

A key battle ground for oil and gas producers is the difference between abated and unabated fossil fuels.

Abatement is the process of capturing CO₂ as fossil fuels are burnt to prevent a proportion of those CO₂ emissions from entering the atmosphere, either by using that CO₂ in products or storing it in geological formations deep underground in near perpetuity, commonly referred to as CCS.

After COP28 there was optimism that the final agreement was significant and covered all fossil fuels without ambiguity around whether they are unabated or abated. 

But the definition of unabated has not actually been agreed within the COP process. During the 2021 COP26 summit, the Glasgow Climate Pact mentioned unabated in reference to coal. Could a gas power station capturing 51 per cent of the emitted CO₂ be considered abated?

And what about the so-called downstream emissions? Downstream emissions from cars, planes, tanker ships and diesel generators etc make up 50–80 per cent of the total emissions from oil – and there are no plans to attach mini-CCS systems to cars.

CCS and engineered carbon removals are also likely to be expensive. Analysis by the Oxford Smith School of Enterprise and the Environment has shown that high CCS pathways to net zero emissions in 2050 would cost at least $30 trillion more than a low CCS pathway with more renewables – roughly $1 trillion more per year.

The costs of CCS have also remained the same for the past 40 years, while the costs of renewables like solar, wind and lithium-ion batteries have dropped radically. Solar costs have declined by 90 per cent in the last decade. 

The rapid cost reductions of solar, wind and batteries are due to their modular nature. Around 70 billion solar cells will be manufactured this year, the majority in China. It is the repetitive modular manufacturing process that has led to rapid efficiency improvements and cost reductions. Each Tesla has around 7,000 lithium-ion battery cells, and the price of these modular batteries fell 14 per cent between 2022 and 2023 alone. 

The modular criteria can help define the technology winners of the future, technologies we should selectively support and accelerate over the coming years. 

While huge industrial power stations, oil rigs and refineries have their benefits, they are not modular in the same way. Their economy of scale is in the large size of each asset. CCS is bolted on to fossil fuel infrastructure but there are less than 50,000 fossil fuel producing assets globally. By contrast, there were 1.5 billion solar panels produced in 2022. The cost of deploying CCS is therefore unlikely to benefit from the rapid cost reductions of modular renewables. Nuclear even less so. There are 440 nuclear power stations in operation today, they take many years to build and remain hugely expensive. 

For many Jamaicans, the deceased are more than just loved ones who have passed on; they are cherished family members who deserve to look as presentable as they did in life. In a culture where the appearance of the deceased is paramount, morticians...

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

α-Linked galactose is a common carbohydrate motif in nature that is processed by a variety of glycoside hydrolases from different families. Terminal Galα1–3Gal motifs are found as a defining feature of different blood group and tissue antigens, as well as the building block of the marine algal galactan λ-carrageenan. The blood group B antigen and linear α-Gal epitope can be processed by glycoside hydrolases in family GH110, whereas the presence of genes encoding GH110 enzymes in polysaccharide utilization loci from marine bacteria suggests a role in processing λ-carrageenan. However, the structure–function relationships underpinning the α-1,3-galactosidase activity within family GH110 remain unknown. Here we focus on a GH110 enzyme (PdGH110B) from the carrageenolytic marine bacterium Pseudoalteromonas distincta U2A. We showed that the enzyme was active on Galα1–3Gal but not the blood group B antigen. X-ray crystal structures in complex with galactose and unhydrolyzed Galα1–3Gal revealed the parallel β-helix fold of the enzyme and the structural basis of its inverting catalytic mechanism. Moreover, an examination of the active site reveals likely adaptations that allow accommodation of fucose in blood group B active GH110 enzymes or, in the case of PdGH110, accommodation of the sulfate groups found on λ-carrageenan. Overall, this work provides insight into the first member of a predominantly marine clade of GH110 enzymes while also illuminating the structural basis of α-1,3-galactoside processing by the family as a whole.

Mammalian Asn-linked glycans are extensively processed as they transit the secretory pathway to generate diverse glycans on cell surface and secreted glycoproteins. Additional modification of the glycan core by α-1,6-fucose addition to the innermost GlcNAc residue (core fucosylation) is catalyzed by an α-1,6-fucosyltransferase (FUT8). The importance of core fucosylation can be seen in the complex pathological phenotypes of FUT8 null mice, which display defects in cellular signaling, development, and subsequent neonatal lethality. Elevated core fucosylation has also been identified in several human cancers. However, the structural basis for FUT8 substrate specificity remains unknown.Here, using various crystal structures of FUT8 in complex with a donor substrate analog, and with four distinct glycan acceptors, we identify the molecular basis for FUT8 specificity and activity. The ordering of three active site loops corresponds to an increased occupancy for bound GDP, suggesting an induced-fit folding of the donor-binding subsite. Structures of the various acceptor complexes were compared with kinetic data on FUT8 active site mutants and with specificity data from a library of glycan acceptors to reveal how binding site complementarity and steric hindrance can tune substrate affinity. The FUT8 structure was also compared with other known fucosyltransferases to identify conserved and divergent structural features for donor and acceptor recognition and catalysis. These data provide insights into the evolution of modular templates for donor and acceptor recognition among GT-B fold glycosyltransferases in the synthesis of diverse glycan structures in biological systems.

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

Toma Keser
Dec 29, 2020; 0:RA120.002433v1-mcp.RA120.002433
Research

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves  are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as  prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer  RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A).  RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.

N-acylethanolamines (NAEs) are endogenous lipid-signaling molecules derived from fatty acids that regulate numerous biological functions, including in the brain. Interestingly, NAEs are elevated in the absence of fatty acid amide hydrolase (FAAH) and following CO₂-induced ischemia/hypercapnia, suggesting a neuroprotective response. Tetracosahexaenoic acid (THA) is a product and precursor to DHA; however, the NAE product, tetracosahexaenoylethanolamide (THEA), has never been reported. Presently, THEA was chemically synthesized as an authentic standard to confirm THEA presence in biological tissues. Whole brains were collected and analyzed for unesterified THA, total THA, and THEA in wild-type and FAAH-KO mice that were euthanized by either head-focused microwave fixation, CO₂ + microwave, or CO₂ only. PPAR activity by transient transfection assay and ex vivo neuronal output in medium spiny neurons (MSNs) of the nucleus accumbens by patch clamp electrophysiology were determined following THEA exposure. THEA in the wild-type mice was nearly doubled (P < 0.05) following ischemia/hypercapnia (CO₂ euthanization) and up to 12 times higher (P < 0.001) in the FAAH-KO compared with wild-type. THEA did not increase (P > 0.05) transcriptional activity of PPARs relative to control, but 100 nM of THEA increased (P < 0.001) neuronal output in MSNs of the nucleus accumbens. Here were identify a novel NAE, THEA, in the brain that is elevated upon ischemia/hypercapnia and by KO of the FAAH enzyme. While THEA did not activate PPAR, it augmented the excitability of MSNs in the nucleus accumbens. Overall, our results suggest that THEA is a novel NAE that is produced in the brain upon ischemia/hypercapnia and regulates neuronal excitation.

Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb₃), globotriaosylsphingosine (lyso-Gb₃), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb₃ isoforms (various fatty acids) and lyso-Gb₃ analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb₃ and lyso-Gb₃ levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb₃ and particular lyso-Gb₃ analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb₃ and lyso-Gb₃ isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb₃ massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb₃ accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb₃ or lyso-Gb₃ may play major roles in the pathogenesis of Fabry disease, and that Gb₃ and lyso-Gb₃ are not responsible for the pathology in all tissues or cell types.

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of ¹⁸F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1^–/– versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1^–/– mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

Influenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between WT IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.