Many-Body Function Corrected Neural Network with Atomic Attention (MBNN-att) for Molecular Property Prediction.

Recent years have seen a surge of machine learning (ML) in chemistry for predicting chemical properties, but a low-cost, general-purpose, and high-performance model, desirable to be accessible on central processing unit (CPU) devices, remains not available. For this purpose, here we introduce an atomic attention mechanism into many-body function corrected neural network (MBNN), namely, MBNN-att ML model, to predict both the extensive and intensive properties of molecules and materials. The MBNN-att uses explicit function descriptors as the inputs for the atom-based feed-forward neural network (NN). The output of the NN is designed to be a vector to implement the multihead self-attention mechanism. This vector is split into two parts: the atomic attention weight part and the many-body-function part. The final property is obtained by summing the products of each atomic attention weight and the corresponding many-body function. We show that MBNN-att performs well on all QM9 properties, i.e., errors on all properties, below chemical accuracy, and, in particular, achieves the top performance for the energy-related extensive properties. By systematically comparing with other explicit-function-type descriptor ML models and the graph representation ML models, we demonstrate that the many-body-function framework and atomic attention mechanism are key ingredients for the high performance and the good transferability of MBNN-att in molecular property prediction.

Two-dimensional metal-organic framework for post-synthetic immobilization of graphene quantum dots for photoluminescent sensing.

Immobilization of graphene quantum dots (GQDs) on a solid support is crucial to prevent GQDs from aggregation in the form of solid powder and facilitate the separation and recycling of GQDs after use. Herein, spatially dispersed GQDs are post-synthetically coordinated within a two-dimensional (2D) and water-stable zirconium-based metal-organic framework (MOF). Unlike pristine GQDs, the obtained GQDs immobilized on 2D MOF sheets show photoluminescence in both suspension and dry powder. Chemical and photoluminescent stabilities of MOF-immobilized GQDs in water are investigated, and the use of immobilized GQDs in the photoluminescent detection of copper ions is demonstrated. Findings here shed the light on the use of 2D MOFs as a platform to further immobilize GQDs with various sizes and distinct chemical functionalities for a range of applications.

Abundance of Low-Energy Oxygen Vacancy Pairs Dictates the Catalytic Performance of Cerium-Stabilized Zirconia.

Cerium-stabilized zirconia (Ce1-xZrxOy, CZO) is renowned for its superior oxygen storage capacity (OSC), a key property long believed to be beneficial to catalytic oxidation reactions. However, 50% Ce-containing CZO recorded with the highest OSC has disappointingly poor performance in catalytic oxidation reactions compared to those with higher Ce contents but lower OSC ability. Here, we employ global neural network (G-NN)-based potential energy surface exploration methods to establish the first ternary phase diagram for bulk structures of CZO, which identifies three critical compositions of CZO, namely, 50, 60, and 80% Ce-containing CZO that are thermodynamically stable under typical synthetic conditions. 50% Ce-containing CZO, although having the highest OSC, exhibits the lowest O vacancy (Ov) diffusion rate. By contrast, 60% Ce-containing CZO, despite lower OSC (33.3% OSC compared to that of 50% Ce-containing CZO), reaches the highest Ov diffusion ability and thus offers the highest CO oxidation catalytic performance. The physical origin of the high performance of 60% Ce-containing CZO is the abundance of energetically favorable Ov pairs along the ⟨110⟩ direction, which reduces the energy barrier of Ov diffusion in the bulk and promotes O2 activation on the surface. Our results clarify the long-standing puzzles on CZO and point out that 60% Ce-containing CZO is the most desirable composition for typical CZO applications.

Manual acupuncture ameliorates inflammatory pain by upregulating adenosine A3 receptor in complete Freund's adjuvant-induced arthritis rats.

BACKGROUND: Adenosine A3 receptor (A3R) exerts analgesic, anti-inflammatory, and anti-nociceptive effects. In this study, we determined the analgesic mechanism of manual acupuncture (MA) in rats with complete Freund's adjuvant (CFA)-induced arthritis and explored whether MA ameliorates inflammation in these rats by upregulating A3R. METHODS: Sixty Sprague Dawley (SD) rats were randomly divided into the following groups: Control, CFA, CFA + MA, CFA + sham MA, CFA + MA + DMSO, CFA + MA + IB-MECA, and CFA + MA + Reversine groups. The arthritis rat model was induced by injecting CFA into the left ankle joints. Thereafter, the rats were subjected to MA (ST36 acupoint) for 3 days. The clinical indicators paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and open field test (OFT) were used to determine the analgesic effect of MA. In addition, to explore the effect of A3R on inflammation after subjecting arthritis rats to MA, IB-MECA (A3R agonist) and Reversine (A3R antagonist) were injected into ST36 before MA. RESULTS: MA ameliorated the pathological symptoms of CFA-induced arthritis, including the pain indicators PWL and PWT, number of rearing, total ambulatory distance, and activity trajectory. Furthermore, after MA, the mRNA and protein expression of A3R was upregulated in CFA-induced arthritis rats. In contrast, the protein levels of TNF-α, IL-1ß, Rap1, and p-p65 were downregulated after MA. Interestingly, the A3R agonist and antagonist further downregulated and upregulated inflammatory cytokine expression, respectively, after MA. Furthermore, the A3R antagonist increased the degree of ankle swelling after MA. CONCLUSION: MA can alleviate inflammatory pain by inhibiting the NF-κB signaling pathway via upregulating A3R expression of the superficial fascia of the ST36 acupoint site in CFA-induced arthritis rats.

Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.

An integrated microfluidic system for automatic detection of cholangiocarcinoma cells from bile.

Cholangiocarcinoma (CCA) is an aggressive cancer that originates from the epithelial cells lining the bile ducts. Due to its location deep within the body and nonspecific symptoms in the early stages, it is often diagnosed at the advanced stage, thus leading to worse prognosis. Circulating tumor cells within liquid biopsies (i.e. blood) have been considered as promising biomarkers for CCA diagnosis, though current methods for profiling them are not satisfactory in terms of sensitivity and specificity. Herein we developed a new cancer cell probing and immuno-tracking assay known as "CAPTURE", which was performed on an integrated microfluidic system (IMS) to automate CCA diagnosis from bile with a sample amount of only 1 mL. The assay utilized magnetic beads surface-coated with two affinity reagents, a nucleic acid aptamer (HN16) and a glycosaminoglycan (SCH 45-mix), for capturing cancer cells in bile; the "gold standard" anti-epithelial cell adhesion molecule was used as a comparison. In a single-blind test of 54 CCA-positive (+) and 102 CCA-negative (-) clinical samples, sensitivities and specificities of 96 and 80%, respectively, were documented with the CAPTURE assay on-bench. An IMS composed of a centrifugal module for sample pretreatment and a CAPTURE module for cell capture and staining was integrated with a new "vertical integration module" for detecting cancer cells from bile without human intervention. Furthermore, a novel micro-tier structure within the centrifugal module was designed to block passage of gallbladder stones with diameters >1 mm, thereby preventing their interference during the subsequent CAPTURE assay. Improved sensitivity and specificity (100 & 83%, respectively) by using three affinity reagents were achieved on the IMS when using 26 clinical bile samples, confirming its clinical bio-applicability for CCA diagnosis. This approach could be therefore used for early-stage CCA diagnostics, ideally enabling effective treatment, as well as reducing potential for relapse.

Amorphous Chloride Solid Electrolytes with High Li-Ion Conductivity for Stable Cycling of All-Solid-State High-Nickel Cathodes.

Solid electrolytes (SEs) are central components that enable high-performance, all-solid-state lithium batteries (ASSLBs). Amorphous SEs hold great potential for ASSLBs because their grain-boundary-free characteristics facilitate intact solid-solid contact and uniform Li-ion conduction for high-performance cathodes. However, amorphous oxide SEs with limited ionic conductivities and glassy sulfide SEs with narrow electrochemical windows cannot sustain high-nickel cathodes. Herein, we report a class of amorphous Li-Ta-Cl-based chloride SEs possessing high Li-ion conductivity (up to 7.16 mS cm-1) and low Young's modulus (approximately 3 GPa) to enable excellent Li-ion conduction and intact physical contact among rigid components in ASSLBs. We reveal that the amorphous Li-Ta-Cl matrix is composed of LiCl43-, LiCl54-, LiCl65- polyhedra, and TaCl6- octahedra via machine-learning simulation, solid-state 7Li nuclear magnetic resonance, and X-ray absorption analysis. Attractively, our amorphous chloride SEs exhibit excellent compatibility with high-nickel cathodes. We demonstrate that ASSLBs comprising amorphous chloride SEs and high-nickel single-crystal cathodes (LiNi0.88Co0.07Mn0.05O2) exhibit ∼99% capacity retention after 800 cycles at ∼3 C under 1 mA h cm-2 and ∼80% capacity retention after 75 cycles at 0.2 C under a high areal capacity of 5 mA h cm-2. Most importantly, a stable operation of up to 9800 cycles with a capacity retention of ∼77% at a high rate of 3.4 C can be achieved in a freezing environment of -10 °C. Our amorphous chloride SEs will pave the way to realize high-performance high-nickel cathodes for high-energy-density ASSLBs.

Embolization of Cavernous Sinus Dural Arteriovenous Fistula with Liquid Materials Under Transarterial Balloon Protection.

AIM: To analyze the clinical and angiographic outcomes of interventional embolization under transarterial balloon protection technique in patients with cavernous sinus dural arteriovenous fistulas. MATERIAL AND METHODS: In a single-center cohort of 30 patients undergoing cavernous sinus dural arteriovenous fistulas embolization under balloon protection. We collected their clinical symptoms, complications, mid-term follow-up angiographic results, and long-term clinical outcomes for the baseline characteristics. RESULTS: Thirty patients with 31 lesions were included in this study. Immediate applications of angiographies after embolization indicated that complete obliteration occurred in 29 lesions (93.5% of 31 lesions). Two cases with permanent trigeminal nerve palsy were treated by arterial approach. Onyx dispersed into the internal carotid artery in one process, and salvage stent implantation was performed to prevent parent artery occlusion. CONCLUSION: Interventional embolization with intra-arterial balloon protection is effective and safe with rarely occurring complications.

Global Neural Network Potential with Explicit Many-Body Functions for Improved Descriptions of Complex Potential Energy Surface.

The high dimensional machine learning potential (MLP) that has developed rapidly in the past decade represents a giant step forward in large-scale atomic simulation for complex systems. The long-range interaction and the poor description of chemical reactions are typical problems of high dimensional MLP, which are mainly caused by the poor structure discrimination of the atom-centered ML model. Herein, we propose a low-cost neural-network-based MLP architecture for fitting global potential energy surface data, namely, G-MBNN, that can offer improved energy and force resolution on a complex potential energy surface. In G-MBNN, a set of many-body energy terms based on the local atomic environment are explicitly included in computing the total energy─the total energy of the system is written as the sum of atomic energy and many-body energy contributions. These extra many-body energy terms are computationally low-cost and, importantly, can provide easy access to delicate energy terms in complex systems such as very short repulsion, long-range attractions, and sensitive angular-dependent covalent interactions. We implement G-MBNN in the LASP code and demonstrate the improved accuracy of the new framework in representative systems, including ternary-element energy materials LiCoOx, TiO2 with defects, and a series of organic reactions.

A Solution-Processable Porphyrin-Based Hydrogen-Bonded Organic Framework for Photoelectrochemical Sensing of Carbon Dioxide.

Detecting CO2 in complex gas mixtures is challenging due to the presence of competitive gases in the ambient atmosphere. Photoelectrochemical (PEC) techniques offer a solution, but material selection and specificity remain limiting. Here, we constructed a hydrogen-bonded organic framework material based on a porphyrin tecton decorated with diaminotriazine (DAT) moieties. The DAT moieties on the porphyrin molecules not only facilitate the formation of complementary hydrogen bonds between the tectons but also function as recognition sites in the resulting porous HOF materials for the selective adsorption of CO2 . In addition, the in-plane growth of FDU-HOF-2 into anisotropic molecular sheets with large areas of up to 23000 µm2 and controllable thickness between 0.298 and 2.407 µm were realized in yields of over 89 % by a simple solution-processing method. The FDU-HOF-2 can be directly grown and deposited onto different substrates including silica, carbon, and metal oxides by self-assembly in situ in formic acid. As a proof of concept, a screen-printing electrode deposited with FDU-HOF-2 was fabricate as a label-free photoelectrochemical (PEC) sensor for CO2 detection. Such a signal-off PEC sensor exhibits low detection limit for CO2 (2.3 ppm), reusability (at least 30 cycles), and long-term working stability (at least 30 days).

An optimal Fe-C coordination ensemble for hydrocarbon chain growth: a full Fischer-Tropsch synthesis mechanism from machine learning.

Fischer-Tropsch synthesis (FTS, CO + H2 → long-chain hydrocarbons) because of its great significance in industry has attracted huge attention since its discovery. For Fe-based catalysts, after decades of efforts, even the product distribution remains poorly understood due to the lack of information on the active site and the chain growth mechanism. Herein powered by a newly developed machine-learning-based transition state (ML-TS) exploration method to treat properly reaction-induced surface reconstruction, we are able to resolve where and how long-chain hydrocarbons grow on complex in situ-formed Fe-carbide (FeCx) surfaces from thousands of pathway candidates. Microkinetics simulations based on first-principles kinetics data further determine the rate-determining and the selectivity-controlling steps, and reveal the fine details of the product distribution in obeying and deviating from the Anderson-Schulz-Flory law. By showing that all FeCx phases can grow coherently upon each other, we demonstrate that the FTS active site, namely the A-P5 site present on reconstructed Fe3C(031), Fe5C2(510), Fe5C2(021), and Fe7C3(071) terrace surfaces, is not necessarily connected to any particular FeCx phase, rationalizing long-standing structure-activity puzzles. The optimal Fe-C coordination ensemble of the A-P5 site exhibits both Fe-carbide (Fe4C square) and metal Fe (Fe3 trimer) features.

Ultrasensitive quantitation of Paraquat based on a small molecule-induced dual-cycle amplification strategy.

Paraquat (PQ) is a typical biotoxic small molecule. Knowledge of how to directly introduce it into cyclic amplification rather than transform it into a secondary target is lacking in current analytical methods. Considering the urgent need for trace pesticide residue detection and the inherent defects of small molecule analysis, a CRISPR/Cas12a-driven small molecule-induced dual-cycle strategy was developed based on the immune competition method. The key to signal amplification is the mutual activation and acceleration between Cycle 1 triggered by the small molecule and Cycle 2 driven by CRISPR/Cas12a. Impressively, small molecules have been successfully incorporated into the dual-cycle strategy, which achieves a low detection limit (3.1 pg/mL) and a wide linear range (from 10 pg/mL to 50 µg/mL). Moreover, the designed biosensor was successfully employed to evaluate the PQ residual level in real samples and showed effective implementation for the bioanalysis of small molecule targets and pesticide residue-related food safety.

The collision-induced dissociation mechanism of sodiated Hex-HexNAc disaccharides.

Determining carbohydrate structures, such as their compositions, linkage positions, and in particular the anomers and stereoisomers, is a great challenge. Isomers of different anomers or stereoisomers have the same sequences of chemical bonds, but have different orientations of some chemical bonds which are difficult to be distinguished by mass spectrometry. Collision-induced dissociation (CID) tandem mass spectroscopy (MS/MS) is a widely used technique for characterizing carbohydrate structures. Understanding the carbohydrate dissociation mechanism is important for obtaining the structural information from MS/MS. In this work, we studied the CID mechanism of galactose-N-acetylgalactosamine (Gal-GalNAc) and glucose-N-acetylglucosamine (Glc-GlcNAc) disaccharides with 1→3 and 1→4 linkages. For Gal-GalNAc disaccharides, the CID mass spectra of sodium ion adducts show significant difference between the α- and ß-anomers of GalNAc at the reducing end, while no difference in the CID mass spectra between two anomers of Glc-GlcNAc disaccharides was found. Quantum chemistry calculations show that for Gal-GalNAc disaccharides, the difference of the dissociation barriers between dehydration and glycosidic bond cleavage is significantly small in the ß-anomer compared to that in the α-anomer; while these differences are similar between the α- and ß-anomers of Glc-GlcNAc disaccharides. These differences can be attributed to the different orientations of hydroxyl and N-acetyl groups located at GalNAc and GlcNAc. The calculation results are consistent with the CID spectra of isotope labelled disaccharides. Our study provides an insight into the CID of 1→3 and 1→4 linked Gal-GalNAc and Glc-GlcNAc disaccharides. This information is useful for determining the anomeric configurations of GalNAc in oligosaccharides.

Use of 3D-printing cerebral aneurysm model assisting microcatheter shaping in neurovascular intervention technique training.

BACKGROUND: Microcatheter shaping plays a vital role in coil embolization of cerebral aneurysms, while the complicated method and insufficient training opportunities make it difficult for junior neurovascular clinicians to master this technique. In this program, we constructed a novel training method and assessment system for microcatheter shaping in coil embolization of cerebral aneurysms with 3D technique, and evaluated its efficacy for microcatheter shaping training in junior neurovascular clinicians. METHODS: Patient-specific models for cerebral aneurysms in different locations and with different morphologies were selected by experienced senior neurovascular clinicians. The solid polylactic acid model and the soft hollow crystal silicone model of intracranial aneurysms were then made separately for shaping reference and assessment in the training course. Twelve residents without prior experience of microcatheter shaping and 25 neurovascular clinicians who have in vivo experience of microcatheter shaping on 3-5 occasions were selected for this training program and randomly divided into the traditional training group and the experimental training group. Four senior neurovascular clinicians assisted and guided the trainees in two groups and evaluated the time and accuracy of microcatheter shaping. RESULTS: Eighteen trainees were assigned to the traditional training group, among which 4 had prior experience in microcatheter shaping. The other 19 were assigned to the experimental training group, including 8 with prior experience. No statistical difference in the distribution of experienced students between the two groups was noted(P = 0.295). After the training session, the shaping time was found shorter in the experimental training group than that in the traditional training group (40.3.5 ± 16.2 s vs. 54.2 ± 16.4 s, P = 0.014), while the shaping score was found higher in the experimental training group than that in the traditional training group (4.4 ± 0.5 vs. 2.6 ± 1.2, P < 0.001). Specifically, for the trainees without prior experience, the experimental training group also showed less time consumption and higher score (Time: 52.7 ± 7.7 vs. 61.5 ± 9.5, P = 0.02; Score 4.1 ± 0.5 vs. 2.3 ± 1.1, P < 0.01). Meanwhile, for the trainees with prior experience, the advantage was noted in shaping score (4.7 ± 0.3 vs. 3.9 ± 0.6, P < 0.01) but not in time consumption (23.3 ± 4.4 vs. 28.5 ± 3.9, P = 0.07). CONCLUSION: This training program is quite effective at teaching junior neurovascular physicians the essential surgical abilities required for coiling cerebral aneurysms.

Toward controllable and predictable synthesis of high-entropy alloy nanocrystals.

High-entropy alloy (HEA) nanocrystals have attracted extensive attention in catalysis. However, there are no effective strategies for synthesizing them in a controllable and predictable manner. With quinary HEA nanocrystals made of platinum-group metals as an example, we demonstrate that their structures with spatial compositions can be predicted by quantitatively knowing the reduction kinetics of metal precursors and entropy of mixing in the nanocrystals under dropwise addition of the mixing five-metal precursor solution. The time to reach a steady state for each precursor plays a pivotal role in determining the structures of HEA nanocrystals with homogeneous alloy and core-shell features. Compared to the commercial platinum/carbon and phase-separated counterparts, the dendritic HEA nanocrystals with a defect-rich surface show substantial enhancement in catalytic activity and durability toward both hydrogen evolution and oxidation. This quantitative study will lead to a paradigm shift in the design of HEA nanocrystals, pushing away from the trial-and-error approach.

Site-specific anisotropic assembly of amorphous mesoporous subunits on crystalline metal-organic framework.

As an important branch of anisotropic nanohybrids (ANHs) with multiple surfaces and functions, the porous ANHs (p-ANHs) have attracted extensive attentions because of the unique characteristics of high surface area, tunable pore structures and controllable framework compositions, etc. However, due to the large surface-chemistry and lattice mismatches between the crystalline and amorphous porous nanomaterials, the site-specific anisotropic assembly of amorphous subunits on crystalline host is challenging. Here, we report a selective occupation strategy to achieve site-specific anisotropic growth of amorphous mesoporous subunits on crystalline metal-organic framework (MOF). The amorphous polydopamine (mPDA) building blocks can be controllably grown on the {100} (type 1) or {110} (type 2) facets of crystalline ZIF-8 to form the binary super-structured p-ANHs. Based on the secondary epitaxial growth of tertiary MOF building blocks on type 1 and 2 nanostructures, the ternary p-ANHs with controllable compositions and architectures are also rationally synthesized (type 3 and 4). These intricate and unprecedented superstructures provide a good platform for the construction of nanocomposites with multiple functionalities and understanding of the structure-property-function relationships.

MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium.

Cadmium (Cd) is a high-risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd-induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd-induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP-response element binding protein at Ser133(CREBS133 ) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage-dependent anion-selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.

The Good, the Bad, and the Ugly Memories of Carbohydrate Fragments in Collision-Induced Dissociation.

Collision-induced dissociation (CID) tandem mass spectrometry is commonly used for carbohydrate structural determinations. In the CID tandem mass spectrometry approach, carbohydrates are dissociated into fragments, and this is followed by the structural identification of fragments through subsequent CID. The success of the structural analysis depends on the structural correlation of fragments before and after dissociation, that is, structural memory of fragments. Fragments that completely lose the memory of their original structures cannot be used for structural analysis. By contrast, fragments with extremely strong correlations between the structures before and after fragmentation retain the information on their original structures as well as have memories of their precursors' entire structures. The CID spectra of these fragments depend on their own structures and on the remaining parts of the precursor structures, making structural analysis impractical. For effective structural analysis, the fragments produced from a precursor must have good structural memory, meaning that the structures of these fragments retain their original structure, and they must not be strongly affected by the remaining parts of the precursors. In this study, we found that most of the carbohydrate fragments produced by low-energy CID have good memory in terms of linkage position and anomericity. Fragments with ugly memory, where fragment structures change with the remaining parts of the precursors, can be attributed to C ion formation in a linear form. Fragments with ugly memory can be changed to have good memory by preventing linear C ion generation by using an alternative CID sequence, or the fragments of ugly memory can become useful in structural analysis when the contribution of linear C ions in fragmentation patterns is understood.

A concise synthesis of l-gulose and its C-6 derivatives.

A convenient route for the preparation of l-gulose and its C-6 derivatives starting from commercially available 2,3:5,6-diisopropylidene-d-mannofuranose via C-5 epimerization as the key step was developed. 1-O-Benzylation followed by regioselective hydrolysis of the 5,6-isopropylidene group furnished benzyl 2,3-isopropylidene-α-d-mannofuranoside, which was subjected upon regioselective one-pot 6-O-benzoylation and 5-O-mesylation, providing the corresponding 5-OMs-6-OBz derivative in excellent selectivity. Treatment of this mesylate compound with potassium t-butoxide to remove the benzoyl group followed by intramolecular SN2 inversion led to benzyl 5,6-anhydro-2,3-isopropylidene-ß-l-gulofuranoside, which could undergo not only nucleophilic substitutions to open the epoxide ring to give various C-6 derivatives, but also acidic hydrolysis to yield 1,6-anhydro-ß-l-gulopyranose for further transformation into l-gulopyranosyl pentaacetate.

Design and Synthesis of 1-O- and 6'-C-Modified Heparan Sulfate Trisaccharides as Human Endo-6-O-Sulfatase 1 Inhibitors.

The extracellular human endo-6-O-sulfatases (Sulf-1 and Sulf-2) are responsible for the endolytic cleavage of the 6-sulfate groups from the internal D-glucosamine residues in the highly sulfated subdomains of heparan sulfate proteoglycans. A trisaccharide sulfate, IdoA2OS-GlcNS6S-IdoA2OS, was identified as the minimal size of substrate for Sulf-1. In order to study the complex structure with Sulf-1 for developing potential drugs, two trisaccharide analogs, IdoA2OS-GlcNS6OSO2NH2-IdoA2OS-OMe and IdoA2OS-GlcNS6NS-IdoA2OS-OMe, were rationally designed and synthesized as the Sulf-1 inhibitors with IC50 values at 0.27 and 4.6 µM, respectively.