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Copper-catalyzed click chemistry offers creative strategies for activation of therapeutics without disrupting biological processes. Despite tremendous efforts, current copper catalysts face fundamental challenges in achieving high efficiency, atom economy, and tissue-specific selectivity. Herein, we develop a facile "mix-and-match synthetic strategy" to fabricate a biomimetic single-site copper-bipyridine-based cerium metal-organic framework (Cu/Ce-MOF@M) for efficient and tumor cell-specific bioorthogonal catalysis. This elegant methodology achieves isolated single-Cu-site within the MOF architecture, resulting in exceptionally high catalytic performance. Cu/Ce-MOF@M favors a 32.1-fold higher catalytic activity than the widely used MOF-supported copper nanoparticles at single-particle level, as first evidenced by single-molecule fluorescence microscopy. Furthermore, with cancer cell-membrane camouflage, Cu/Ce-MOF@M demonstrates preferential tropism for its parent cells. Simultaneously, the single-site CuII species within Cu/Ce-MOF@M are reduced by upregulated glutathione in cancerous cells to CuI for catalyzing the click reaction, enabling homotypic cancer cell-activated in situ drug synthesis. Additionally, Cu/Ce-MOF@M exhibits oxidase and peroxidase mimicking activities, further enhancing catalytic cancer therapy. This study guides the reasonable design of highly active heterogeneous transition-metal catalysts for targeted bioorthogonal reactions.

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The exploration of new properties and functionality of covalent organic frameworks (COFs) rely mostly on the covalent modification of the starting building blocks or linkages. Noncovalent forces that guide the assembly and adhesion of layers to develop two-dimensional (2D) COFs and improve their bulk properties and functionalities, however, are rarely explored. Herein, the "conformational lock" (CL) effect in 2D hydrazine-linked COFs with intralayer F-H interaction is discovered and regulated to stabilize interlayer adhesion and develop a facile strategy to increase their stability, promote selectivity and efficiency in reactive singlet oxygen (1O2)-triggered photocatalytic transformation when acting as photocatalysts. The CL strategy endows the fluorinated COFs with an efficient intersystem crossing process for 1O2 generation and strong interlayer π-π stacking interaction. The 4F-COF with the strongest F-H noncovalent interaction exhibits the highest photocatalytic conversion and selectivity (exceeding 98%) in typical 1O2-dependent transformations, even over 7 continuous photocatalytic cycles. This work demonstrates that promoting intralayer noncovalent interaction in 2D-COFs can impart high photocatalytic activity and stability, and would vigorously inspire their developments in heterogeneous catalysis.

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Sonodynamic therapy can trigger immunogenic cell death to augment immunotherapy, benefiting from its superior spatiotemporal selectivity and non-invasiveness. However, the practical applications of sonosensitizers are hindered by their low efficacy in killing cancer cells and activating immune responses. Here, two US Food and Drug Administration-approved drug ligands (ferricyanide and nitroprusside) and two types of metals (copper/iron) are selected to construct a bimetal-biligand framework (Cu[PBA-NO]). Through elaborate regulation of multiple metal/ligand coordination, the systemically administered Cu[PBA-NO] nanoagent shows sono-catalytic and NO release ability under ultrasound irradiation, which can be used for effective sono-immunotherapy. Moreover, Cu[PBA-NO] can downregulate intracellular glutathione levels that would destroy intracellular redox homeostasis and facilitate reactive oxygen species accumulation. The released tumor-associated antigens subsequently facilitate dendritic cell maturation within the tumor-draining lymph node, effectively initiating a T cell-mediated immune response and thereby bolstering the capacity to identify and combat cancer cells. This study paves a new avenue for the efficient cancer sono-immunotherapy.

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BACKGROUND: Creatinine-to-cystatin C ratio (CCR) has been associated with multiple adverse outcomes. However, little is known about its relationship with frailty. We aimed to explore the association between CCR and frailty among older adults. METHODS: A total of 2599 participants aged ≥ 60 years (mean age 67.9 ± 6.0 years, 50.4% males) were included from the China Health and Retirement Longitudinal Study (2011-2015). Baseline CCR was calculated as plasma creatinine (mg/dL) / cystatin C (mg/L) × 10 and was grouped by quartiles. Frailty was evaluated by the validated physical frailty phenotype (PFP) scale and was defined as PFP score ≥ 3. The generalized estimating equations model was used to explore the relationship between CCR and frailty. RESULTS: The frailty risk decreased gradually with increasing CCR in the quartiles (P for trend = 0.002), and the fourth CCR quartile was associated with a significantly lower risk of frailty compared with the lowest quartile (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.70). When modeling as a continuous variable, per 1-unit increase in CCR was related to 17% decreased odds of frailty (OR 0.83, 95% CI 0.74-0.93). The association was consistent in male and female participants (P for interaction = 0.41). Poisson models revealed that frailty score was negatively associated with CCR (ß= -0.11, 95% CI= -0.19 to -0.04), and sex did not significantly moderate the associations (P for interaction = 0.22). The results were not affected by further adjusting for high-sensitivity C-reactive protein. Similar results were observed by analyses with multiple imputation technique and analyses excluding participants with baseline frailty. CONCLUSIONS: Higher CCR was associated with a lower frailty risk. CCR may be a simple marker for predicting frailty in older adults.

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Objective: To analyze the characteristics of deliberate drug ingestion in adolescents and its related influencing factors. Method: This was a retrospective study. A total of 158 cases of deliberate drug ingestion as observation group and 160 cases of other diseases in adolescents as control group were treated in the Emergency Department of Baoding Hospital of Beijing Children's Hospital Affiliated to Capital Medical University from January 2020 to December 2022. The clinical characteristics of adolescents who engaged in deliberate drug ingestion were analyzed, and various factors that could potentially influence deliberate drug ingestion in adolescents were subjected to both univariate and multivariate analysis. Result: There was a progressive increase in the number of patients presenting with mental health issues year by year. Univariate analysis showed that family type, guardian's education level, place of residence, whether they were only children, parents' knowledge of medication, awareness of medication safety, depression/anxiety, negative life events, and social support were risk factors for deliberate drug ingestion in adolescents (all p<0.05). Logistic regression analysis showed that family type, parents' knowledge of medication, awareness of medication safety, whether they were depressed/anxious, negative life events, and social support were independent risk factors for deliberate drug ingestion in adolescents (p<0.05). Conclusion: The incidence of deliberate drug ingestion in adolescents is increasing year by year, and their behavior is influenced by multiple factors. Interventions should be targeted at controllable influencing factors to prevent or reduce deliberate drug ingestion in adolescents.

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This study investigated the effects of dietary energy levels during late gestation on mineral content in the plasma, colostrum, and milk of jennies postpartum. Twenty-four pregnant multiparous DeZhou jennies, aged 6.0 ± 0.1 years, with a body weight of 292 ± 33 kg, an average parity number of 2.7 ± 0.1, and similar expected dates of confinement (74 ± 4 days), were randomly allocated to three groups and fed three diets: high energy (12.54 MJ/kg, HE), medium energy (12.03 MJ/kg, ME), and low energy (11.39 MJ/kg, LE). Blood samples were collected from the jugular vein of each jenny at time points of 0 h, 24 h, 48 h, 5 d, 7 d, and 14 d after parturition. Additionally, milk samples were collected through manual milking, and an analysis of the mineral content was conducted. The results showed that compared with HE, both ME and LE significantly increased the levels of calcium (Ca), phosphorus (P), zinc (Zn), selenium (Se), molybdenum (Mo), and cobalt (Co) in the plasma and Ca, P, magnesium (Mg), copper (Cu), manganese (Mn), Zn, selenium (Se), molybdenum (Mo), and Co in the milk of jennies postpartum (p < 0.05); ME also increased the levels of potassium (K), iron (Fe), and Mn in plasma and K and Fe in milk (p < 0.05). The levels of Ca, K, Mg, P, Fe, Cu, Mn, Co, Se, Zn, and Mo in plasma and milk gradually decreased with increasing postpartum time. Their contents were the highest at 0 h postpartum, rapidly decreased after 24 h postpartum, and declined to the lowest on day 14 postpartum. The interaction between dietary energy level and postpartum time showed that although the concentrations of the minerals Ca, P, K, Mg, Fe, Cu, Mn, Zn, Co, Se, and Mo decreased in jennies' plasma and milk in the treatment groups with different energy levels as postpartum time increased, the pattern of change was also influenced by dietary energy level. The influence of dietary energy level in late gestation on the mineral content of milk and plasma during the postpartum colostrum phase was higher than that during the milk phase. In conclusion, this study demonstrated that, under the current experimental conditions, the mineral content of the colostrum, milk, and plasma of jennies after parturition was dependent on the dietary energy level during late gestation.

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Within living organisms, numerous nanomachines are constantly involved in complex polymerization processes, generating a diverse array of biomacromolecules for maintaining biological activities. Transporting artificial polymerizations from lab settings into biological contexts has expanded opportunities for understanding and managing biological events, creating novel cellular compartments, and introducing new functionalities. This review summarizes the recent advancements in artificial polymerizations, including those responding to external stimuli, internal environmental factors, and those that polymerize spontaneously. More importantly, the cutting-edge biomedical application scenarios of artificial polymerization, notably in safeguarding cells, modulating biological events, improving diagnostic performance, and facilitating therapeutic efficacy are highlighted. Finally, this review outlines the key challenges and technological obstacles that remain for polymerizations in biological organisms, as well as offers insights into potential directions for advancing their practical applications and clinical trials.

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BACKGROUND: Handgrip strength (HGS) weakness and asymmetry were recently reported to be associated with age-related health conditions. However, little is known about their combined effects on depression. We aimed to explore the joint association of HGS asymmetry and weakness with depressive symptoms in Chinese middle and older aged population. METHODS: 8700 participants aged ≥45 years were enrolled from China Health and Retirement Longitudinal Study (2015-2018). HGS weakness was determined as maximal HGS < 28 kg in males and <18 kg in females. HGS asymmetry was measured by HGS ratio and was defined using two different rules. Specifically, HGS ratio < 0.90 or >1.10 (10 % rule) and <0.80 or >1.20 (20 % rule) were considered as asymmetry. Participants were classified into four groups: normal and symmetric HGS, asymmetry only, weakness only, and both weakness and asymmetry. Depressive symptoms were assessed by the 10-item Center for Epidemiologic Studies Depression Scale, with scores ≥12 defined as depression. The logistic regression and multiple linear regression models were conducted to estimate the associations between HGS status and depressive symptoms. RESULTS: The three-year incidence of depression was 19.2 %. After adjusting for covariates, compared to normal and symmetric HGS, participants with both HGS asymmetry and weakness showed the greatest risk of incident depression (10 % rule: OR 1.55, 95 % CI 1.19-2.02; 20 % rule: OR 1.71, 95 % CI 1.16-2.50). The coexistence of asymmetry and weakness was related to a significant increase in depression score (10 % rule: ß 0.96, 95 % CI 0.38-1.54; 20 % rule: ß 0.94, 95 % CI 0.08-1.81). The complete case analysis supported the results, and the associations were not modified by age, sex, and hand dominance. LIMITATIONS: Depressive assessment was based on self-reported screening instrument. CONCLUSIONS: The presence of both HGS asymmetry and weakness was associated with a higher risk of depression. Examining HGS asymmetry along with weakness may aid in identifying individuals at risk of depression to enable early interventions.

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[This corrects the article DOI: 10.3389/fimmu.2022.857311.].

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PURPOSE: The classification of sleep stages based on Electroencephalogram (EEG) changes has significant implications for evaluating sleep quality and sleep status. Most polysomnography (PSG) systems have a limited number of channels and do not achieve optimal classification performance due to a paucity of raw data. To leverage the data characteristics and enhance the classification accuracy, we propose and evaluate a novel dual-link deep neural network model, 'DoubleLinkSleepCLNet'. METHODS: The DoubleLinkSleepCLNet model performs feature extraction and efficient classification on both the raw EEG and the EEG processed with the Hilbert transform. It leverages the frequency domain and time domain feature modules, resulting in superior performance compared to other models. RESULTS: The DoubleLinkSleepCLNet model, using the 2 Raw/2 Hilbert data modes, achieved the highest classification performance with an accuracy of 88.47%. The average accuracy of the EEG was improved by approximately 4.08% after the application of the Hilbert transform. Additionally, Convolutional Neural Network (CNN) demonstrated superior performance in processing phase information, whereas Long Short-Term Memory (LSTM) excelled in handling time series data. CONCLUSION: The application of the Hilbert transform to EEG data, followed by processing it with a convolutional neural network, enhances the accuracy of the model. These findings introduce novel concepts for accelerating sleep stage prediction research, suggesting potential applications of these methods to other EEG analyses.

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Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.

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Spiro-OMeTAD doped with lithium-bis(trifluoromethylsulfonyl)-imide (Li-TFSI) and tertbutyl-pyridine (t-BP) is widely used as a hole transport layer (HTL) in n-i-p perovskite solar cells (PSCs). Spiro-OMeTAD based PSCs typically show poor stability owing to the agglomeration of Li-TFSI, the migration of lithium ions (Li+), and the existence of potential mobile defects originating from the perovskite layer. Thus, it is necessary to search for a strategy that suppresses the degradation of PSCs and overcomes the Shockley Queisser efficiency limit via harvesting excess energy from hot charge carrier. Herein, two covalent organic frameworks (COFs) including BPTA-TAPD-COF and a well-defined donor-acceptor COF (BPTA-TAPD-COF@TCNQ) were developed and incorporated into Spiro-OMeTAD HTL. BPTA-TAPD-COF and BPTA-TAPD-COF@TCNQ could act as multifunctional additives of Spiro-OMeTAD HTL, which improve the photovoltaic performance and stability of the PSC device by accelerating charge-carrier extraction, suppressing the Li+ migration and Li-TFSI agglomeration, and capturing mobile defects. Benefiting from the increased conductivity, the addition of BPTA-TAPD-COF@TCNQ in the device led to the highest power conversion efficiency of 24.68% with long-term stability in harsh conditions. This work provides an example of using COFs as additives of HTL to enable improvements of both efficiency and stability for PSCs.

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Heat shock is a global health concern as it causes permanent damage to living cells and has a relatively high mortality rate. Therefore, diagnostic tools that facilitate a better understanding of heat shock damage and the defense mechanism at the sub-cellular level are of great importance. In this report, we have demonstrated the use of a pyridinium-based fluorescent molecule, PM-ER-OH, as a 'multichannel' imaging probe to monitor the pH change associated with a heat shock in the endoplasmic reticulum. Among the three pyridinium derivatives synthesized, PM-ER-OH was chosen for study due to its excellent biocompatibility, good localization in the endoplasmic reticulum, and intracellular pH response signaled by a yellow fluorescence (λ max = 556 nm) at acidic pH and a far red fluorescence (λ max = 660 nm) at basic pH. By changing the excitation wavelength, we could modulate the fluorescence signal in 'turn-ON', single excitation ratiometric and 'turn-OFF' modes, making the fluorophore a 'multichannel' probe for both ex vitro and in vitro pH monitoring in the endoplasmic reticulum. The probe could efficiently monitor the pH change when heat shock was applied to cells either directly or in a pre-heated manner, which gives insight on cellular acidification caused by heat stress.

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Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.

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Anaplastic thyroid cancer (ATC) is a rare disease with a poor prognosis and accounts for a high proportion of thyroid cancer deaths. The present study reported on a 56-year-old male patient with ATC and examined the clinical manifestations, pathological features, differential diagnosis and genetic mutations. Immunohistochemical analysis showed positivity for vimentin, Ki-67 and cytokeratin in the tumor specimen. In addition, pathological mitotic figures of tumor cells and intra-lymph node metastasis were observed. Genetic analysis revealed the presence of a novel mutation (c.388C>T, p.R130X) in exon 5 of the phosphatase and tensin homolog (PTEN) gene, which was first detected in ATC. Gene conservation analysis showed that R130 is a highly conserved amino acid. Protein structure model predictions implied that p.R130X mutation results in a severe defect of the C2 domain and the TAD domain of PTEN, which may be a reason for the high malignancy of the tumor. The present case report highlights a novel mutation of PTEN in ATC, which expands the molecular spectrum of PTEN and further underlines the importance of PTEN.

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Tick-borne Encephalitis (TBE) is a zoonotic disease caused by the Tick-borne Encephalitis virus (TBEV), which affects the central nervous system of both humans and animals. Currently, there is no specific therapy for patients with TBE, with symptomatic treatment being the primary approach. In this study, the effects of minocycline (MIN), which is a kind of tetracycline antibiotic, on TBEV propagation and cellular protection in TBEV-infected cell lines were evaluated. Indirect immunofluorescence, virus titers, and RT-qPCR results showed that 48 h post-treatment with MIN, TBEV replication was significantly inhibited in a dose-dependent manner. In addition, the inhibitory effect of MIN on different TBEV multiplicities of infection (MOIs) in Vero cells was studied. Furthermore, the transcriptomic analysis and RT-qPCR results indicate that after incubation with MIN, the levels of TBEV and CALML4 were decreased, whereas the levels of calcium channel receptors, such as RYR2 and SNAP25, were significantly increased. MIN also regulated MAPK-ERK-related factors, including FGF2, PDGFRA, PLCB2, and p-ERK, and inhibited inflammatory responses. These data indicate that administering MIN to TBEV-infected cells can reduce the TBEV level, regulate calcium signaling pathway-associated proteins, and inhibit the MAPK-ERK signaling pathway and inflammatory responses. This research offers innovative strategies for the advancement of anti-TBEV therapy.

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J-aggregation brings intriguing optical and electronic properties to molecular dyes and significantly expands their applicability across diverse domains, yet the challenge for rationally designing J-aggregating dyes persists. Herein, we developed a large number of J-aggregating dyes from scratch by progressively refining structure of a common heptamethine cyanine. J-aggregates with sharp spectral bands (full-width at half-maximum≤38 nm) are attained by introducing a branched structure featuring a benzyl and a trifluoroacetyl group at meso-position of dyes. Fine-tuning the benzyl group enables spectral regulation of J-aggregates. Analysis of single crystal data of nine dyes reveals a correlation between J-aggregation propensity and molecular arrangement within crystals. Some J-aggregates are successfully implemented in multiplexed optoacoustic and fluorescence imaging in animals. Notably, three-color multispectral optoacoustic tomography imaging with high spatiotemporal resolution is achieved, owing to the sharp and distinct absorption bands of the J-aggregates.

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Vascular calcification (VC) is considered a common pathological process in various vascular diseases. Accumulating studies have confirmed that VC is involved in the inflammatory response in heart disease, and SPP1+ macrophages play an important role in this process. In VC, studies have focused on the physiological and pathological functions of macrophages, such as pro-inflammatory or anti-inflammatory cytokines and pro-fibrotic vesicles. Additionally, macrophages and activated lymphocytes highly express SPP1 in atherosclerotic plaques, which promote the formation of fatty streaks and plaque development, and SPP1 is also involved in the calcification process of atherosclerotic plaques that results in heart failure, but the crosstalk between SPP1-mediated immune cells and VC has not been adequately addressed. In this review, we summarize the regulatory effect of SPP1 on VC in T cells, macrophages, and dendritic cells in different organs' VC, which could be a potential therapeutic target for VC.

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Sialyl Lewisa (sLea), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a tetrasaccharide glycan 1 structurally derived from sLea are reported. Challenges involved in the chemical synthesis include the highly stereoselective construction of 1,2-cis-α-L-fucoside and α-D-sialoside, as well as the assembly of the 3,4-disubstituted N-acetylglucosamine subunit. Perbenzylated thiofucoside and N-acetyl-5-N,4-O-oxazolidinone protected sialic acid thioglycoside were employed as glycosyl donors, respectively, for the efficient preparation of the desired α-fucoside and α-sialoside. The 3,4-branched glucosamine backbone was established through a 3-O and then 4-O glycosylation sequence in which the 3-hydroxyl group of the glucosamine moiety was glycosylated first and then the 4-hydroxyl. A facile chemoenzymatic approach was also exploited to synthesize the target molecule. The chemically obtained free disaccharide 30 was sequentially sialylated and fucosylated in an enzyme-catalyzed regio- and stereospecific manner to form 1 in high yields. The linker appended 1 can be covalently attached to a carrier protein for further immunological studies.

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