Prospective performers and their families are invited to learn about Pacific Crest, our 2025 season, and auditions. A brief presentation will be followed by an AUA (ask us anything) session. All […]

Rows of armed agents were deployed around the protests in Washington, D.C. this past week, but it was not obvious who they were: They had no name tags, no badge numbers and no emblems to identify which agencies they worked for. Their arrival sparked shock and alarm. Now, Democratic lawmakers are calling for legislation that would make it illegal for these officers to not identify themselves. In the Senate, Minority Leader Chuck Schumer (D-N.Y.) and Chris Murphy (D-Conn.) are cosponsoring a bill that would require officers to identify themselves while "engaged in crowd control or arresting individuals involved in civil disobedience or protests in the United States." In the House, Virginia Democrat Don Beyer, whose district is just across the Potomac River from Washington, D.C., is working on similar legislation. "How do we tell these alleged federal police officers from white supremacist militia groups?" Beyer said in an interview Sunday with NPR's Weekend Edition . "How do you ever

Hidden changes are warping the already broken ecosystem that determines how many citizens—particularly in America—construct their sense of reality. (slSubstack)

Y'all, I know there are folks who don't like Substack/NYT links but here we are and I thought this was worth posting in the aftermath of a disastrous election.

Alejandra Borrero, Patrick Delmas y Rafael Zea protagonizan la obra adaptada por Carolina Mejía

What Danielle Smith posted on her subscribers-only social media; how litter boxes in schools became a Republican talking point; Yankee scented candle reviews as COVID indicator; a surgeon struggles to care for patients through Ethiopia's civil war; Brent Bambury returns and more.

Numerous new developments in CONTACT’s Elements platform and innovative digitalisation strategies will take centre stage at this year’s Open World.

A response from Fang Wengen, the lawyer of Mrs Yang Huiyan

Ascot announced today the appointment of Ian Grayson as Chief Information Officer for UK/ Bermuda. A spokesperson said, “In this newly created role, Ian is responsible for developing and executing a technology transformation strategy and driving technology-based innovation and growth to support the company’s robust UK and Bermuda platforms. He will report to Owen Williams, […]

The Transformational Living Centre [TLC] for Families is now utilizing solar power which they said “will provide most of the energy required to power their electrical needs.” A spokesperson said, “Gil Nolan, operations manager of Sunny Side Solar and Nick Hutchings, a volunteer for the non-profit solar company that donated the solar panels to the […]

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 […]

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 →

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 →

1. Amerikaanse militair Jack Teixeira (22), die geheime informatie over oorlog lekte, krijgt 15 jaar cel  Het Nieuwsblad
2. Jonge Amerikaanse militair die Pentagon-documenten lekte veroordeeld tot 15 jaar cel  VRT.be
3. Live - Oorlog in Oekraïne. Jack Teixeira, die geheime documenten over oorlog lekte, veroordeeld tot 15 jaar cel • Noord-Koreaanse soldaten betrokken bij gevechten, zeggen VS  De Morgen
4. 15 jaar cel voor Amerikaanse militair die geheime documenten lekte  NOS
5. 15 jaar cel voor Amerikaanse militair die geheime informatie op internet deelde  NU.nl

1. Nu Bart De Wever (N-VA) aan zet blijft als formateur: krijgt hij in 2 weken rond wat al 5 maanden niet lukt?  VRT.be
2. “De Wever wil Open Vld én Vooruit in federale regering”  Het Laatste Nieuws
3. De Wever wil Arizona nog eens reanimeren met ‘trucje’, maar of Vooruit deze keer hapt?  Het Laatste Nieuws
4. De Wever grijpt naar beproefd recept om Vooruit snel weer aan tafel te krijgen: het ‘saucissoneren’  De Morgen
5. Formatie: ‘Bart De Wever voert een toneeltje op’  Knack.be

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…

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?

If your format happened quickly, it's unlikely your data was actually erased. I'll show you the difference.

Will Formatting a Disk Erase All Data? from Ask Leo!.
Get the Confident Computing weekly newsletter: https://newsletter.askleo.com

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.

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.

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.

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.

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.

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.

Resetting Africa-Europe relations: From self-deception to economic transformation 28 October 2024 — 12:30PM TO 1:30PM Anonymous (not verified) 16 October 2024 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.

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

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

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

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

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.

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.

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.

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.

Daniel Le, Bao V. Le Hung, Stefano Morra, Chol Park and Zicheng Qian
Trans. Amer. Math. Soc. 377 (), 5749-5786.
Abstract, references and article information

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

Yongqiang Liu, Laurentiu Maxim and Botong Wang
Proc. Amer. Math. Soc. 152 (), 5279-5288.
Abstract, references and article information

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.

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

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

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.

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

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…"

     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.

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as acceptor for subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from Gaucher disease patients. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyse formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.