DiFashion-Personalized-Outfit-Generation-and-Recommendation

Efficient-Cloud-Edge-Model-Adaptation-via-Entropy-Distillation

Neural-Video-Compression-with-Feature-Modulation-Addressing-Critical-Challenges-in-NVC-Evolution

A-Quantum-Approach-to-Synthetic-Minority-Oversampling-Technique-SMOTE-Enhancing-Machine-Learning-with-Quantum-Computing

Backpropagation-Based-Analytical-Derivatives-of-EKF-Covariance-for-Active-Sensing-Enhancing-Robot-State-Estimation

Retrieval-Based-Text-Generation-Paradigm-Shift

2069-Years-Since-the-First-Leap-Day-Unveiling-Timekeeping-Secrets

Novel-Spectral-Methods-for-Shock-Capturing-and-Tyger-Removal-in-Computational-Fluid-Dynamics


ヒト硫酸化グルコサミン N-アセチルトランスフェラーゼ(HGSNAT)は、リソソーム内でヘパラン硫酸の分解に必要な重要な酵素である。本研究では、HGSNAT-アセチルCoA複合体の高分解能構造を明らかにし、HGSNAT触媒反応の分子機構と、ミューコ多糖症IIIC(MPS IIIC)を引き起こす変異の構造的基盤を解明した。


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Degradation of heparan sulfate (HS), a glycosaminoglycan (GAG) comprised of repeating units of N -acetylglucosamine and glucuronic acid, begins in the cytosol and is completed in the lysosomes. Acetylation of the terminal non-reducing amino group of α-D-glucosamine of HS is essential for its complete breakdown into monosaccharides and free sulfate. Heparan-α-glucosaminide N -acetyltransferase (HGSNAT), a resident of the lysosomal membrane, catalyzes this essential acetylation reaction by accepting and transferring the acetyl group from cytosolic acetyl-CoA to terminal α-D-glucosamine of HS in the lysosomal lumen. Mutation-induced dysfunction in HGSNAT causes abnormal accumulation of HS within the lysosomes and leads to an autosomal recessive neurodegenerative lysosomal storage disorder called mucopolysaccharidosis IIIC (MPS IIIC). There are no approved drugs or treatment strategies to cure or manage the symptoms of, MPS IIIC. Here, we use cryo-electron microscopy (cryo-EM) to determine a high-resolution structure of the HGSNAT-acetyl-CoA complex, the first step in HGSNAT catalyzed acetyltransferase reaction. In addition, we map the known MPS IIIC mutations onto the structure and elucidate the molecular basis for mutation-induced HGSNAT dysfunction.

### Competing Interest Statement

The authors have declared no competing interest.

Structure of the human heparan-α-glucosaminide N-acetyltransferase (HGSNAT)

ヒト硫酸化グルコサミン-n-アセチルトランスフェラーゼ-hgsnat-の構造


ヒト硫酸化グルコサミン N-アセチルトランスフェラーゼ(HGSNAT)の構造


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プリオン病の進行に伴い、骨格筋におけるグルタミン合成酵素(GLUL)の発現が一貫して上昇し、グルタミン/グルタメート代謝に変化が生じる。この変化はプリオン病特異的であり、他の神経変性疾患では見られない。


In prion diseases, aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase ( GLUL ) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.

### Competing Interest Statement

The authors have declared no competing interest.

Prion diseases disrupt the glutamate/glutamine metabolism in skeletal muscle

プリオン病の前臨床段階において骨格筋グルタミン合成酵素が上方制御される


2-オキソグルタル酸はMethanosarcina mazei グルタミンシンテターゼの活性化に必要不可欠であり、2-オキソグルタル酸結合によりドデカマー構造が形成され、さらに活性部位の構造変化を引き起こすことで酵素活性が高まる。


Glutamine synthetases (GS) are central enzymes essential for the nitrogen metabolism across all domains of life. Consequently, they have been extensively studied for more than half a century. Based on the ATP dependent ammonium assimilation generating glutamine, GS expression and activity are strictly regulated in all organisms. In the methanogenic archaeon Methanosarcina mazei , it has been shown that the metabolite 2-oxoglutarate (2-OG) directly induces the GS activity. Besides, modulation of the activity by interaction with small proteins (GlnK1 and sP26) has been reported. Here, we show that the strong activation of M. mazei GS (GlnA1) by 2-OG is based on the 2-OG dependent dodecamer assembly of GlnA1 by using mass photometry (MP) and single particle cryo-electron microscopy (cryo-EM) analysis of purified strep-tagged GlnA1. The dodecamer assembly from monomers/dimers occurred without any detectable intermediate oligomeric state and was not affected in the presence of GlnK1. The 2.39 Å cryo-EM structure of the dodecameric complex in the presence of 12.5 mM 2-OG demonstrated that 2-OG is binding between two monomers. Thereby, 2-OG appears to induce the dodecameric assembly in a cooperative way. Furthermore, the active site is primed by an allosteric interaction cascade caused by 2-OG-binding towards an adaption of the transition state catalytic conformation. In the presence of additional glutamine, strong feedback inhibition of GS activity was observed. Since glutamine dependent disassembly of the dodecamer was excluded by MP, feedback inhibition most likely relies on an allosteric binding of glutamine to the catalytic site. Based on our findings, we propose that under nitrogen limitation the induction of M. mazei GS into a catalytically active dodecamer is not affected by GlnK1 and crucially depends on the presence of 2-OG.

### Competing Interest Statement

The authors have declared no competing interest.

2-oxoglutarate triggers assembly of active dodecameric Methanosarcina mazei glutamine synthetase

2-オキソグルタル酸がmethanosarcina-mazei-グルタミンシンテターゼの活性化に必要不可欠である


2-オキソグルタル酸がMethanosarcina mazei グルタミンシンテターゼの活性化に必要不可欠である



ジフルオロメチルオルニチン(DFMO)は、スナイダー-ロビンソン症候群患者由来の細胞において、スペルミジンの蓄積を減少させ、スペルミンの生成を促進することで、異常なスペルミジン/スペルミン比を是正する。


Snyder-Robinson Syndrome (SRS) is caused by mutations in the spermine synthase ( SMS ) gene, the enzyme product of which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonic musculature, and seizures, along with other, more variable symptoms. Currently, medical management focuses on treating symptoms without addressing the underlying molecular cause of the disease.

Reduced SMS catalytic activity in cells of SRS patients causes the accumulation of spermidine, while spermine levels are reduced. The resulting exaggeration in spermidine-to-spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity in the patient. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this polyamine imbalance and investigate the potential of this approach as a therapeutic strategy for affected individuals.

Here we report the use of 2-difluoromethylornithine (DFMO; eflornithine), an FDA-approved inhibitor of polyamine biosynthesis, in re-establishing normal spermidine-to-spermine ratios in SRS patient cells. Through mechanistic studies, we demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of existing spermidine into spermine in cell lines with hypomorphic variants of SMS . Further, DFMO treatment induces a compensatory uptake of exogenous polyamines, including spermine and spermine mimetics, cooperatively reducing spermidine and increasing spermine levels. In a Drosophila SRS model characterized by reduced lifespan, adding DFMO to the feed extends lifespan. As nearly all known SRS patient mutations are hypomorphic, these studies form a foundation for future translational studies with significant therapeutic potential.

### Competing Interest Statement

The Casero and Stewart Laboratory receive funding from Panbela Therapeutics, Inc. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome: mechanism of action and therapeutic potential

スナイダー-ロビンソン症候群における異常なポリアミン比を是正するジフルオロメチルオルニチン-作用機序と治療の可能性


スナイダー-ロビンソン症候群における異常なポリアミン比を是正するジフルオロメチルオルニチン: 作用機序と治療の可能性



7,8-ジヒドロキシフラボンは、ビタミンB6リン酸分解酵素(PDXP)を直接的に阻害し、神経細胞内のビタミンB6活性型(PLP)レベルを上昇させる。


Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small molecule screening, protein crystallography and biolayer interferometry, we discover, visualize and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.

### Competing Interest Statement

A.G. is a recipient of a research project grant from Boehringer Ingelheim International GmbH. This project funding is independent of and has no overlap with the work described in this manuscript. The other authors declare no competing interests.

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

ビタミンb6リン酸分解酵素-pdxp-を直接阻害する7-8-ジヒドロキシフラボン


ビタミンB6リン酸分解酵素(PDXP)を直接阻害する7,8-ジヒドロキシフラボン



ウリン酸は CD38 を直接阻害することで NAD+ の利用可能性を維持し、過剰な炎症を抑制する。


Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.

### Competing Interest Statement

The authors have declared no competing interest.

Functional identification of soluble uric acid as an endogenous inhibitor of CD38

ウリン酸が-cd38-の生理的機能を担う


ウリン酸が CD38 の生理的機能を担う
