Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal “head” domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.

‘Hong Kong is now in the hands of its people – they cannot rely on others to stick up for them now.’ Expert comment sysadmin 29 June 2017

Kerry Brown on ‘one country, two systems’, the UK’s diminishing influence and the territory’s future, 20 years after the handover.

1 July marks the 20th anniversary of the transfer of Hong Kong’s sovereignty from Britain to China. Kerry Brown speaks with Jason Naselli about what the future holds for the territory.

How sustainable is the ‘one country, two systems’ framework? Will the arrangement last the full 50 years (until 2047) as originally envisioned?

It is questionable whether the arrangement that exists today was the one envisioned in 1997 when the handover happened. It was always a very abstract, flexible system, granting Hong Kong a high degree of autonomy, meaning it could maintain its capitalist system. Of course, in the lead up to 1997 all these things were broadly seen as being in Beijing’s interests to preserve.

But these days, the one thing that few said in 1997 has come to pass – the People’s Republic has maintained one-party rule as a political system, but become one of the world’s great economies. It has been so far a huge success.

Hong Kong therefore has diminished in importance over the years to the point that maintaining at least some semblance of one country, two systems is almost like an act of charity. It has been nibbled at, compromised and seems to grow weaker by the day. Most in Hong Kong would say there is a system: one country, one system. That’s the deal.

The central government’s deepening involvement in the territory’s politics is a subject of growing controversy in Hong Kong. Does the Chinese government need to alter its approach?

Not particularly. It doesn’t want to see Hong Kong fail as an economy. That doesn’t suit its interests at all. But nor does it want a truculent, disobedient polity that is meant to be part of its sovereign territory.

So it has increasingly set political parameters. Hong Kong can have its unique system – as long as it is obedient. And on the whole, that is the deal that all of the city’s chief executives until now have internally understood perfectly.

As part of the 1997 handover, the UK has ‘a continuing moral and political obligation’ to Hong Kong. How will this relationship play out as Brexit shifts Britain’s place in the world?

The Foreign Office offers a six-monthly report to Parliament, updating on how the handover deal is going. As the years go on, however, it becomes increasingly illusive how the UK has any real locus to say much about the situation on Hong Kong. It did say, rightly, that the detainment of one of the booksellers taken in in 2015 was a violation of the treaty because he was British. This was the strongest wording that has ever appeared from an official British source. But with dependence on creating a new kind of relationship with China now foremost in people’s minds because of Brexit and other economic pressures, it is not surprising that the priority increasingly lies elsewhere.

With direct management of Hong Kong gone, the UK was always going to be more and more irrelevant. That has happened. And in any case, relations with China have had to become more complex and multifaceted. Hong Kong was always the tail wagging the dog for the UK relations with China. Now there has been a rebalancing, the calculation always has to be how much unilaterally supporting Hong Kong will damage relations with Beijing. This has become an increasingly asymmetrical question: in a playoff, preserving links with Beijing will always prevail. That’s just the reality of the new world we are seeing come into being.

Hong Kong has played an important financial role for China over the past 20 years, but where will it fit as markets and financial institutions on the mainland mature?

It maintains is role as a major RMB hub, and as a finance centre. But it is surrounded by competition. Singapore, and Sydney, and other places in the region have RMB deals. Shanghai and Tianjin aspire to be portals for entry to the domestic Chinese market. Hong Kong every day has to think of new ways to maintain its relevance and beat back competition. So far, it has done well. But this is an issue it can never be complacent about.

What has been the most significant change in Hong Kong society since 1997?

The rising cultural and linguistic influence of the mainland on Hong Kong. Hong Kong has maintained its difference – but it has had to change. It is clear that Hong Kong is now in the hands of Hong Kongese – they cannot rely on others to stick up for them now. The culture, identity and future of the territory are in their hands. In that sense, they have autonomy.

Ran Gu and Bing Gao
Math. Comp. 93 (), 2837-2860.
Abstract, references and article information

Lutz Mattner
Theor. Probability and Math. Statist. 111 (), 45-122.
Abstract, references and article information

Dynamic singer Tosh Alexander has been lighting up the music scene with her latest track, ' My Ting Different', a thrilling collaboration with American rapper and songwriter Lady London. The song fuses R...

The Clarendon police have arrested and charged 25-year-old landscaper Anthony Marshall, of Lamparth district, Trout Hall in the parish for allegedly stealing oranges from a property in his community on Sunday.

19 August 2020

Peptidoglycan (PG) is an essential constituent of the bacterial cell wall. During cell division, the machinery responsible for PG synthesis localizes mid-cell, at the septum, under the control of a multiprotein complex called the divisome. In Escherichia coli, septal PG synthesis and cell constriction rely on the accumulation of FtsN at the division site. Interestingly, a short sequence of FtsN (Leu75–Gln93, known as EFtsN) was shown to be essential and sufficient for its functioning in vivo, but what exactly this sequence is doing remained unknown. Here, we show that EFtsN binds specifically to the major PG synthase PBP1b and is sufficient to stimulate its biosynthetic glycosyltransferase (GTase) activity. We also report the crystal structure of PBP1b in complex with EFtsN, which demonstrates that EFtsN binds at the junction between the GTase and UB2H domains of PBP1b. Interestingly, mutations to two residues (R141A/R397A) within the EFtsN-binding pocket reduced the activation of PBP1b by FtsN but not by the lipoprotein LpoB. This mutant was unable to rescue the ΔponB-ponAts strain, which lacks PBP1b and has a thermosensitive PBP1a, at nonpermissive temperature and induced a mild cell-chaining phenotype and cell lysis. Altogether, the results show that EFtsN interacts with PBP1b and that this interaction plays a role in the activation of its GTase activity by FtsN, which may contribute to the overall septal PG synthesis and regulation during cell division.

Kyle Swovick
Dec 28, 2020; 0:RA120.002301v1-mcp.RA120.002301
Research

The heterotrimeric G proteins are known to have a variety of downstream effectors, but Gs was long thought to be specifically coupled to adenylyl cyclases. A new study indicates that activated Gs can also directly interact with a guanine nucleotide exchange factor for Rho family small GTPases, PDZ-RhoGEF. This novel interaction mediates activation of the small G protein Cdc42 by Gs-coupled GPCRs, inducing cytoskeletal rearrangements and formation of filopodia-like structures. Furthermore, overexpression of a minimal PDZ-RhoGEF fragment can down-regulate cAMP signaling, suggesting that this effector competes with canonical signaling. This first demonstration that the Gαs subfamily regulates activity of Rho GTPases extends our understanding of Gαs activity and establishes RhoGEF coupling as a universal Gα function.

Neurodegeneration in Parkinson's disease (PD) can be recapitulated in animals by administration of α-synuclein preformed fibrils (PFFs) into the brain. However, the mechanism by which these PFFs induce toxicity is unknown. Iron is implicated in PD pathophysiology, so we investigated whether α-synuclein PFFs induce ferroptosis, an iron-dependent cell death pathway. A range of ferroptosis inhibitors were added to a striatal neuron-derived cell line (STHdhQ7/7 cells), a dopaminergic neuron–derived cell line (SN4741 cells), and WT primary cortical neurons, all of which had been intoxicated with α-synuclein PFFs. Viability was not recovered by these inhibitors except for liproxstatin-1, a best-in-class ferroptosis inhibitor, when used at high doses. High-dose liproxstatin-1 visibly enlarged the area of a cell that contained acidic vesicles and elevated the expression of several proteins associated with the autophagy-lysosomal pathway similarly to the known lysosomal inhibitors, chloroquine and bafilomycin A1. Consistent with high-dose liproxstatin-1 protecting via a lysosomal mechanism, we further de-monstrated that loss of viability induced by α-synuclein PFFs was attenuated by chloroquine and bafilomycin A1 as well as the lysosomal cysteine protease inhibitors, leupeptin, E-64D, and Ca-074-Me, but not other autophagy or lysosomal enzyme inhibitors. We confirmed using immunofluorescence microscopy that heparin prevented uptake of α-synuclein PFFs into cells but that chloroquine did not stop α-synuclein uptake into lysosomes despite impairing lysosomal function and inhibiting α-synuclein toxicity. Together, these data suggested that α-synuclein PFFs are toxic in functional lysosomes in vitro. Therapeutic strategies that prevent α-synuclein fibril uptake into lysosomes may be of benefit in PD.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Cells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

Subsidies and Sustainable Agriculture: Mapping the Policy Landscape Research paper sysadmin 10 December 2019

Agricultural subsidies shape production and consumption patterns, with potentially significant effects on poverty, nutrition and other sustainability concerns. This paper maps the different types of support provided by governments to the agricultural sector, and highlights some of the complex political economy dynamics that underpin the relevant policies.

Summary

• Agricultural subsidies, a mainstay of government policy, have a large part in shaping production and consumption patterns, with potentially significant effects as regards poverty, food security, nutrition, and other sustainability concerns such as climate change, land use practices and biodiversity.
• There are multiple types of direct and indirect support provided by governments to various actors in the agricultural sector; and in terms of political economy, there are complex dynamics underpinning the policies that sustain these subsidies.
• Overall, subsidies targeting producers have the most significant effect on production, and the greater trade-distorting effect. These subsidies promote domestic production and discourage imports, leading to overproduction that is largely disposed of on the international market, with the help of export subsidies. This can tend to intensify negative environmental agricultural practices, such as cultivating marginal land, unsustainable types of intensification, or incentivizing excessive pesticide and fertilizer use.
• On the other hand, producer subsidies that are not tied to output of a specific commodity (i.e. delinked) have far fewer distorting impacts and could help to deliver sustainable outcomes. For example, this type of subsidies can require crop diversification or be linked to conservation of permanent grassland.
• Subsidies that enable transfers to consumers, for example through food stamp programmes, also serve to delink production from consumption, can foster healthier diets, can play an important role in delivering food accessibility and security among low-income groups, and can represent one of the less trade-distorting subsidies.
• If subsidies are to be reformed to help promote healthier diets and encourage more sustainable production, it is essential to understand not only the type and amount of support that key countries provide, but also the domestic dynamics that can shape such policies.
• While price support, input subsidies or investment aids remain the central pillars of programmes in large developing countries such as Brazil, China or India, other economies – notably including the EU and Japan – focus on direct payments, support for general services and set-aside schemes, as well as significant border protection. The US, for its part, has tended to focus on subsidized insurance schemes and food programmes for poorer consumers.
• If subsidies are to deliver policy objectives, their design and implementation should delink production from consumption. For example, consumer subsidies designed to deliver nutrition and food security, or payments for environmental services to enable more environmentally friendly production systems, could prove to be the most effective, least trade-distorting means of achieving more sustainable and equitable agricultural production.
• The political economy of food means that the removal of subsidies is often highly sensitive, and tends to be met with significant resistance. However, reform that delinks support from production through a gradual transition process could ultimately prove successful in delivering effective subsidy schemes.
• Effective subsidy schemes must by design be truly result- and performance-based, supported by robust and objective indicators. At the same time, engaging multiple actors along key commodity value chains – including leading importing and exporting countries, traders and transporters – could lead to the development of international, commodity-specific arrangements that are able to deliver effective nutrition and sustainability goals.

Higher Education in South Africa: Demands for Inclusion and the Challenges of Reform 17 October 2018 — 5:00PM TO 6:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

Russian imperial mindset must change for real victory Expert comment NCapeling 8 December 2022

The attitude of Russia’s elite – and wider population – to the states which used to constitute the USSR needs to change in order to solve the Russia challenge.

Although the reverberations of Russia’s invasion of Ukraine clearly stretch around the globe, the strongest shocks are – and will continue to be – felt by those countries Moscow used to directly rule.

These countries struggle to shrug off a Soviet legacy as, to varying degrees – linguistically, technologically, culturally, and politically – they bear psychological and physical scars of Russia’s colonial past and its present mentality.

It does not help that these countries lack an appropriate collective descriptor. Over the years there has been ‘Newly Independent States’ – hardly appropriate after 31 years – the now-defunct ‘Commonwealth of Independent States’, the ‘post-Soviet space’ and ‘Former Soviet Union’ which both reference the past, and simply ‘Eurasia’ which is hardly appropriate for either Ukraine or Turkmenistan.

Some of these former ‘colonies’ are as badly governed and as sinister – albeit not as lethal beyond their borders – as Russia itself. Others, most notably the Baltic states, are modern, liberal, affluent societies, but Moscow’s shadow still looms.

There is a strong mindset in most of Russia’s citizens that, because that it used to rule these other countries, it either still has privileged rights over them or they are not real countries at all – but instead historical aberrations to be extinguished.

What is past is gone

As historian Timothy Snyder has noted, whatever the wrongs of Putin’s ‘history-based’ assertions about the ‘return of historic lands’, all historical claims are bunkum anyway. If the past brings validity, almost no land border on earth would be beyond dispute. It is agreements which count, and Russia signed away the other successor states in 1991.

The Russia and Eurasia programme at Chatham House has, for the last 31 years, always taken as a starting position that these countries are as sovereign as any other. This of course this means they can choose to be in Russia’s embrace if they wish. But none do because Russia is insufficiently attractive. Some have better relationships with Moscow than others – mainly the more autocratic ones – but no former slave goes back to their master willingly.

At the recent Chatham House conference Russia’s war: How will it shape the region’s future? (note the avoidance of a specific descriptor), the overwhelming consensus was that Russia must lose, that Ukraine must be reconstructed and planning for that must start now, and that the regional economy is convulsing.

But another key view was that, in Russia, rent seeking and buying loyalty are likely to lead to the separation of the Russian people and the regime, especially as the population ages and young men being sent to die at the front. Putin may still be popular in some places in Russia, but not in others – although popularity can rise and fall fast in Russia. However, few at the conference foresaw the disintegration of Russia any time soon.

With continued skill, determination, and more weaponry, Ukraine may well vanquish Russia on the battlefield, and this remains a necessary pre-requisite for European security. But even a Ukraine victory will not erase malign intent.

The Russian imperial itch is so deeply embedded, it must be excised not just from Russian capability but from the intention and mindset of elites and in the popular imagination. That is hard to achieve when so many believe in it as fervently as a religion – even the Russian Orthodox Church invokes a messianism in Russia’s imperial ‘rights’.

The wider region is suffering

Getting Russians to look upon their neighbours as equals requires widescale self-reassessment in a post-Putin Russia. But, for now, the wider region will surely be looking to simply neuter Russia’s destructive capacities.

A Qantas airlines flight made an emergency landing at Sydney Airport on Friday afternoon after suffering engine failure shortly after takeoff, the company said.

Costco voluntarily recalled 79,200 pounds of two types of its store-brand butter over the past month because their labels may not have said the products contain milk.

CHANDLER, Ariz., Oct. 23, 2024 — The global edge computing market is expected to grow by more than 30 percent in the next five years, serving mission-critical applications in the […]

The post Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing appeared first on HPCwire.

A pair of strong earthquakes has struck off the southern coast of Cuba, inflicting damage and causing landslides.

PALO ALTO, Calif., Oct. 30, 2024 — D-Wave Quantum Inc. today announced the appointments of veteran technology industry leaders, John DiLullo and Rohit Ghai, to its board of directors. The new […]

The post D-Wave Expands Board with Industry Veterans John DiLullo and Rohit Ghai appeared first on HPCwire.

Alex Ovechkin calmly slid into the right circle and sniped a snapshot past a blinded Juuse Saros to lead the Washington Capitals to a 3-2 triumph over the Nashville Predators.

Mike Gesicki and Jonnu Smith are among UPI senior sports writer Alex Butler's four must-start fantasy football tight ends for Week 10.

A South Carolina woman ended up calling the police for help after she walked into her apartment's bathroom and found a large ball python behind her toilet.

SAN ANTONIO, Nov. 5, 2024 — Rackspace Technology has announced the expansion of Rackspace Spot with a new geographic location and an on-demand GPU-as-a-Service powered by NVIDIA. The expansion comes […]

The post Rackspace Expands Spot Platform with On-Demand NVIDIA GPU-as-a-Service for AI Workloads appeared first on HPCwire.

FREMONT, Calif., Nov. 6, 2024 — AMAX, an AMD Elite Partner and a global leader in end-to-end GPU cluster solutions and advanced cooling technologies, announced its latest lineup of servers powered […]

The post AMAX Expands Server Portfolio with New AMD EPYC 9005 Series Processors for AI and HPC Workloads appeared first on HPCwire.

From meditation to smiling, researchers take a second look at studies claiming to reveal what makes us happy

Costco voluntarily recalled 79,200 pounds of two types of its store-brand butter over the past month because their labels may not have said the products contain milk.

President Joe Biden on Monday addressed a Veterans Day crowd at the national cemetery in Virginia where he revealed newly-expanded veteran benefits and urged Americans to "come together" and "keep faith."

The Indiana man accused of killing two teenage girls in a wooded area near Delphi was found guilty on Monday and faces a mid-December sentencing date.

SpaceX on Saturday successfully launched a Falcon 9 rocket carrying a payload of 22 Starlink Internet communications satellite from Cape Canaveral in Florida, marking a state record 73rd orbital rocket launch this year.

The two motivational keys to becoming a champion.

We tend to consider romantic partners and family ties to be our most important relationships, but deep friendships can be just as meaningful. In a perspective-shifting talk, author Rhaina Cohen introduces us to the people unsettling norms by choosing a friend as a life partner — and shows why we're all better off recognizing there's more than one kind of significant other.