1. Why Virat Kohli, Jasprit Bumrah were missing from Perth nets; India ramp up privacy amid Manchester United-like security  Hindustan Times
2. Virat Kohli in focus: Intense net session begins for upcoming Test series against Australia  The Times of India
3. Virat Kohli in Australia for BGT: A timeline  India Today
4. Black veil of secrecy: India begin training in privacy in Perth  ESPNcricinfo
5. India to play intra-squad warm-up match at WACA on Friday ahead of Australia Tests but BCCI denies public viewing  Hindustan Times

Matthew Nicholson threw down a two-handed slam to help the Northwestern Wildcats lead over the the UIC Flames going into the half.

To navigate the dangerous new era, Keir Starmer must end the culture of denial around the biggest strategic mistake of modern times The 35th anniversary of the Berlin Wall coming down was not commemorated much in Britain last weekend. It is no Poppy Day. The unravelling of the iron curtain doesn’t…

In this episode of the Arsenal Women Arsecast, Tim and Jamie talk about Arsenal’s 1-0 win over Leicester at the King Power. Tim and Jamie discuss a rotated starting line-up, how much the packed early season schedule contributed to a leggy performance, whether the game can be taken in isolation or whether concerns about the attack in particular persist and the performances of Daphne van Domselaar, Alessia Russo, the midfield partnership of Lia Walti and Kyra Cooney-Cross, defensive injuries and a lack of creativity without Mariona and Kafaji starting the game.

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Jordan will also receive the American Historical Society's Award for Scholarly Distinction in January.

With roots in America, western-style furniture is a traditional and vintage style. There are many reasons to admire such furniture, whether captivated by its timeless beauty or collecting and displaying them as part of one’s house decor. People have a particular appreciation for and attraction to Western-style because of its traditional and rustic charm. People ... Read more

The post Western Rustic Charm: Creating A Personalized Retreat With Western-Style Furniture appeared first on Star Two.

All architecture is great architecture after sunset; perhaps architecture is really a nocturnal art, like the art of fireworks.

The beloved butterflies had fallen to critical levels in recent years. Experts weigh in on what might be causing their remarkable return.

The trains could be charged in a matter of minutes before setting off on their journeys

People are angry at the authorities' handling of floods which killed more than 200 people.

Pro-Palestinian demonstrators gathered following violence against Israeli football fans earlier in the week.

The Verge's roundup of smart rings seems representative of a general consensus: Oura is just ahead of the game when it comes to these inconspicious gadgets. The competition is either too rough in one repect or another, be it software, syncing or the basic credibility of measurements, and the best is a model from Samsung that requires other Samsung stuff to work right. — Read the rest

The post Oura the best smart ring, say testers appeared first on Boing Boing.

For anyone thinking that 'social justice' is less about 'justice' and more about being a delivery system for a poisoned ideology, the story of Dr Hassan Diab, is the proverbial 'Exhibit A'.

The post Convicted Jihadi Terrorist Hired As Social Justice Prof In Western University appeared first on Clash Daily.

Independent Thinking: Western tanks head for Ukraine Audio NCapeling 26 January 2023

Episode 12 of our weekly podcast analyses the deployment of international battle tanks to Ukraine and the contentious diplomacy putting pressure on Germany.

The panel examines what kind of capabilities will new weapons give to Ukraine amid fears of a new Russian offensive looming in the spring, and the intense pressure Olaf Scholz’s German government has been under since the invasion of Ukraine started.

How has Germany’s standing changed over the past 12 months, and what are the challenges facing the country in its relations with Russia as a long and cold winter sets in?   

Joining Bronwen Maddox this week from Chatham House are Orysia Lutsevych, head of the Ukraine Forum, and Marion Messmer, senior research fellow in the International Security programme, along with Jeremy Cliffe, writer-at-large for The New Statesman magazine, and Ed Arnold, research fellow for European security at the Royal United Services Institute (RUSI).

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Independent Thinking: Will debt constrain Western foreign policy? Audio john.pollock 24 October 2024

Patrick Wintour and Ranil Dissanayake join the podcast ahead of the UK Budget to discuss the high debt facing G7 economies and its impact on foreign, defence and development policies.

On this episode

Ahead of a crucial Budget by Chancellor Rachel Reeves, UK national debt is at almost 100 per cent of GDP – and it’s not alone. Many G7 economies face massive debt levels, restricting ambitions when it comes to foreign policy and global engagement. 

Bronwen Maddox is joined by Patrick Wintour, the Guardian’s diplomatic editor and Ranil Dissanayake, a senior research fellow at the Centre for Global Development. With them are Olivia O’Sullivan and David Lubin from Chatham House.

About Independent Thinking

Independent Thinking is a weekly international affairs podcast hosted by our director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

More ways to listen: Apple Podcasts, Spotify.

As the ruling party claims victory in Georgia’s disputed election, Western condemnation is no longer enough Expert comment LToremark 29 October 2024

As tens of thousands take to the streets to protest the election results, Georgia faces a familiar crisis – with a few key differences.

As the people of Georgia went to the polls on 26 October, many were hoping not only for a democratic change of government but also for an end to one-party dominance and a return to the path of European integration. The previously weak and divided opposition had grouped itself into four major electoral centres, promising a coalition government and framing these elections as a choice between Europe and Russia. 

Ahead of the election, President Salome Zourabishvili had put forward the Georgian Charter, a blueprint for a stable and democratic transition to a new style of governance and for initiating reforms to fulfil conditions for EU accession. It was signed by all pro-European and pro-Western opposition parties. 

The official election results gave the ruling Georgian Dream party a 54 per cent majority in contrast with exit polls that gave the opposition a 10 per cent lead. President Zourabishvili and the opposition parties refuse to recognize the results, beginning a long process of contestation with allegations of fraud and street protests. As the disappointment sets in and the streets once again replace the ballot box as a conduit for democratic change, there is a sense of déja vu.

Georgia has seen this before. A party sweeps to power on the tide of popular protest, initiates reforms to meet public expectations but, by the end of its second term, it takes an authoritarian turn. As it overstays its welcome, it starts manipulating elections to cling to power. People once again take to the streets and a new party wins by a landslide only to repeat the same cycle. But with each turn, the grip the ruling elites have on power gets stronger and the methods they use become more sophisticated. State security becomes equated with regime stability, leaving no space for normal democratic contestation or expressions of dissent. 

Although what is happening in Georgia fits this familiar pattern, there are some consequential differences. 

First, these were the first fully proportional elections. Previously, a mixed system of representation meant that the incumbency always had an advantage by dominating majoritarian districts. A new electoral system had created a not unreasonable expectation that these elections, if held freely, would result in a coalition government. The hope was this could help break the vicious cycle of Georgian politics, sustained by an extreme form of majoritarianism and a winner-takes-all political culture.

The Georgian Dream party was contesting its fourth consecutive term against a backdrop of falling popularity and growing societal mobilization in opposition to its authoritarian inclinations. Despite all this, it secured – some would insist manufactured – an absolute majority in elections that international observers say were marred by serious irregularities and fell short of democratic standards. 

The second important difference is that these elections were not only about saving Georgia’s democracy but also about rescuing its European perspective. Since Georgia was granted EU candidate status in December 2023, its parliament has adopted Russian-style laws on foreign agents and combating LGBTIQ+ ‘propaganda’. 

It has also adopted a strongly Eurosceptic political discourse, pushing back on international criticism and accusing EU and US officials of interference in domestic affairs and disregard for Georgia’s sovereignty. In response, the EU has suspended accession talks with Georgia indefinitely while the US has imposed targeted sanctions on high-ranking Georgian officials and judges. 

Georgia’s democratic backsliding at home and its pivot away from the West are both simultaneous and interrelated. It was widely hoped these elections would be a course correction and return Georgia to the path of European and Euro-Atlantic integration. The election results, if they stick, will prevent this from happening. A Georgian Dream government will not work to fulfil conditions for EU accession, viewed as a challenge to its hold on power. 

The third and final difference is that these elections took place in the context of heightened geopolitical confrontation. The Georgian Dream ‘victory’ is a win for anti-liberal, conservative forces around the world championed, among others, by Hungary’s Viktor Orbán. He was the first to congratulate Georgian Dream for its declared success and even visited Tbilisi in a show of solidarity and ideological alignment. 

The election result is also a win for Russia. It strengthens Moscow’s influence in the South Caucasus, which has waned as a result of the war in Ukraine and the fall of Nagorny-Karabakh. Russian officials and propagandist were quick to congratulate Georgian Dream, wishing them success in standing up to Western pressures and offering help in case things got tough. 

From Moscow’s perspective, Georgia’s elections are part of a global hybrid war. They represent a local battle in the ongoing geopolitical contest between Russia and the West, between the rules-based global order and competitive multipolarity. 

As Georgia repeats a familiar pattern, what do the election results mean for its future? While clear predictions are difficult at this stage, it is worth bearing in mind that as the democratic resilience of the Georgian society has strengthened over time, so too has the state capacity to supress and control. 

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

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles

W Gamble
Nov 1, 1978; 19:1068-1070
Articles

CJ Fielding
Aug 1, 1997; 38:1503-1521
Reviews

John M. Dietschy
Aug 1, 2004; 45:1375-1397
Thematic Reviews

JM Dietschy
Oct 1, 1993; 34:1637-1659
Reviews

JF Oram
Dec 1, 1996; 37:2473-2491
Reviews

George H. Rothblat
May 1, 1999; 40:781-796
Reviews

AR Tall
Aug 1, 1993; 34:1255-1274
Reviews

AE Christian
Nov 1, 1997; 38:2264-2272
Articles

G Lepage
Jan 1, 1986; 27:114-120
Articles

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

John A. Glomset
Mar 1, 1968; 9:155-167
Reviews

CJ Fielding
Feb 1, 1995; 36:211-228
Reviews

Katherine Baker, Lehel Banjai and Mariya Ptashnyk
Math. Comp. 93 (), 2711-2743.
Abstract, references and article information

Twenty-eight-year-old labourer Michael Ennis, of Manning's Hill district in Manchester, has been charged with smoking ganja in a public place following an incident in May Pen, Clarendon on Monday.

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.

CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in both health and disease.

Members of the B-cell lymphoma (BCL-2) protein family regulate mitochondrial outer membrane permeabilization (MOMP), a phenomenon in which mitochondria become porous and release death-propagating complexes during the early stages of apoptosis. Pro-apoptotic BCL-2 proteins oligomerize at the mitochondrial outer membrane during MOMP, inducing pore formation. Of current interest are endogenous factors that can inhibit pro-apoptotic BCL-2 mitochondrial outer membrane translocation and oligomerization. A mitochondrial-derived peptide, Humanin (HN), was reported being expressed from an alternate ORF in the mitochondrial genome and inhibiting apoptosis through interactions with the pro-apoptotic BCL-2 proteins. Specifically, it is known to complex with BAX and BID. We recently reported the fibrillation of HN and BAX into β-sheets. Here, we detail the fibrillation between HN and BID. These fibers were characterized using several spectroscopic techniques, protease fragmentation with mass analysis, and EM. Enhanced fibrillation rates were detected with rising temperatures or pH values and the presence of a detergent. BID fibers are similar to those produced using BAX; however, the structures differ in final conformations of the BCL-2 proteins. BID fibers display both types of secondary structure in the fiber, whereas BAX was converted entirely to β-sheets. The data show that two distinct segments of BID are incorporated into the fiber structure, whereas other portions of BID remain solvent-exposed and retain helical structure. Similar analyses show that anti-apoptotic BCL-xL does not form fibers with humanin. These results support a general mechanism of sequestration of pro-apoptotic BCL-2 proteins into fibers by HN to inhibit MOMP.

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

Pectins are a major dietary nutrient source for the human gut microbiota. The prominent gut microbe Bacteroides thetaiotaomicron was recently shown to encode the founding member (BT1017) of a new family of pectin methylesterases essential for the metabolism of the complex pectin rhamnogalacturonan-II (RG-II). However, biochemical and structural knowledge of this family is lacking. Here, we showed that BT1017 is critical for the metabolism of an RG-II–derived oligosaccharide ΔBT1017oligoB generated by a BT1017 deletion mutant (ΔBT1017) during growth on carbohydrate extract from apple juice. Structural analyses of ΔBT1017oligoB using a combination of enzymatic, mass spectrometric, and NMR approaches revealed that it is a bimethylated nonaoligosaccharide (GlcA-β1,4-(2-O-Me-Xyl-α1,3)-Fuc-α1,4-(GalA-β1,3)-Rha-α1,3-Api-β1,2-(Araf-α1,3)-(GalA-α1,4)-GalA) containing components of the RG-II backbone and its side chains. We showed that the catalytic module of BT1017 adopts an α/β-hydrolase fold, consisting of a central twisted 10-stranded β-sheet sandwiched by several α-helices. This constitutes a new fold for pectin methylesterases, which are predominantly right-handed β-helical proteins. Bioinformatic analyses revealed that the family is dominated by sequences from prominent genera of the human gut microbiota, including Bacteroides and Prevotella. Our re-sults not only highlight the critical role played by this family of enzymes in pectin metabolism but also provide new insights into the molecular basis of the adaptation of B. thetaiotaomicron to the human gut.

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

Ryunosuke Ohkawa
Dec 1, 2020; 61:1577-1588
Research Articles

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

Michael E. Abrams
Dec 1, 2020; 61:1538-1538
Images in Lipid Research

Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails the interplay between de novo synthesis, uptake, intra-retinal sterol transport, metabolism and efflux. Defects in these complex processes are associated with several congenital and age-related disorders of the visual system. Herein, we provide an overview of the following topics: a) cholesterol synthesis in the neural retina; b) lipoprotein uptake and intraretinal sterol transport in the neural retina and the retinal pigment epithelium (RPE); c) cholesterol efflux from the neural retina and the RPE; and d) biology and pathobiology of defects in sterol synthesis and sterol oxidation in the neural retina and the RPE. We focus, in particular, on studies involving animal models of monogenic disorders pertinent to the above topics, as well as in vitro models using biochemical, metabolic, and omic approaches. We also identify current knowledge gaps as well as opportunities in the field that beg further research in this topic area.

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.