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Registration open for NOTOCON XIV

Registration is now open for National O.T.O. Conference XIV, to be held in Denver, Colorado, August 3-6 2023. NOTOCON is normally held every two years, but it was canceled in 2021 due to the pandemic, so this will be our first NOTOCON since 2019.




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NOTOCON Hotel Registration Closing

NOTOCON XIV is fast approaching! The cutoff date to receive our group rate at the hotel is Friday, July 21st. Please reserve now. The speaker schedule has been published on the NOTOCON website. Event registration is still open! We can’t wait to see all of you in August, and wish you all safe travels!




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College Football Playoff Rankings: Oregon, Ohio State on top; Alabama enters top 10

The second set of College Football Playoff Predictions were released Tuesday night, with Oregon, Ohio State and Texas listed in the top three spots. See the complete rankings!




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Portuguese FM warns of EU’s ‘cultural tendency’ to overregulate

Portuguese Foreign Minister Paulo Rangel warned on Tuesday of the downside of Europe's "cultural tendency" to "over-regulate" and called for a better "balance" between technological development and the defence of democracy and human rights. Read more. "Europe has a cultural tendency to…




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China's renaming of its regional jet is another clear sign its homegrown planemaker is coming for Boeing and Airbus

The ARJ21, COMAC's first commercially available plane, was rebranded on Tuesday to the C909. Chen Xiao/VCG via Getty Images China's COMAC is rebranding its regional jet to the C909, keeping with the naming style of its newer C919. That might not get COMAC more C909 sales, but it markets the plane…




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Trump appoints SpaceX's Elon Musk to help head regulation-slashing 'Department of Government Efficiency'

President-elect Donald Trump has tapped Elon Musk and Vivek Ramaswamy to lead the new Department of Government Efficiency, which aims to 'dismantle government bureaucracy.'




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Real numbers and points on the number line with regard to Cantor’s diagonal argument

Cantor’s diagonal argument claims that ℝ is uncountable. When we see real numbers as points on the number line, we can put a name on each point and put the names into a list without contravening Cantor’s diagonal argument because we cannot create a diagonal from a list of names. However, we do not need...




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F&S willen nu echt regulering (NRC, ma, 19-08-24)




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Forced to Carry: The Reality of Rape-Related Pregnancies in a Post-Roe World

Photo by freestocks The issue of rape-related pregnancies is a crucial yet often-overlooked aspect of the broader debate surrounding abortion access. As more states implement strict abortion bans, the implications for survivors of sexual violence become increasingly severe and far-reaching. When Hadley Duvall was just 12 years old, she was raped and impregnated by her stepfather. […]

The post Forced to Carry: The Reality of Rape-Related Pregnancies in a Post-Roe World appeared first on Feminist Majority Foundation.




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Oregon green building design embraces timber throughout

Have you heard about Mississippi? It's a construction project brought to life by Waechter Architecture after more than 10 years of planning and investigation. This building isn't just your ordinary structure; it's a game-changer in terms of sustainability and creativity.[...]






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Election 2024: How Princeton's Vote100 encourages students to register, vote and be more civically engaged

Voting registration rates among Princeton undergraduate and graduate students have more than doubled largely thanks to the program.




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A Conversation on Middle East Regional Security with Peter Berkowitz

Peter Berkowitz, Director of Policy Planning at the Department of State from 2019 to 2021 will discuss Middle East regional security.




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NBA Hall of Famer Reggie Miller Is Breaking the Cycling Mold



“Me being 6 feet 7 inches, I’m not your normal height-weight type cyclist. But that motivates me to get better, to be better, to go against these guys.”




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How do psychedelics work? This brain region may explain their effects

The claustrum seems to act as a switchboard, telling different parts of the brain when to turn on and off. But what happens when the switchboard operator steps away?




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NOVA Science Studio 2023-2024 Program Registration

Engage your students with science journalism about issues in their communities with the NOVA Science Studio program!




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How This Stingray May Have Gotten Pregnant Without a Mate

No sex? No problem. At least not for Charlotte the stingray.




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Dear Life Kit: Is it a faux pas to create a 'happy graduation' registry for myself?

An NPR listener is graduating soon with her MBA. She wants to know if it's OK celebrate her achievement by asking loved ones to buy her gifts from a registry, similar to what people do for weddings.




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Gayle King Calls out Pelosi For Using ‘Egregious’ Language In Referring To Trump Supporters As ‘Henchmen’

CBS News’s Gayle King criticized House Speaker Nancy Pelosi(D-CA) for calling President Trump’s supporters “henchmen,” reminding her the language she used is “just as egregious” as the insults the president directs towards her. King made the remarks Friday morning on CBS This Morning show when she asked the House Speaker about the upcoming Tuesday’s presidential […]

The post Gayle King Calls out Pelosi For Using ‘Egregious’ Language In Referring To Trump Supporters As ‘Henchmen’ appeared first on Hispolitica.




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velocityconf: Call for speakers and registration is open for @webperfdays in Silicon Valley http://t.co/cJKBmynkjI June 22, Google HQ (cc @sfwebperf)

velocityconf: Call for speakers and registration is open for @webperfdays in Silicon Valley http://t.co/cJKBmynkjI June 22, Google HQ (cc @sfwebperf)




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China's renaming of its regional jet is another clear sign its homegrown planemaker is coming for Boeing and Airbus

The ARJ21 is now to be known as the C909. The renaming plays into COMAC's ambition to enter the global market.




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A novel method produces native light-harvesting complex II aggregates from the photosynthetic membrane revealing their role in nonphotochemical quenching [Bioenergetics]

Nonphotochemical quenching (NPQ) is a mechanism of regulating light harvesting that protects the photosynthetic apparatus from photodamage by dissipating excess absorbed excitation energy as heat. In higher plants, the major light-harvesting antenna complex (LHCII) of photosystem (PS) II is directly involved in NPQ. The aggregation of LHCII is proposed to be involved in quenching. However, the lack of success in isolating native LHCII aggregates has limited the direct interrogation of this process. The isolation of LHCII in its native state from thylakoid membranes has been problematic because of the use of detergent, which tends to dissociate loosely bound proteins, and the abundance of pigment–protein complexes (e.g. PSI and PSII) embedded in the photosynthetic membrane, which hinders the preparation of aggregated LHCII. Here, we used a novel purification method employing detergent and amphipols to entrap LHCII in its natural states. To enrich the photosynthetic membrane with the major LHCII, we used Arabidopsis thaliana plants lacking the PSII minor antenna complexes (NoM), treated with lincomycin to inhibit the synthesis of PSI and PSII core proteins. Using sucrose density gradients, we succeeded in isolating the trimeric and aggregated forms of LHCII antenna. Violaxanthin- and zeaxanthin-enriched complexes were investigated in dark-adapted, NPQ, and dark recovery states. Zeaxanthin-enriched antenna complexes showed the greatest amount of aggregated LHCII. Notably, the amount of aggregated LHCII decreased upon relaxation of NPQ. Employing this novel preparative method, we obtained a direct evidence for the role of in vivo LHCII aggregation in NPQ.




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Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the {alpha}/{beta}-fold epoxide hydrolase Alp1U [Enzymology]

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.




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Structure, mechanism, and regulation of mitochondrial DNA transcription initiation [Enzymology]

Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.




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The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2 [Computational Biology]

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.




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Business Briefing: Assessing the geopolitical implications of EU AI regulation

Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) Chatham House

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology.

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology

Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?

In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.

This conversation will cover the following questions:

  • Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?
  • What lessons can we learn from the successes and shortcomings of GDPR?
  • How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?
  • Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future?




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M8R tropomyosin mutation disrupts actin binding and filament regulation: The beginning affects the middle and end [Molecular Bases of Disease]

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.




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Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL [Signal Transduction]

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.




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Network Power in the Asia-Pacific: Making Sense of the New Regionalism and Opportunities for Cooperation

Network Power in the Asia-Pacific: Making Sense of the New Regionalism and Opportunities for Cooperation 7 February 2020 — 9:45AM TO 5:30PM Anonymous (not verified) 17 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

The Asia-Pacific region continues to increase in geopolitical and geoeconomic importance. The rise of China and tensions with the US are affecting bilateral relationships and traditional alliances in the region. Whether seen from the perspective of the Quad – Australia, India, Japan and the US – or the Indo-Pacific concept embraced by a wide range of countries but with no shared consensus on scope and objectives or with ASEAN who insists on the importance of its own centrality, the region is redefining and reconceptualising itself.

With a diverse range of initiatives – including the Regional Comprehensive Economic Partnership (RCEP) and Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) – there are a plethora of regional agreements and institutional groupings that add further complexity.

As the Bretton Woods architecture continues to be dominated by Western powers, China is also spearheading parallel governance initiatives such as the Asian Infrastructure Investment Bank (AIIB), the Belt and Road Initiative and the Shanghai Cooperation Organization (SCO) as a means of enhancing its geopolitical and geoeconomic influence.

This one-day conference will focus on how such networks and alliances have been built, and sustained, in the Asia-Pacific region. In order to understand how new regional initiatives might open up opportunities for new forms of international cooperation, the conference will focus on the themes of cyber-technology and innovation, sustainable development and mitigating the impacts of climate change and new infrastructure initiatives. It will assess whether there is a zero-sum conflict between competing networks and agendas or whether a common approach can be developed.




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A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles

Sebastian A. Wagner
Oct 1, 2011; 10:M111.013284-M111.013284
Research




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Microtubule affinity-regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration [Neurobiology]

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.




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Evolving Turkey–Iran relations and implications for regional reordering

Evolving Turkey–Iran relations and implications for regional reordering

This project examines the nature of the bilateral relationship between Turkey and Iran in relation to Middle Eastern countries and in the context of broader regional dynamics.

LJefferson

The 2016–21 period in Turkish–Iranian relations, which was marked by both sides’ structured cooperation through the Astana Process and Sochi summits on conflict management in Syria, and their largely shared opposition to US policy in Syria and at the broader regional level, to Iraqi Kurdistan’s independence referendum, and to the blockade of Qatar, has run its course. 

However, the new shape of these bilateral relations remains undefined, and understanding them is essential to effective policymaking in the region. How they will evolve will have direct ramifications for Iraq, Syria, regional Kurdish geopolitics, and the process of regional reordering and connectivity in the Middle East and South Caucasus. They will also have direct implications for US and European policymaking and role in the region. 

This project studies the evolving nature of Turkish–Iranian relations through Iraq, Syria and regional Kurdish politics. It examines how Turkey and Iran approach regional connectivity projects and major regional initiatives, and how ongoing regional developments, including the war in Gaza, have and may impact Turkey–Iran relations and EU, US and UK security considerations and policy towards the two countries.

The Centre for Applied Turkey Studies (CATS) at the Stiftung Wissenschaft und Politik (SWP) in Berlin is funded by Stiftung Mercator and the Federal Foreign Office. CATS is the curator of the CATS Network, an international network of think-tanks and research institutions working on Turkey. 

Evolving Turkey–Iran Relations and Implications for Regional Reordering is a project of the CATS Network.




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Somaliland's Regional Priorities and Strategic Partnerships




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Jordan: Regime Survival and Politics Beyond the State




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




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Undercurrents: Episode 30 - The Crisis in Kashmir, and How to Regulate Big Tech




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Iraq and its Role in the Region




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Who Should Regulate Free Speech Online?




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Security Challenges in the Mediterranean Region




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Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews




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Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth

MS Brown
Jul 1, 1980; 21:505-517
Reviews




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Gene expression regulation by retinoic acid

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews




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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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The Future of Investment Dispute Settlement Regimes

The Future of Investment Dispute Settlement Regimes 30 June 2020 — 2:00PM TO 3:30PM Anonymous (not verified) 9 February 2021 Online

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

Is an ‘atomized’ approach to cross-border investment dispute resolution inevitable? Has the multiplicity of mechanisms helped or hindered inclusivity in and transparency in governance? Is there a need for, and scope to, increase the international coordination of dispute resolution mechanisms? If so, what form should it take? What could be the implications for international economic law?




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The regional and international implications of restrictions to online freedom of expression in Asia

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.




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The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm [Computational Biology]

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box–driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1−/−Cry2−/− double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.




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Amyloid precursor protein is a restriction factor that protects against Zika virus infection in mammalian brains [Gene Regulation]

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.




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A novel stress-inducible CmtR-ESX3-Zn2+ regulatory pathway essential for survival of Mycobacterium bovis under oxidative stress [Microbiology]

Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.