Simone Cecchini and Rudolf Zeidler
Trans. Amer. Math. Soc. 377 (), 5271-5288.
Abstract, references and article information

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.
Abstract, references and article information

Ta Cong Son, Tran Manh Cuong, Le Quang Dung and Le Van Dung
Theor. Probability and Math. Statist. 111 (), 153-165.
Abstract, references and article information

Olha Prykhodko and Kostiantyn Ralchenko
Theor. Probability and Math. Statist. 111 (), 123-135.
Abstract, references and article information

Claudio Macci and Barbara Pacchiarotti
Theor. Probability and Math. Statist. 111 (), 21-43.
Abstract, references and article information

Shengyu Tang
Proc. Amer. Math. Soc. 152 (), 5381-5394.
Abstract, references and article information

Luiz Ricardo Abreu Melo
Proc. Amer. Math. Soc. 152 (), 5373-5380.
Abstract, references and article information

Ferdinand Ihringer
Proc. Amer. Math. Soc. 152 (), 5355-5365.
Abstract, references and article information

Frederic Heihoff
Proc. Amer. Math. Soc. 152 (), 5229-5247.
Abstract, references and article information

Anh Tuan Nguyen, Tómas Caraballo and Nguyen Huy Tuan
Proc. Amer. Math. Soc. 152 (), 5175-5189.
Abstract, references and article information

Benjamin Jaye and Manasa N. Vempati
Proc. Amer. Math. Soc. 152 (), 5105-5116.
Abstract, references and article information

Donghyeok Lim and Christian Maire
Proc. Amer. Math. Soc. 152 (), 5013-5024.
Abstract, references and article information

R. Gibara and D. Kinzebulatov
St. Petersburg Math. J. 35 (), 445-460.
Abstract, references and article information

Roland Donninger
Bull. Amer. Math. Soc. 61 (), 659-685.
Abstract, references and article information

Kenta Suzuki of the Massachusetts Institute of Technology (MIT) is awarded the 2025 American Mathematical Society (AMS)-Mathematical Association of America (MAA)-Society for Industrial and Applied Mathematics (SIAM) Frank and Brennie Morgan Prize for his extraordinary research in the representation theory of $p$-adic groups. His papers, including two solo works, represent significant progress in different areas of the field.

From the citation

Suzuki worked on deep problems in representation theory, and he has authored and coauthored six research papers. In particular, he has made important contributions to the representation theory of $p$-adic groups. His results include asymptotics for the dimension of spaces fixed by a congruence subgroup in an admissible representation of $GL(n).$ His joint works include working out the local Langlands correspondence for several rank two $p$-adic groups, and the determination of canonical bases in the subregular quotient of the affine Hecke algebra and its antispherical module, along with their “coherent” categorifications.

Response of Kenta Suzuki

It is an honor for me to receive the Frank and Brennie Morgan Prize. I thank the Morgan family and the AMS, MAA, and SIAM for their generosity. I thank my mentors throughout the years, Toshihiko Nakazawa, Li Li, Michael Zieve, and Colin Hinde, for kindling my interest in mathematics. Toshihiko Nakazawa patiently explored mathematics with me from a young age and continues to inspire me with his insights. I thank Roman Bezrukavnikov, Wei Zhang, Zhiwei Yun, Ivan Losev, Vasily Krylov, and Calder Morton-Ferguson for further stimulating my interest in mathematics at MIT and introducing me to the many wonders of representation theory. Wei Zhang’s unwavering support has motivated me to explore many areas of mathematics. I leave every conversation with Roman Bezrukavnikov with new ideas, and he has helped me grow as a researcher by encouraging me to pursue even my most ambitious ideas. The mathematical community at MIT and Harvard have been supportive and taught me so much, both mathematical and nonmathematical. Finally, I thank my parents, particularly my mother, for supporting me throughout my journey in every possible way. She has been my role model and is one of the most intelligent and charismatic people I know.

Biographical sketch of Kenta Suzuki

Kenta Suzuki is a fourth-year undergraduate at MIT from Tokyo, Japan, and Plymouth, Michigan. Suzuki’s work focuses on the representation theory of $p$-adic groups and geometric representation theory. Suzuki is particularly interested in applying geometric methods to solve problems of representation theory. In his free time, he runs, reads, and is (slowly) learning how to cook.

About the prize

The AMS-MAA-SIAM Frank and Brennie Morgan Prize for Outstanding Research in Mathematics by an Undergraduate Student is awarded annually to an undergraduate (or students for joint work) for outstanding research in mathematics. The prize recipient's research can include more than one paper, however, the paper or papers to be considered for the prize must be completed while the student is an undergraduate. Publication of research is not required.

Established in 1995, the prize is entirely endowed by a gift from Mrs. Frank (Brennie) Morgan. The current prize amount is $1,200.

The prize will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the prize and previous recipients.

Contact: AMS Communications

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

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. 

Robert McCann, University of Toronto, will receive the 2025 American Mathematical Society (AMS) - Society for Industrial and Applied Mathematics (SIAM) Norbert Wiener Prize in Applied Mathematics “in recognition of his groundbreaking contributions to optimal transport theory, and for pioneering deep applications to economics and physics,” according to the citation. McCann holds a Canada Research Chair in Mathematics, Economics, and Physics.

From the citation

Robert McCann has made fundamental contributions to optimal transport theory, reflecting remarkable technical abilities and amazing conceptual creativity. His discovery of displacement convexity and his solution to Monge’s (1746-1818) problem for different transportation costs were early, foundational advances that preceded by nearly 30 years the current enormous attention bestowed on optimal transport theory and its applications. Beyond these, McCann produced many important, unexpected results, linking optimal transport to new areas of application within and outside mathematics: different notions of curvature, new and hidden convexities in the economics of information, and a non-smooth theory of gravity based on the interaction of entropy with the Einstein field equation.

Response of Robert McCann

I am honored and humbled to have my work on optimal transportation and its applications to economics and physics recognized by the AMS-SIAM 2025 Norbert Wiener Prize (endowed by MIT). I think the whole optimal transport community can join me in taking pride in this acknowledgement of the impact and success of our efforts and can view this award as an incentive to further achievements. After singling out my PhD advisor, Elliott Lieb, who first taught me about the mines and the factories, I'd like to thank the many other mentors, collaborators, colleagues, and students – too numerous to name – who shared in my mathematical, physical, and economic adventures (and those who wrote letters to document!). Our interactions inspire and sustain me on my scientific journey; I could not have achieved these results without you, and my life is enriched by your presence. I try to pass it forward by giving as good as I got, and I encourage you to do the same. I also thank my family for their love and support, and their willingness to share me by putting up with my long hours of distraction and frequent travels. I hope this recognition helps to reassure them that their sacrifices are not for nought.

Biographical sketch of Robert McCann

Robert McCann studied engineering and physics before graduating with a degree in mathematics from Queen's University at Kingston, Ontario, and a doctorate from Princeton University. Following a Tamarkin appointment at Brown University and a postdoctoral fellowship at Institut des Hautes Études Scientifiques (IHES), he became a professor of mathematics at the University of Toronto, where he now holds a Canada Research Chair in Mathematics, Economics, and Physics. He is an authority on optimal transportation and has played a pioneering role in its rapid development since the 1990s. In particular, the notion of displacement convexity introduced in his 1994 PhD thesis lies behind many of the area's myriad applications. He serves on the editorial board of various journals, and as editor-in-chief of the Canadian Journal of Mathematics since 2007 (with a hiatus from 2017-21). His research has been recognized by awards such as an invitation to lecture at the 2014 International Congress of Mathematicians in Seoul; election to the Royal Society of Canada in 2014; the 2017 Jeffery-Williams Prize of the Canadian Mathematical Society; and the 2023 W.T. and Idalia Reid Prize of the Society for Industrial and Applied Mathematics (SIAM).

About the prize

The AMS-SIAM Norbert Wiener Prize in Applied Mathematics is awarded every three years for an outstanding contribution to applied mathematics in the highest and broadest sense.The American Mathematical Society (AMS) and the Society for Industrial and Applied Mathematics (SIAM) award the prize jointly. Recipients must be a member of one of these societies. 

This prize was established in 1967 in honor of Professor Norbert Wiener and was endowed by a fund from the Department of Mathematics of the Massachusetts Institute of Technology. The endowment was supplemented further by a generous donor. The current award is $5,000.

The 2025 prize will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the prize and previous recipients.

Contact: AMS Communications

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

Sophie Morier-Genoud of the University of Reims Champagne-Ardenne and Valentin Ovsienko of the Centre National de la Recherche Scientifique, Reims, are awarded the 2025 AMS David P. Robbins Prize for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma.

“In this groundbreaking work .. it is shown that the new concept has striking connections and applications to a wide range of mathematical areas,” according to the prize citation. “The paper has subsequently inspired a profusion of significant further research developments.”

From the citation

The David P. Robbins Prize is awarded to Sophie Morier-Genoud and Valentin Ovsienko for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma, in 2020.

The authors provide an entirely novel and natural definition of a $q$-analog of the rational numbers. Although a $q$-analog of the integers has been used extensively since the work of Euler, a satisfactory and meaningful $q$-analog of the rationals had remained elusive until this paper. The definition also leads to a natural $q$-analog of the real numbers and has a wide range of fascinating and far-reaching applications.

A $q$-analog of a mathematical concept is a generalization of the concept which depends on a new parameter $q$ in such a way that the original concept is recovered when $q$ is set to 1, and various interesting or useful properties also arise.

Response of Sophie Morier-Genoud

I am thrilled and honored to receive the 2025 David P. Robbins Prize. This is a fantastic recognition and a great encouragement to keep doing what I like to do. I always had a lot of fun doing mathematics and I feel privileged to do it as a profession. 

I am grateful to everyone who helped me in making this path possible. 

I would like to thank all my collaborators and colleagues in the Math Department at the University of Reims and also everywhere in the world who show interest in the math we are doing and contribute to enrich the theory of $q$-numbers.

Response of Valentin Ovsienko

I am deeply moved to receive this prize, named in honor of David P. Robbins, the creator of mathematical concepts that will forever remain among the most beautiful.

My scientific life has been spent trying to connect different topics in algebra, geometry, and mathematical physics. The $q$-numbers, which is a combinatorial notion, are the result of my journey with my younger and much smarter collaborator Sophie Morier-Genoud, following this route. We tried to better understand connections between cluster algebra, Coxeter friezes, Conway’s ideas, the Jones polynomial... We realized that it is impossible to $q$-deform a singular object, but only an infinite sequence of them! In order to $q$-deform rationals, one needs to count them all. We chose the way of counting determined by continued fractions and the action of the modular group.

Working on this subject has been and remains the happiest part of my scientific life. I was captivated by $q$-rationals and I was completely haunted by $q$-irrationals. This happiness, enhanced by interest of other researchers, in itself is reward enough. 

My collaboration with Sophie produced a variety of results, including two energetic children, Lisa and Anatole; the $q$-numbers are also little kids who need to grow up!

Biographical sketch of Sophie Morier-Genoud

Sophie Morier-Genoud is currently full professor at the University of Reims Champagne-Ardenne in France. She completed her PhD at the University of Lyon (2006) under the supervision of Philippe Caldero. She was T.H. Hildebrandt Assistant Professor at the University of Michigan (2006-2008), postdoctoral fellow of the Fondation Sciences Mathématiques de Paris (2008-2009) and associate professor at Sorbonne Université (2009-2021). Her research work is mainly related to algebraic combinatorics and representation theory. She currently serves as an editor for the column “Gems and Curiosities” of the Mathematical Intelligencer.

Biographical sketch of Valentin Ovsienko

Valentin Ovsienko was born in 1964 in the Soviet Union. He received his PhD in 1989 from Moscow State University under the supervision of Alexandre Kirillov. Ovsienko is currently in Reims, Champagne, as a senior researcher at the French Centre National de la Recherche Scientifique. He worked in projective differential geometry, infinite-dimensional Lie algebras, integrable systems, octonions, and, more recently, in combinatorics. Together with Sophie Morier-Genoud, he is the editor of the column “Gems and Curiosities” of the Mathematical Intelligencer, and he invites everyone to write beautiful articles for it.

About the prize

The David P. Robbins Prize is awarded every three years for a paper with the following characteristics: It reports on novel research in algebra, combinatorics, or discrete mathematics and has a significant experimental component; and it is on a topic which is broadly accessible and provides a simple statement of the problem and clear exposition of the work. Papers published within the six calendar years preceding the year in which the prize is awarded are eligible for consideration.

The 2025 prize will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the prize and previous recipients.

Contact: AMS Communications.

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

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...

Nigy Boy's management team was forced to put out a scam alert on Thursday as news surfaced that a promoter in the Turks and Caicos Islands, inadvertently wired thousands of US dollars to who he believed was the artiste's booking team as a deposit...

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...

When a scuba diver comes up from the deep too quickly, the rapid decrease in pressure can give them a case of "the bends" or decompression sickness. It is caused by bubbles of gas building up in the body, causing pain. It can also be fatal....

UK-based, Jamaica-born dancehall artiste Dubbi believes latest single, ' Side Chick' is a bona fide hit as its popularity has surged on the dancehall scene in the United Kingdom. "It is also streaming well in France and seems to be a real hit on...

The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.

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...

After parking his taxi cab along the sidewalk, Leon Thompson exited his vehicle and held on tightly to the tiny hands of his four small passengers. They all walked towards a makeshift bridge, and Thompson lifted each child, making four trips,...

In a touching display of compassion and solidarity, a group of St Thomas residents has come together to organise the funeral of a a well-known and beloved man with intellectual challenges. For years, Donovan Sinclair was a familiar face in the...

If you connect to a FTP/TLS server that is configured to use implicit FTP/TLS, FILENAME FTP/TLS might fail with the following error:

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.

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.

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.

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.

α-Linked galactose is a common carbohydrate motif in nature that is processed by a variety of glycoside hydrolases from different families. Terminal Galα1–3Gal motifs are found as a defining feature of different blood group and tissue antigens, as well as the building block of the marine algal galactan λ-carrageenan. The blood group B antigen and linear α-Gal epitope can be processed by glycoside hydrolases in family GH110, whereas the presence of genes encoding GH110 enzymes in polysaccharide utilization loci from marine bacteria suggests a role in processing λ-carrageenan. However, the structure–function relationships underpinning the α-1,3-galactosidase activity within family GH110 remain unknown. Here we focus on a GH110 enzyme (PdGH110B) from the carrageenolytic marine bacterium Pseudoalteromonas distincta U2A. We showed that the enzyme was active on Galα1–3Gal but not the blood group B antigen. X-ray crystal structures in complex with galactose and unhydrolyzed Galα1–3Gal revealed the parallel β-helix fold of the enzyme and the structural basis of its inverting catalytic mechanism. Moreover, an examination of the active site reveals likely adaptations that allow accommodation of fucose in blood group B active GH110 enzymes or, in the case of PdGH110, accommodation of the sulfate groups found on λ-carrageenan. Overall, this work provides insight into the first member of a predominantly marine clade of GH110 enzymes while also illuminating the structural basis of α-1,3-galactoside processing by the family as a whole.

α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.