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BPS Renew Appeal For Information On Shooting

Three years after the shooting at Robin Hood Restaurant, the police are urging anyone with information on this case to come forward. A police spokesperson said, “Around 6pm on Tuesday 26th October 2021, Police operations received several 911 calls from persons reporting gunshots from inside the Robin Hood Restaurant, located at #25 Richmond Road, Pembroke. “The […]




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Penzijní reforma je nevyhnutelná. Opozice nabízí jen destrukci, populismus a ztrátu paměti

Vláda si může připsat úspěch, když ve sněmovně prosadila důchodovou reformu. Zatímco odborná sféra ji považuje za důležitý krok ke stabilizaci veřejných financí, opoziční strany křičí, že ji zruší. Řídí se heslem po nás potopa.




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Glenn Greenwald says that the Democratic Party, NSA, CIA, Neocons, Silicon Valley, Wall Street, mainstream media have united to impose an authoritarian government of censorship and suppression of information

The CIA from the very first days of the Trump administration, even before he was inaugurated, devoted themselves to sabotaging the administration because Donald Trump questioned just a few of their pieties. And that can't be done in Washington. Whoever does that must be destroyed. And so the CIA and the Deep State operatives became heroes of the liberal left, the people who support the Democratic party. They're now in a full union with the neocons, the Bush Cheney operatives, the CIA, Silicon Valley, and Wall Street. That is the union of power along with mainstream media outlets that are fully behind the Democratic party, which is likely to at least take over one branch of government, if not all of them, with the coming election, and that is a very alarming proposition because they're authoritarian, they believe in censorship, and they believe in suppression of information that exposes them in any kind of a critical light. Continue reading




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The government is instructing social media companies what shouldn’t be allowed to be on the internet even though these companies are the least competent to judge what is misinformation

The government is instructing social media companies what should and shouldn't be allowed to be on the internet, these are the people least competent to judge what is misinformation. Continue reading




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TIFF Day 4: Masterful Performances from Frances McDormand and Mads Mikkelsen

Nomadland [US, Chloé Zhao, 5] When her town closes down in the wake of its gypsum mine’s closure, a self-reliant widow (Frances McDormand) moves into her van and joins the ranks of the nomad subculture, people who rove the US, taking whatever hard work they can get and living out of their vehicles. Rooted in social realist cinema, marked by a triad of transcendent qualities: poetic visual beauty, an indelible central performance and a deep love for the characters from the writer/director.

This is from Searchlight, formerly Fox Searchlight, now part of the Disney empire, so you’ll get a chance to see it. Likely as part of awards season, whatever the heck that’s gonna look like this year. Normally I don’t spend festival slots on titles with distribution but that’s out the window in the COVID-verse.

(At the moment cinemas are open, with distancing, here in Ontario but if you look at the numbers we’re in the early denial phase of a reimposition of lockdown measures. Whatever the deal is I don’t plan to be inside a theater in any foreseeable time frame.)

Her next project is a huge pivot from poetic verite dramas like this and The Rider— Marvel’s The Eternals. 

Memory House [Brazil, João Paulo Miranda Maria, 1] Racist harassment from German co-workers drives dairy worker to vengeance. Blunts the political anger of its subject matter with enervating pacing.

Another Round [Denmark, Thomas Vinterberg, 4.5] Burned out high school teacher (Mads Mikkelsen) embarks with three colleagues on an experiment to enhance their performance by maintaining a blood alcohol level of 0.5% throughout their days at work. Not only an original booze movie, but a big one, full of turns and ambiguities, and an utterly masterful performance from Mikkelsen.

Shadow in the Cloud [New Zealand, Roseanne Liang, 4] When an WWII RAF Flight Officer (Chloe Grace Moretz) boards a Samoa-bound cargo plane bearing a mysterious package, a monstrous gremlin on board is just one of the surprises. Enclosed space horror-action thriller tips an 80s-style hat to Carpenter and Cameron.


Capsule review boilerplate: Ratings are out of 5. I’ll be collecting these reviews in order of preference in a master post the Monday after the fest. Films shown on the festival circuit will appear in theaters, disc and/or streaming over the next year plus.



  • toronto international film festival

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TIFF Day 6: Gay Teen Melodrama, A Brilliant Anthony Hopkins Performance, and Epic Municipal Poetry

City Hall [US, Frederick Wiseman, 4] The latest of Wiseman’s distinctive epic-length observational documentaries studies the quotidian, procedural and human moments of human life as seen through the processes of municipal government in Boston, as held together by the thoughtful charisma of Mayor Martin Walsh. Improbably absorbing as always, this institutional cross-section offers a beguiling vision of an oasis of good government in the USA.

In a normal year I’d wait for the four and a half hour Wiseman documentary to arrive on television rather than taking up two time slots to watch it from the confines of a cinema seat at TIFF. But this is not such a year and with a digital screening you get a pause button when you need it. This is bound for PBS and due to the breadth of its subject matter will serve as an excellent introduction to those unfamiliar with this pillar of the documentary form. Or track down 2017’s Ex Libris, about the New York Public Library. In North America Wiseman’s filmography can be found on the Kanopy platform, which you may be able to access through your public library system.

The Father [UK, Florian Zeller, 4] Retired engineer (Anthony Hopkins) struggles to piece together the confusing reality of his living circumstances as his daughter (Olivia Colman) copes with his progressing dementia. Impeccably performed stage play adaptation puts the viewer inside the contradictory shifts of the protagonist’s subjective viewpoint.

Forget Draculas and Cthulhus. This is the real terror.

Summer of 85 [France, Francois Ozon, 4] Love between two young men in a French beach town leads to a bizarre crime. Teen emotions run high in a sunlit melodrama of Eros and Thanatos.


Capsule review boilerplate: Ratings are out of 5. I’ll be collecting these reviews in order of preference in a master post the Monday after the fest. Films shown on the festival circuit will appear in theaters, disc and/or streaming over the next year plus.



  • toronto international film festival



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Perplexity says it will begin experimenting with ads on its platform in the US starting this week; ads will be formatted as “sponsored follow-up questions”

AI-powered search engine Perplexity says it’ll begin experimenting with ads on its platform starting this week. Ads will appear in the U.S. to start, formatted as “sponsored follow-up questions.” (E.g., “How can I use LinkedIn to enhance my job search?”) Paid media will be positioned to the side…




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Intel Promises Fix for Arrow Lake Performance Issues Within a Month

Intel has announced that it will address the performance issues plaguing its recently launched Core Ultra 200S series, particularly in gaming. The company acknowledged that the launch did not meet expectations and plans to roll out updates by the end of November or early December to rectify the situation.

The post Intel Promises Fix for Arrow Lake Performance Issues Within a Month appeared first on ThinkComputers.org.




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How do we ensure that training and information support contributes to positive outcomes for carers?

This is a paper produced as part of the PROP2 (Practitioner Research: Outcomes and Partnership) programme, a partnership between the Centre for Research on Families and Relationships (CRFR) at the University of Edinburgh and Iriss that was about health and social care in Scotland. This paper was written by Alan Gilmour from Glasgow City Community Health Partnership who participated in the PROP2 programme. This research aimed to gain an understanding of how training and information support contributes to positive outcomes for carers. It provided a range of information to answer specific questions such as: • Do carers feel that their needs are identified appropriately at different stages of their journey? • Does training contribute to the carer’s outcomes? • What are the barriers to carers engaging in training?




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Steve Coogan’s Five Most Essential Comedy Performances

By Tara Ariano Published: November 12th, 2024





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FBI says hackers are sending fraudulent police data requests ot tech giants to steal people's private information




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Mapping brain function, safer autonomous vehicles are focus of Schmidt Transformative Technology fund

Two projects — one that maps the function of the brain’s neuronal network in unprecedented detail and another that combines robotics and light-based computer circuits to create safe self-driving vehicles — have been awarded funding through Princeton’s Eric and Wendy Schmidt Transformative Technology Fund.




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Theater Performance Co-curricular Classes with Vivia Font

In this co-curricular workshop series with Vivia Font, develop your acting chops! Geared towards students who want to continue developing their acting practice, as well as beginner students who are acting-curious. Drop-in; students may attend 1 session or all 8.




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Cannabis doesn’t enhance performance. So why is it banned in elite sports?

Here’s how cannabis use became prohibited—and the science of its biological, psychological, and social effects.





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'Norris' hopes crushed by Verstappen performance for the ages'

Lando Norris’ already slim world title hopes were crushed at the Sao Paulo Grand Prix by a performance for the ages from Max Verstappen.




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The Efficacy of Digital Media Resources in Improving Children’s Ability to Use Informational Text: An Evaluation of Molly of Denali From PBS KIDS

Informational text — resources whose purpose is to inform — is essential to daily life and fundamental to literacy. Unfortunately, young children typically have limited exposure to informational text. Two 9-week randomized controlled trials with 263 first-grade children from low-income communities examined whether free educational videos and digital games from the PBS KIDS show “Molly of Denali” supported children’s ability to use informational text to answer real-world questions. Study 1 found significant positive intervention impacts on child outcomes; Study 2 replicated these findings.




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Improve the performance of your Joomla articles (part 1)

The performance of the default article system in Joomla really sucks big time, that's a well know fact.

It''s actually one of the reasons we built K2 in the first place.

And as we venture into Joomla 4 territory, instead of seeing performance improvements (finally) for the entire database scheme, we actually witness new ways to mess up performance (if that was even possible). Apparently the Joomla core team likes to exercise who knows PHP's syntax better instead of actually building working code that doesn't break for extension developers every so.

Oh well, we're used to the mess.

Back to our topic.

Wanna improve the performance of the Joomla article system, especially in sites that filter/order content in various ways? Well, for starters add a few indices to the "content" table, e.g. using phpMyAdmin.

ALTER TABLE `#__content` ADD INDEX `idx_publishup` (`publish_up`);
ALTER TABLE `#__content` ADD INDEX `idx_publishdown` (`publish_down`);
ALTER TABLE `#__content` ADD INDEX `idx_modifiedby` (`modified_by`);
ALTER TABLE `#__content` ADD INDEX `idx_created` (`created`);
ALTER TABLE `#__content` ADD INDEX `idx_modified` (`modified`);

Just remember to replace #__ with your actual database prefix for Joomla.

But what's the measurable improvement? Well, something like this after you apply the above changes (on a really busy site that sorts articles by published date, aka 99% of Joomla sites)...

Yeap.

And that's performance tip no.1. We'll come back with more in the future as we delve into the software architectural wonder that is Joomla 4.

Or do yourself a favour & switch to K2 which recently passed 4 million downloads, yeah! :)

To those who might say, hey why aren't you contributing that back to Joomla, well, our answer is that if you've ever contributed in Joomla, you know the painful process & bureaucracy and you juuuust might wish to keep your sanity.

Until next time.




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Analysis of {beta}-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism [Enzymology]

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.




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Biosynthesis of the sactipeptide Ruminococcin C by the human microbiome: Mechanistic insights into thioether bond formation by radical SAM enzymes [Microbiology]

Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and posttranslationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC's antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to-α-carbon thioether–containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of nonnatural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC–MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element, present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the peptide recognition element and the core peptide for the installation of posttranslational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation.




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A drug-resistant {beta}-lactamase variant changes the conformation of its active-site proton shuttle to alter substrate specificity and inhibitor potency [Microbiology]

Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance.




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High temperature promotes amyloid {beta}-protein production and {gamma}-secretase complex formation via Hsp90 [Neurobiology]

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.




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Resetting Africa-Europe relations: From self-deception to economic transformation

Resetting Africa-Europe relations: From self-deception to economic transformation 28 October 2024 — 12:30PM TO 1:30PM Anonymous (not verified) Chatham House and Online

Experts assess the status of ties between Africa and Europe in a rapidly changing world, launching a new book that explores how misconceptions in the relationship can harm Africa’s economic agenda.

The relationship between Africa and Europe has long been shaped by colonial legacies, power imbalance and shifting geopolitical interests.

Almost three years on from the last EU-AU summit in Brussels in February 2022, questions remain over the delivery of headline commitments under the continent-to-continent partnership – ranging from the EU’s Global Gateway infrastructure strategy to wider climate financing promises.

As Africa seeks to strengthen its standing on the global stage, marked by the African Union’s upcoming debut at the G20 summit in November, a critical reassessment of these dynamics is needed to examine whether the continent’s relationship with Europe can overcome stigmatized narratives in search of genuine economic benefit.

At this event, which launches a new book by Professor Carlos Lopes: The Self-Deception Trap: Exploring the Economic Dimensions of Charity Dependency within Africa-Europe Relations, speakers assess the prospects for a transformative shift towards a more equitable and mutually beneficial Africa-Europe partnership.




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Preparing for Digital Transformation




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Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles




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Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles




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Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells

JL Dixon
Feb 1, 1993; 34:167-179
Reviews




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Bile salt biotransformations by human intestinal bacteria

Jason M. Ridlon
Feb 1, 2006; 47:241-259
Reviews




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Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations [Molecular Biophysics]

Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization.




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The Impact of Brexit on Energy Transformation in the UK and EU

The Impact of Brexit on Energy Transformation in the UK and EU 28 March 2019 — 8:15AM TO 9:45AM Anonymous (not verified) 3 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

The UK’s decision to leave the EU will fundamentally reshape many of the UK’s policies and its relations with countries around the world. For energy and climate, the changes could be significant and will need to be managed carefully to secure ongoing investment, stable energy prices and ambitious climate objectives. The UK’s departure will also affect the balance of political support for climate and energy policies with the EU institutions and potentially impact upon regional initiatives.

This roundtable will discuss:

  • The impact on the energy sector of Brexit during the transition period through until December 2020 including the operation of interconnectors and access to the Internal energy market, ongoing engagement in European research collaboration and the replacement of European financial resources.
  • The possible opportunities and risks for the UK’s energy sector in 2021 and beyond.
  • The implications of Brexit on the EU’s energy and climate policy.

The roundtable will discuss the role of the public and business in shaping the future deal as it will need to be ratified by the parliaments of all member states.

Attendance at this event is by invitation only.




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Power Sector Transformation, New Market Dynamics and Geopolitical Implications

Power Sector Transformation, New Market Dynamics and Geopolitical Implications 7 November 2018 — 8:00AM TO 9:30AM Anonymous (not verified) 6 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

The global electricity sector is experiencing profound change due to a confluence of technological innovation, environmental policies and regulatory reform. The effect is most obvious in the EU28, Australia and parts of North America.

However, this is just the beginning and the success of the next phase of electricity sector transformations hinges on enhancing system flexibility to facilitate unhindered low-cost deployment of renewables. It remains to be seen how utilities will seek to navigate this second phase of electricity transformations.

This session starts with a presentation and discussion that focuses on:

  • Public and private sector risks of the transformation of the power sector, changes in generation mix and their implications for supply chain, employments and investment patterns.
  • The role of government and the regulatory framework in light of changing market structure, new entrants and big data.
  • Wider geopolitical issues including the implication for fossil fuel producers and the rise in demand for new materials and changes in land use.
  • The possible implications on the power sector on the electrification of heat and transport.

The discussion then moves to the speed of transformation and what this means for existing and new market actors.




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Food system transformation: A blind spot for climate and biodiversity action?

Food system transformation: A blind spot for climate and biodiversity action? 20 October 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 5 October 2022 Chatham House and Online

How can COP27 and COP15 accelerate the agenda for sustainable food systems and land use?

Tackling the dual crises of climate change and biodiversity loss requires extraordinary levels of action at an unprecedented speed. Agriculture is the biggest user of land, the biggest source of methane emissions, a major contributor to total greenhouse gas emissions and the leading driver of biodiversity loss.

Anything short of a food system transformation puts climate and biodiversity objectives in peril. However, governments have not yet produced credible pathways and strong policies for tackling our growing ‘foodprint’ – the negative impacts of what we grow and eat.

In advance of COP27 in Sharm El-Sheikh for climate and COP15 in Montreal for biodiversity, Chatham House has published a new briefing paper which examines aligning food systems with climate and biodiversity targets.

The paper reviews the climate and biodiversity policy landscape to 2030, with a focus on land-based aspects and the inclusion of food and agriculture. The paper highlights serious conflicts between the impacts of the food system and goals to protect and restore biodiversity and mitigate climate change.

In light of this, opportunities for joined-up action on food, climate and biodiversity are identified, including three key steps for countries to take this decade to produce suitably ambitious and effective policies across the climate–biodiversity–food nexus.

This event brings together leading voices from the international policy arenas for climate and biodiversity to react to the briefing paper and discuss how COP27 and COP15 can accelerate the agenda for sustainable food systems and land use.




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Deformation of Artinian Algebras and Jordan Type

Anthony Iarrobino, Pedro Macias Marques, Maria Evelina Rossi and Jean Vallès, editors. American Mathematical Society, 2024, CONM, volume 805, approx. 252 pp. ISBN: 978-1-4704-7356-3 (print), 978-1-4704-7665-6 (online).

This volume contains the proceedings of the AMS-EMS-SMF Special Session on Deformations of Artinian Algebras and Jordan Type, held July 18–22,...





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On Lamperti transformation and AR(1) type characterisations of discrete random fields

Marko Voutilainen, Lauri Viitasaari and Pauliina Ilmonen
Theor. Probability and Math. Statist. 111 (), 181-197.
Abstract, references and article information





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Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery [Enzymology]

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.




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

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




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Formal Representation for Young People Enhances Politics for All

10 September 2020

Ben Horton

Communications Manager, Communications and Publishing

Michel Alimasi

Member, Common Futures Conversations, Italy

Gift Jedida

Member, Common Futures Conversations, Kenya

Sanne Thijssen

Member, Common Futures Conversations, Netherlands

Mondher Tounsi

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

CFC Youth Participation EC_10092020.png

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

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

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

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

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

Putting youth representation into government

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

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

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

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

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

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

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

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

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




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




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

Visual Abstract




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Pacific Rim timeline: Information for defenders from a braid of interlocking attack campaigns

Sophos X-Ops unveils five-year investigation tracking China-based groups targeting perimeter devices




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Plasma proteomic data can contain personally identifiable, sensitive information and incidental findings

Philipp Emanuel Geyer
Dec 17, 2020; 0:RA120.002359v1-mcp.RA120.002359
Research




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Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation [Cell Biology]

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.




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Human glucocerebrosidase mediates formation of xylosyl-cholesterol by {beta}-xylosidase and transxylosidase reactions.

Daphne E.C. Boer
Dec 23, 2020; 0:jlr.RA120001043v1-jlr.RA120001043
Research Articles




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Problem Notes for SAS®9 - 66438: You see the message "The informat $ could not be loaded, probably due to insufficient memory" after attempting to insert data into a MySQL database

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…"




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Lipid Conformational Order and the Etiology of Cataract and Dry Eye [Thematic Reviews]

     Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen than any other tissue and contains almost no intracellular organelles. The tear film lipid layer (TFLL) is also unique. The TFLL is a thin, 100 nm layer of lipid on the surface of tears covering the cornea that contributes to tear film stability. The major lipids of the TFLL are wax esters and cholesterol esters that are not found in the lens. The hydrocarbon chains associated with the esters are longer than those found anywhere in the body, as long as 32 carbons, and many are branched. Changes in the composition and structure of the 30,000 different moieties of TFLL contribute to the instability of tears. The focus of the current review is how spectroscopy has been used to elucidate the relationships between lipid composition, conformational order and function and the etiology of cataract and dry eye.