Christoforos Neofytidis
Trans. Amer. Math. Soc. 377 (), 5289-5321.
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

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Bero Roos
Theor. Probability and Math. Statist. 111 (), 137-151.
Abstract, references and article information

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

Chris A.J. Klaassen
Theor. Probability and Math. Statist. 111 (), 9-19.
Abstract, references and article information

Paweł Hitczenko and Nick Wormald
Proc. Amer. Math. Soc. 152 (), 5411-5427.
Abstract, references and article information

Lauri Hitruhin and Sauli Lindberg
Proc. Amer. Math. Soc. 152 (), 5265-5278.
Abstract, references and article information

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

YoungJu Choie, Winfried Kohnen and Yichao Zhang
Proc. Amer. Math. Soc. 152 (), 5025-5037.
Abstract, references and article information

Naoki Endo and Shiro Goto
Proc. Amer. Math. Soc. 152 (), 5007-5011.
Abstract, references and article information

P. Lochak
St. Petersburg Math. J. 35 (), 477-535.
Abstract, references and article information

N. Lebedeva and A. Petrunin
St. Petersburg Math. J. 35 (), 473-476.
Abstract, references and article information

Zhanqiang Bai, Jia-Jun Ma, Wei Xiao and Xun Xie
Represent. Theory 28 (), 498-513.
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. 

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.

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...

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.

Family, friends, and community members gathered on Saturday at the Falmouth First Assembly Church to celebrate the life of 15-year-old Jahmarie Reid, a William Knibb High student who tragically lost his life at sea on August 27 in what is believed...

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For many Jamaicans, the deceased are more than just loved ones who have passed on; they are cherished family members who deserve to look as presentable as they did in life. In a culture where the appearance of the deceased is paramount, morticians...

As I walked into the embalming room at Jones Funeral Home and Supplies in Kingston on Sunday, I immediately felt the weight of the room. The air was thick with the scent of various chemicals used in the trade permeating the space. Tools such as...

A growing number of motor vehicle crashes across Jamaica has been attributed to drivers operating the vehicles under the influence of marijuana, according to Health Minister Dr Christopher Tufton. "The data is clear, we are seeing more people...

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

A father who pleaded guilty to sexually molesting his 13-year-old daughter was sentenced to several years of imprisonment in the St Catherine Circuit Court on Tuesday.

Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.

Knockout mouse models have been extensively used to study the antiviral activity of IFIT (interferon-induced protein with tetratricopeptide repeats). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of “self” in higher eukaryotes, whereas unmodified cap0-RNA is recognized as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess “nonself” cap0-mRNAs. However, in mice and other rodents, the IFIT1 orthologue has been lost, and the closely related Ifit1b has been duplicated twice, yielding three paralogues: Ifit1, Ifit1b, and Ifit1c. Although murine Ifit1 is similar to human IFIT1 in its cap0-RNA–binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, whereas binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict WT mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families to facilitate better design and interpretation of mouse models of human infection and sheds light on the evolutionary plasticity of the IFIT family.

Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit.

Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases.

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.

Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.

VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.