Prioritizing equity and justice in climate action 30 June 2021 — 11:00AM TO 12:00PM Anonymous (not verified) 10 June 2021 Online

London Climate Action Week event: Why understanding equity and justice is essential to the ability to meaningfully inform climate politics.

Citizen-led climate activism is demonstrating the need to think about climate change ‘not just as a problem for science to solve’ but also as a problem of equity, human rights and justice.

The disproportionate impacts of climate change on the poor and the marginalized across the world means that understanding equity and justice is essential for the ability to meaningfully inform climate politics.

Excluding these issues risks ignoring, or intentionally omitting, the consequences of policies, tools and frameworks on those who are most likely to face the severe costs of any climate action or inaction.

In a pivotal year for climate decision-making, this event explores the necessity of equity and justice in climate action and how the world can move the political conversation to one that is more inclusive.

The speakers explore how communities themselves articulate the justice dimensions of climate change and how fairness can create a greener future for current and future generations.

This event is being hosted as a part of Strengthening Climate Diplomacy, a series of events from Chatham House during London Climate Action Week 2021.

COVID-19 and food security in southern Africa 16 July 2021 — 10:00AM TO 11:30AM Anonymous (not verified) 10 June 2021 Online

This event aims to take a deeper look at the interlinking issues of food security, nutrition, climate change and food systems in southern Africa.

Developing climate smart agri-food systems in sub-Saharan Africa is a precondition for achieving the Sustainable Development Goals. Over the years household food security has been affected by different shocks including climate change and the recent COVID-19 pandemic.

The impact on rural households in southern Africa, in particular, has been significant due to the structure of food systems in the region.

This event aims to take a deeper look at the interlinking issues of food security, nutrition, climate change and food systems in southern Africa and consider how practitioners and policymakers can build more equitable, resilient and better food systems. 

The Ukraine war and threats to food and energy security 13 April 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 6 April 2022 Online

What are the potential impacts on food and energy markets emerging from the situation in Ukraine?

Russia and Ukraine are key players in global energy, food, fertilizer and mineral markets. In the first few days after Russia’s invasion, both the threat and reality of resource flows being reduced drove up global prices, and has impacted the day-to-day life of people and businesses around the world.

Developing and nutrition-fragile countries across Africa and the Middle East will be hit the hardest – Somalia, for example, is reliant on Russia and Ukraine for 100 per cent of its wheat imports and is currently experiencing its worst drought in years.

The potential scale of disruption to food and energy markets increases with every week the war continues. This event launches the Environment and Society programme’s latest briefing paper The Ukraine war and threats to food and energy security: Cascading risks from rising prices and supply disruptions.

The panel discusses:

• The political, socio-economic and resource pressures already faced by the international community prior to Russia’s invasion of Ukraine.
• Direct and cascading impacts on the complex and interconnected energy, minerals, food and fertilizer markets, and policy or market responses that may exacerbate these impacts.
• Geopolitical ramifications that will affect the evolution of the conflict, as well as longer-term international cooperation and security.
• Measures that governments can take to build resilience, both to the ongoing impacts of the situation in Ukraine and to future risks of market disruption and geopolitical upheaval.

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.

Twenty Years After Hong Kong Handover, Does ‘One Country, Two Systems’ Still Work? Expert comment sysadmin 28 June 2017

This unique constitutional framework can endure – if Hong Kong society can reconcile its different visions of the future.

Twenty years after the handover of Hong Kong from British to Chinese sovereignty, the ‘one country, two systems’ arrangement – the main aim of which was to guarantee the continuity of Hong Kong’s open society and way of life – can be said to have worked well. Street protests remain a regular feature of Hong Kong’s political culture. Freedom of information and expression are alive and well. Hong Kong retains its ‘capitalist way of life’, its legal system based on common law and independent judiciary, and its status as an international financial centre. As a result the city remains one of the most open economies across Asia, with robust institutions and transparency which are hard to find anywhere else in the region.

Yet the 79-day ‘occupy’ protests of autumn 2014 showed that something is not quite right in the city of Hong Kong.

The protests themselves had a number of causes. Partly they reflected socioeconomic concerns, especially the rise in income inequality and lack of affordable housing. These might have been dealt with to some extent by better governance over the years, but they are also a feature of many societies in the current phase of globalization – a case, perhaps, of too much ‘capitalist way of life’.

Politically, the desire expressed by many in 2014 was for a form of ‘genuine universal suffrage’ for the selection of Hong Kong’s chief executive which went beyond a provision of Hong Kong’s mini constitution, the Basic Law, that candidates should be put forward by a ‘nominating committee’. It was on this point that the possibility of constitutional reform foundered in 2015, leaving Hong Kong no further ahead in its ‘gradual progress’ towards democracy.

But this episode also brought to the surface the tension between different visions for Hong Kong’s future. In particular, many in Hong Kong are still uncomfortable with the ‘one country’ part of the deal, rejected by some (especially young people) in the ways that they conceptualize Hong Kong identity – according to one recent survey, as little as 3.1% of Hong Kong youths identify themselves as ‘Chinese’. These issues are likely to constrain political development for some time to come.

At their sharpest, some of these visions are for some form of self-determination, or even independence, for Hong Kong. This is not just anathema to the national authorities in Beijing, but contradicts a basic tenet of Hong Kong’s handover in 1997, the return to Chinese sovereignty. This is not just something on which Beijing will never compromise, but will seek to challenge.

It is this which explains the sense in Hong Kong that the central government has been looking to become politically more involved since 2014. But the challenge of influencing Hong Kong society is great, and other than strengthening relations with the establishment camp, Beijing has not been able to tighten its grip. If anything, the centre of gravity of Hong Kong politics has continued to drift away from Beijing, not towards it.

How this will play out remains to be seen. Some amelioration of social tensions could help. But the fundamental divergence in visions of Hong Kong’s future will not be resolved so easily.

Looking forward therefore, the key to the continued success of ‘one country, two systems’ lies in Hong Kong society. If mainstream acceptance of the compromises involved can return, then this unique constitutional framework can still work for years to come.

China, Liu Xiaobo and the New Reality of Human Rights Expert comment sysadmin 18 July 2017

Liu Xiaobo, Chinese Nobel laureate and human rights campaigner, died on 13 July while serving an 11-year prison sentence for ‘subversion’. Steve Tsang tells Jason Naselli that the reaction to Liu’s death reflects the growing confidence of the Chinese government that it can ignore Western criticism.

What does the Communist Party’s handling of the case of Liu Xiaobo tell us about its approach to dissidents and freedom of speech in the Xi era?

What it tells us is the party is tightening control much more than before. The Liu Xiaobo case shows that the party is not comfortable with people asking for the constitution of the People’s Republic of China to be enforced. Charter 08, for which Liu Xiaobo was jailed, ultimately amounts to asking for the rights of Chinese citizens, as articulated in the constitution, to be fully implemented. That resulted in Liu Xiaobo being incarcerated.

But what is really important isn’t so much that the party is tightening its control – that is happening anyway. What is more important is that the party is not that worried about how the Liu Xiaobo case affects international opinion.

If that’s the case, what lessons should countries looking to trade with China but concerned about human rights abuses take from Liu’s case?

We haven’t seen any major Western country come out to strongly and clearly hold the Chinese government to account over Liu Xiaobo’s human rights situation. A few leading governments have asked for Liu Xiaobo’s widow to be allowed to choose to stay or leave China. But so far there is no indication of any government backing that up with anything concrete.

That is very weak support for human rights in China. And it reflects a new reality: of the unwillingness of leading democracies to challenge the Chinese government on human rights matters, and the confidence on the part of the Chinese government to simply ignore what the rest of the world may think about it.

Given that there has been much discussion of China taking a larger global leadership role in the wake of an inward political turn in the US, what are the implications of Liu’s case for China’s global standing?

The implications are really small. There is a stronger expectation and desire to see China playing a global role because Donald Trump has damaged the standing of the United States as a global leader. It is not because of something that the Chinese government has done; it’s because of Trump.

That wider context hasn’t changed. So the Chinese government’s calculation is that the negative international reaction to Liu Xiaobo’s death will blow over in a matter of days – at worst, a couple of weeks – and then things will get back to normal.

There is no serious reason to believe that the Chinese government is wrong in their calculation. At the moment, the major Western countries are focusing on the economic relationship, and doing what they have to do pro forma about human rights issues in China. No major Western government is going to say that they are going to reconsider a major trade deal with China because of how Liu Xiaobo or his family has been treated. The Chinese government knows that and they act accordingly.

Moving on from the international reaction, how does Liu’s situation resonate within China?

Most Chinese don’t even know who Liu Xiaobo is. Within China, you cannot even search Liu Xiaobo’s name, or any permutation of Liu Xiaobo’s name, or the English initials of Liu Xiaobo. Anything potentially about or related to Liu Xiaobo is being censored.

Some things still get through; the ingenuity of a lot of bloggers is infinite. But most Chinese don’t even know what happened to Liu Xiaobo, or if they do, they mostly see him as a shill of the Western world trying to infiltrate and destabilize China.

If Western governments won’t engage China over human rights, what implications does that have for the global treatment of human rights as China becomes a bigger global player?

You can ‘engage’ in the sense of raising the issue with the Chinese authorities, as indeed the UK government and the German government have done, for example. But they haven’t actually taken any concrete steps.

The type of engagement where Western governments would get the Chinese government to demonstrate that something concrete was being done to improve the human rights situation – that era has gone. It is not going to come back in the foreseeable future. And therefore, the situation in terms of human rights in China will not be improving in the foreseeable future.

But what is more significant is how the Chinese government is asserting itself and dealing with domestic and international challenges, including on human rights issues. For many other countries around the world, China is showing an example for how to deal with the West. They don’t see it as being negative; they see it in positive terms.

There are still more countries in the world that abuse human rights than respect human rights. Most of those governments are pleased to see what the Chinese government has done in terms of how it handles the West.

Gender and equality

Exploring empowerment in areas such as women’s rights, equality and discrimination, the sharing of unpaid work, and the role of gender in achieving the SDGs.

Many women are still excluded from economic decision-making within their own household, receive lower salaries than men, and work longer hours. They are also often excluded from the labour market, do not have access to finance, and are denied property rights.

Wider areas of interest include examining the potential for foreign policies that prioritize gender equality, the physical, cultural and practical challenges to integrating women into close combat roles in the military, and the future of women in peace and security.

Equality and diversity research work also examines why people from black and minority ethnic groups still do less well in terms of education and the jobs they do than people from other groups, and considers the rights of workers across the world. It is strongly linked with promoting human rights and freedoms, based on principles such as dignity and respect.

Bangladesh: The Trade-Off Between Economic Prosperity and Human Rights 11 March 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 28 February 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

Bangladesh’s recent gains in economic and social indices, set against its record of corruption and poor civil rights, has at times been termed the ‘Bangladesh Paradox’. Yet this label is overly simplistic; the current situation proves that these trends can coexist.

The Awami League government, in power since 2009, has increased political stability, delivered unprecedented economic and social advances, and adopted a counter-terrorism strategy to stamp out extremist groups. At the same time, it is criticized for curbing civil rights and failing to hold credible elections. However, as the two previous regimes have demonstrated, the rights situation is unlikely to improve even if the Awami League were replaced.

How did worsening rights become a feature of the state irrespective of its political dispensation? An unresolved contest between political and non-political state actors may hold the key to that puzzle. The perils of the current dispensation have recently manifested in weakening economic indicators, which jeopardize the very stability and social progress for which the country has garnered much praise.

Zhaonan Wang and Yingpu Deng
Math. Comp. 93 (), 2921-2942.
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Ole Løseth Elvetun and Bjørn Fredrik Nielsen
Math. Comp. 93 (), 2811-2836.
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Buyang Li, Zongze Yang and Zhi Zhou
Math. Comp. 93 (), 2557-2586.
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Yinji Li, Zhiwei Wang and Xiangyu Zhou
Trans. Amer. Math. Soc. 377 (), 5947-5992.
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Guido De Philippis, Nicola Fusco and Massimiliano Morini
Trans. Amer. Math. Soc. 377 (), 5787-5835.
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Kazuhiro Ishige, Paolo Salani and Asuka Takatsu
Trans. Amer. Math. Soc. 377 (), 5705-5748.
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Nathan Brownlowe, Alcides Buss, Daniel Gonçalves, Jeremy B. Hume, Aidan Sims and Michael F. Whittaker
Trans. Amer. Math. Soc. 377 (), 5513-5560.
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dannyhennesy posted a photo:

On the Capital planet the rebellious droids had followed maily the Bat-Bot, but as time progressed his circuits had gone all mushy at 780 years or so without maintenance…

Several splinter groups all with their local bot leaders emerged such as the Che-bot, the traffic-light-robot and the Butt-bot, but none of these collected enough sentient circuits to call themselves a popular (or Animata) mass movement!

That was until a cyborg came along, one known as Jones, a long time prisoner and terrorist, his easy solutions to every problem rang well in the masses' auditory circuits!!!

His slogans and simple rhetoric were simple enough for the simple traffic-light to comprehend and cheer!

His language was full of hate towards the organics and especially the humans who were the most common races among the ruling class of the federation!!!

Despite being a “Fleshie” himself his message collected the angry enslaved
bot community by only weeks all rebellious robots except for a few fringe loonies had forgotten the old leaders…

One morning at Jones gave the signal…

All over the capital planet hordes and swarms of any form of mechanical sentient beings attacked first the police stations, then the Company boards running the planet and the federation as well as their starfleet…

Many died, especially the low level police and army! Many mechanicals died too, but their ranks were soon filled by Mutant fleshie allies of the lower levels who hated the Federation feudal society and upper classes as much as their technological allies…

The Federation state apparatus and ruling class, most of their fleet army fled when they knew the game was up, they activated the emergency escape plan and whole city blocks with important factories, administrational units, valuable assets and so on separated from the capital by hidden rocket engines and homed in their course to Mars…

On Mars the federation regrouped and formed their new society…

On the Capital planet, the robots proclaimed the first Techno-republic of the advanced inorganic civilization, the low level fleshies left behind, became slaves and their mutant allies got to rule their own minute chiefdoms as protectorates under the Techno-republic…

Jones was now the undisputed ruler of the capital planet, but the victory was a pyrros one since, all important buildings, all of value was now one Mars!

But as Jones put it:

Our proud race the Techno-species didn’t need the Fleshies administration, their infrastructure, their spaceships…

We shall start from scratch, with a new administration, a new order, every droid shall work at 4x speed than they did during human oppression since now we are free and the fleshies shall work twice as hard than the Techno-Race, until we have breed enough new fleshies so they can do all work!

Our future is bright and shiny like glistering shiny metal!

The snapshot seen here is from the first police station attacked in sector 45-34v-ss-g the first one to fall according to official techno-history!

———————————————/
Designers note:

I am sad to say that this is the last episode in this years-spanning space series… At least for a while, I will still post LEGO hobby stuff here but without a storyline, perhaps small designs and builds… and occasionally a story when I feel like it!!!

I would like to thank all who had been in this journey of our heros, but it has taken far to much time and effort and since the state of the world is as it is, I am spiraling down in another depression, I must stop it before I reach the abyss, so I have remove some stress out of my equation… I ended it in a cliffhanger so I can easily restart it when my mental health improves… I hope that won’t be forever???

I would love if someone used my characters or ideas, please send me a link if you do, I would love to read it or look at it!!!

But there will be more Lego, just in different format without long stories, I need to focus more on my art and to be honest that is the only time the mental pain eases, when I create!!!


Peace and Noise!

MushroomBrain a FOL

Christian Weiss
Theor. Probability and Math. Statist. 111 (), 199-209.
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Marko Voutilainen, Lauri Viitasaari and Pauliina Ilmonen
Theor. Probability and Math. Statist. 111 (), 181-197.
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Olha Prykhodko and Kostiantyn Ralchenko
Theor. Probability and Math. Statist. 111 (), 123-135.
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Lutz Mattner
Theor. Probability and Math. Statist. 111 (), 45-122.
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Chris A.J. Klaassen
Theor. Probability and Math. Statist. 111 (), 9-19.
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Paweł Hitczenko and Nick Wormald
Proc. Amer. Math. Soc. 152 (), 5411-5427.
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Xiaoshang Jin
Proc. Amer. Math. Soc. 152 (), 5327-5337.
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Frederic Heihoff
Proc. Amer. Math. Soc. 152 (), 5229-5247.
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Friedrich Haslinger
Proc. Amer. Math. Soc. 152 (), 5219-5227.
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Anh Tuan Nguyen, Tómas Caraballo and Nguyen Huy Tuan
Proc. Amer. Math. Soc. 152 (), 5175-5189.
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András Kroó
Proc. Amer. Math. Soc. 152 (), 5149-5162.
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Yong Suk Moon
Proc. Amer. Math. Soc. 152 (), 5095-5103.
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Donghyeok Lim and Christian Maire
Proc. Amer. Math. Soc. 152 (), 5013-5024.
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Naoki Endo and Shiro Goto
Proc. Amer. Math. Soc. 152 (), 5007-5011.
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Mohammed Abouzaid and Nathaniel Bottman
Bull. Amer. Math. Soc. 61 (), 525-608.
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Forty-six mathematical scientists have been named recipients of AMS-Simons Research Enhancement Grants for Primarily Undergraduate Institution (PUI) Faculty. Each awardee will receive $3,000 per year for three years. 

The grants foster and support research collaboration by full-time mid-career mathematicians at US institutions that do not offer a mathematics doctoral degree.

This year’s grant recipients hail from 42 institutions across 21 US states. The grants will support their research in several different areas, from number theory to applied mathematics.

This is the grant program’s second cohort, said Sarah Bryant, associate vice president of programs. “Over the first two years, we’ve worked with faculty from 75 different institutions, including 19 minority-serving institutions, which shows just how much this program is expanding and making an impact,” Bryant said. She noted that “in the first year, the grants supported 87 trips, helped produce 70 publications and preprints, and gave awardees the resources needed to collaborate and advance their work.”

The grant allows for any activities that will further the awardee’s research program. Expenses include but are not limited to conference participation, institute visits, collaboration travel (awardee or collaborator), computer equipment or software, family-care expenses, and teaching assistants.

Administration of the award by the grantee’s institution is required; annual discretionary funds for a grantee’s department and administrative funds for a grantee's institution will be available at the end of each grant year.

The grants are made possible through funding from the Simons Foundation and the American Mathematical Society (AMS), as well as Eve, Kirsten, Lenore, and Ada of the Menger family.

Applications for the next cohort are anticipated to open on MathPrograms.org on January 9, 2025. Visit the AMS website to view an informational PowerPoint or sign up to receive email updates about the program. Faculty who applied for but did not receive the 2023 or 2024 awards are encouraged to reapply if they are still eligible for the grant. 

In 2020, when Anthony Parker, known to his fans as DJ Specs, decided to trade his textbooks for turntables, he didn't just pivot his career -- he pivoted his entire life. At just 25 years old, this Kingston-born DJ has already carved out a space...

Earlier this month when Alicea Samaru-Brown walked across the stage at The University of the West Indies (UWI) graduation, she beamed with pride. Her husband, Dennis Brown, and her son, Orlando Brown, cheered the loudest from the audience and this...

Carnosine (β-alanyl-l-histidine) and anserine (β-alanyl-3-methyl-l-histidine) are abundant peptides in the nervous system and skeletal muscle of many vertebrates. Many in vitro and in vivo studies demonstrated that exogenously added carnosine can improve muscle contraction, has antioxidant activity, and can quench various reactive aldehydes. Some of these functions likely contribute to the proposed anti-aging activity of carnosine. However, the physiological role of carnosine and related histidine-containing dipeptides (HCDs) is not clear. In this study, we generated a mouse line deficient in carnosine synthase (Carns1). HCDs were undetectable in the primary olfactory system and skeletal muscle of Carns1-deficient mice. Skeletal muscle contraction in these mice, however, was unaltered, and there was no evidence for reduced pH-buffering capacity in the skeletal muscle. Olfactory tests did not reveal any deterioration in 8-month-old mice lacking carnosine. In contrast, aging (18–24-month-old) Carns1-deficient mice exhibited olfactory sensitivity impairments that correlated with an age-dependent reduction in the number of olfactory receptor neurons. Whereas we found no evidence for elevated levels of lipoxidation and glycation end products in the primary olfactory system, protein carbonylation was increased in the olfactory bulb of aged Carns1-deficient mice. Taken together, these results suggest that carnosine in the olfactory system is not essential for information processing in the olfactory signaling pathway but does have a role in the long-term protection of olfactory receptor neurons, possibly through its antioxidant activity.

Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune responses. C. difficile genome analysis showed that 12 genes potentially encode N-deacetylases; however, which of these N-deacetylases are involved in peptidoglycan N-deacetylation remains unknown. Here, we report the enzymes responsible for peptidoglycan N-deacetylation and their respective regulation. Through peptidoglycan analysis of several mutants, we found that the N-deacetylases PdaV and PgdA act in synergy. Together they are responsible for the high level of peptidoglycan N-deacetylation in C. difficile and the consequent resistance to lysozyme. We also characterized a third enzyme, PgdB, as a glucosamine N-deacetylase. However, its impact on N-deacetylation and lysozyme resistance is limited, and its physiological role remains to be dissected. Finally, given the influence of peptidoglycan N-deacetylation on host defense against pathogens, we investigated the virulence and colonization ability of the mutants. Unlike what has been shown in other pathogenic bacteria, a lack of N-deacetylation in C. difficile is not linked to a decrease in virulence.

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

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.

The actin cytoskeleton is of profound importance to cell shape, division, and intracellular force generation. Profilins bind to globular (G-)actin and regulate actin filament formation. Although profilins are well-established actin regulators, the distinct roles of the dominant profilin, profilin 1 (PFN1), versus the less abundant profilin 2 (PFN2) remain enigmatic. In this study, we use interaction proteomics to discover that PFN2 is an interaction partner of the actin N-terminal acetyltransferase NAA80, and further confirm this by analytical ultracentrifugation. Enzyme assays with NAA80 and different profilins demonstrate that PFN2 binding specifically increases the intrinsic catalytic activity of NAA80. NAA80 binds PFN2 through a proline-rich loop, deletion of which abrogates PFN2 binding. Small-angle X-ray scattering shows that NAA80, actin, and PFN2 form a ternary complex and that NAA80 has partly disordered regions in the N-terminus and the proline-rich loop, the latter of which is partly ordered upon PFN2 binding. Furthermore, binding of PFN2 to NAA80 via the proline-rich loop promotes binding between the globular domains of actin and NAA80, and thus acetylation of actin. However, the majority of cellular NAA80 is stably bound to PFN2 and not to actin, and we propose that this complex acetylates G-actin before it is incorporated into filaments. In conclusion, we reveal a functionally specific role of PFN2 as a stable interactor and regulator of the actin N-terminal acetyltransferase NAA80, and establish the modus operandi for NAA80-mediated actin N-terminal acetylation, a modification with a major impact on cytoskeletal dynamics.

Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain, in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal or multiple metals from the cytoplasm, and it is not known whether the CTD takes an active regulatory role in metal recognition and discrimination during cation transport. Here, the model CDF protein MamM, an iron transporter from magnetotactic bacteria, was used to probe the role of the CTD in metal recognition and selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of their binding sites, thermodynamics, and binding-dependent conformations, both in crystal form and in solution, which suggests a varying level of functional discrimination between CDF domains. Furthermore, these results provide the first direct evidence that CDF CTDs play a role in metal selectivity. We demonstrate that MamM's CTD can discriminate against Mn2+, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn2+ incorporation.

Mammalian Asn-linked glycans are extensively processed as they transit the secretory pathway to generate diverse glycans on cell surface and secreted glycoproteins. Additional modification of the glycan core by α-1,6-fucose addition to the innermost GlcNAc residue (core fucosylation) is catalyzed by an α-1,6-fucosyltransferase (FUT8). The importance of core fucosylation can be seen in the complex pathological phenotypes of FUT8 null mice, which display defects in cellular signaling, development, and subsequent neonatal lethality. Elevated core fucosylation has also been identified in several human cancers. However, the structural basis for FUT8 substrate specificity remains unknown.Here, using various crystal structures of FUT8 in complex with a donor substrate analog, and with four distinct glycan acceptors, we identify the molecular basis for FUT8 specificity and activity. The ordering of three active site loops corresponds to an increased occupancy for bound GDP, suggesting an induced-fit folding of the donor-binding subsite. Structures of the various acceptor complexes were compared with kinetic data on FUT8 active site mutants and with specificity data from a library of glycan acceptors to reveal how binding site complementarity and steric hindrance can tune substrate affinity. The FUT8 structure was also compared with other known fucosyltransferases to identify conserved and divergent structural features for donor and acceptor recognition and catalysis. These data provide insights into the evolution of modular templates for donor and acceptor recognition among GT-B fold glycosyltransferases in the synthesis of diverse glycan structures in biological systems.

The bacterial enhancer-binding protein (bEBP) FlrC, controls motility and colonization of Vibrio cholerae by regulating the transcription of class-III flagellar genes in σ54-dependent manner. However, the mechanism by which FlrC regulates transcription is not fully elucidated. Although, most bEBPs require nucleotides to stimulate the oligomerization necessary for function, our previous study showed that the central domain of FlrC (FlrCC) forms heptamer in a nucleotide-independent manner. Furthermore, heptameric FlrCC binds ATP in “cis-mediated” style without any contribution from sensor I motif 285REDXXYR291 of the trans protomer. This atypical ATP binding raises the question of whether heptamerization of FlrC is solely required for transcription regulation, or if it is also critical for ATPase activity. ATPase assays and size exclusion chromatography of the trans-variants FlrCC-Y290A and FlrCC-R291A showed destabilization of heptameric assembly with concomitant abrogation of ATPase activity. Crystal structures showed that in the cis-variant FlrCC-R349A drastic shift of Walker A encroached ATP-binding site, whereas the site remained occupied by ADP in FlrCC-Y290A. We postulated that FlrCC heptamerizes through concentration-dependent cooperativity for maximal ATPase activity and upon heptamerization, packing of trans-acting Tyr290 against cis-acting Arg349 compels Arg349 to maintain proper conformation of Walker A. Finally, a Trp quenching study revealed binding of cyclic-di-GMP with FlrCC. Excess cyclic-di-GMP repressed ATPase activity of FlrCC through destabilization of heptameric assembly, especially at low concentration of protein. Systematic phylogenetic analysis allowed us to propose similar regulatory mechanisms for FlrCs of several Vibrio species and a set of monotrichous Gram-negative bacteria.

Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset.