Site-Specific Analysis of Core and Antenna Fucosylation on Serum Glycoproteins.

Fucosylation is an important structural feature of glycans and plays an essential role in the regulation of glycoprotein functions. Fucosylation can be classified into core- (CF) and antenna-fucosylation (AF, also known as (sialyl-) Lewis) based on the location on N-glycans, and they perform distinct biological functions. In this study, core- and antenna-fucosylated N-glycans on human serum glycoproteins that hold great clinical application values were systematically characterized at the site-specific level using StrucGP combined with the recently developed fucosylation assignment method. The results showed that fucosylation was widely distributed on serum glycoproteins, with 50% of fucosylated glycopeptides modified by AF N-glycans, 37% by CF N-glycans, and 13% by dual-fucosylated N-glycans. Interestingly, CF and AF N-glycans preferred to modify different groups of serum glycoproteins with different tissue origins and were involved in distinctive biological processes. Specifically, AF N-glycoproteins are mainly from the liver and participated in complement activation, blood coagulation, and endopeptidase activities, while CF N-glycoproteins originate from diverse tissues and are mainly involved in cell adhesion and signaling transduction. These data further enhanced our understanding of fucosylation on circulation glycoproteins.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Modular Strategy for Constructing para-Cage[n]arenes, meta-Cage[n]arenes, and meta-Bimacrocyclic-Arenes.

Here, we present a versatile modular strategy for crafting novel covalent organic cages (para-cage[n]arenes and meta-cage[n]arenes, n = 3,4) and bimacrocycles (meta-bimacrocyclic-arenes) with stable backbones and modifiable rims. These structures can be synthesized from commercially available aromatic multialdehydes in a three-step process: quantitative bromination, Suzuki-Miyaura reaction (yielding over 60%), and a rapid one-pot Friedel-Crafts reaction with paraformaldehyde. Notably, the cage[n]arenes exhibit a well-defined prismatic shape, and the bimacrocyclic-arenes display both dimeric and monomeric configurations.

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

Longitudinal evaluation of cerebral perfusion evolution after revascularization surgery in moyamoya disease by CT perfusion.

OBJECTIVE: To assess the longitudinal evolution of cerebral perfusion after revascularization surgery in patients with moyamoya disease (MMD) by CT perfusion (CTP). MATERIALS AND METHODS: Thirty-one clinically confirmed MMD patients (12 males and 19 females, average age: 33.26 y, Suzuki stages 3 and 4: 19 and 11, respectively) who underwent revascularization surgery (bilateral (n=13) or unilateral (n=18)) were studied retrospectively. All patients underwent CTP examinations before and in the week after surgery and long-term (>3 months). CTP metrics (CBF, CBV, MTT, TTP, and delay TTP) were derived. The corresponding CTP metric values of the ROIs, which were manually drawn in the white matter (WM) and gray matter (GM), were recorded. RESULTS: Six patients developed a new or progressive cerebral infarction/hemorrhage. In all patients, compared with the preoperative level, the TTP of GM and WM decreased in the short term after the surgery (P ≤ 0.005). Concurrently, the WM CBF increased significantly a week after surgery (P =0.02). However, in the long-term follow-up, the CBV and CBF in the GM and WM decreased to equal to or lower than the preoperative level, especially for CBV in the WM (P =0.012). Furthermore, cerebral perfusion began to decrease in the sixth month, and a continuous decline was observed over the next two months. It returned to the presurgical level after one year. In addition, the improvement in postsurgical perfusion was greater in Suzuki stage 3 patients than stage 4 patients. CONCLUSION: Cerebral perfusion in patients with MMD improved shortly after surgery. However, in the long-term, brain perfusion decreased, most seriously in 6-8 months postoperatively, which might indicate that patients with MMD need timely follow-up and long-term intervention.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.

Structural Conjugation Tuning in Covalent Organic Frameworks Boosts Charge Transfer and Photocatalysis Performances.

Structural conjugation greatly affects the optical and electronic properties of the COF photocatalyst. Herein, we show that 2D hydrazone COFs with either π-extended biphenyl (BPh-COF) or acetylene (AC-COF) frameworks demonstrated distinct charge transfer and photocatalytic performances. The two COFs show good crystallinity and decent porosity as their frameworks are enforced by intra/interlayers hydrogen bonding. However, computational and experimental data reveal that AC-COF managed broader visible-light absorption and narrower optical bandgaps and performed efficient photoinduced charge separation and transfer in comparison with BPh-COF, meaning that the ethynyl skeleton with enhanced planarity better improves the π-conjugation of the whole structure. As a result, AC-COF exhibited an ideal bandgap for rapid oxidative coupling of amines under visible-light irradiation. Furthermore, taking advantage of its better charge transfer properties, AC-COF demonstrated considerable enhanced product conversion and notable functional tolerance for metallaphotocatalytic C-O cross-coupling of a wide range of both aryl bromides and chlorides with alcohols. More importantly, besides being recoverable, AC-COF showcased the previously inaccessible etherification of dihaloarene. This report shows a facile approach for manipulating the structure-activity relationship and paves the way for the development of a COF photocatalyst for solar-to-chemical energy conversion.

Acyclic Cucurbit[n]urils: Effective Taste Masking Nanocontainers for Cationic Bitter Compounds.

New acyclic cucurbit[n]urils (ACBs) with eight carboxylate groups were synthesized. These hosts are highly soluble in water, and can form stable inclusion complexes with cationic bitter compounds. ACBs are confirmed to be non-toxic and biocompatible. Two-bottle preference (TBP) tests on mice show that all ACBs are tasteless to mammals. ACBs are discovered to mask the bitterness of berberine and denatonium benzoate, but not quinine hydrochloride, due to different binding modes.

A Multilayered Magnetoelectric Transmitter with Suppressed Nonlinearity for Portable VLF Communication.

Acoustically actuated magnetoelectric (ME) antenna based on the efficient oscillation of magnetic dipoles has recently been considered as a promising solution for portable very-low-frequency communications. However, the severe nonlinear dynamic behavior in the case of strong-field excitation results in insufficient radiation capability and poor communication performance for a conventional ME antenna. In this work, we propose to suppress the nonlinearity of an ME antenna by neutralizing the spring-hardening effect in amorphous Metglas and the spring-softening effect in piezoelectric ceramics through an ME multilayered transmitter (ME-MLTx) design. With a driving voltage of 50 Vpp at the resonance frequency of 21.2 kHz, a magnetic flux density as high as 108 fT at a distance of 100 m is produced from a single ME-MLTx. In addition, ME-MLTx performs a decreased mechanical quality factor (Q m) less than 40.65, and, thus, a broadened bandwidth of 500 Hz is generated. Finally, a communication link transmitting binary American Standard Code for Information Interchange-coded message is built, which allows for an error-free communication with a distance of 18 m and a data rate of 300 bit/s in the presence of heavy environment noise. The communication distance can be further estimated over 100 m when using a femtotesla-class-inductive magnetic field receiver. The obtained results are believed to bring ME antennas one step closer to being applicable in very-low-frequency communications.

The early effects of sleeve gastrectomy on postprandial chylomicron triglycerides during the progression of type 2 diabetes.

BACKGROUND: It remains unclear whether early sleeve gastrectomy (SG) improves postprandial very-low-density lipoprotein (VLDL) as well as chylomicron triglycerides (TGs) in a weight-independent manner in patients with or without type 2 diabetes (DM). Herein we investigated the early effects of SG on postprandial VLDL and chylomicron kinetics. METHODS: A liquid meal test was performed before and after 1 week of SG. The plasma was collected for postprandial triglyceride-rich lipoprotein kinetics analyses, including VLDLs and chylomicrons, isolated by high-speed ultracentrifugation. Lipidomics and metabolomics were used to profile lipid and metabolite compositions of plasma and postprandial chylomicrons. De novo fatty acid synthesis in intestinal epithelial cells treated with chylomicron metabolites was examined using RT-PCR, immunoblotting, and free fatty acid measurement. RESULTS: We found that patients with DM had markedly higher VLDL TGs than patients without DM, and such an increase was still retained after SG. In contrast, SG significantly decreased postprandial chylomicron TGs, but surprisingly, the degree of the reduction in patients with DM was less prominent than in patients without DM, confirmed by untargeted lipidomics analysis. Moreover, 5 unique metabolites potentially linked to de novo fatty acid synthesis from the pathway analysis were discovered by further metabolomic analysis of postprandial chylomicrons from patients with DM who underwent SG and verified by In vitro intestinal epithelial cell culture experiments. CONCLUSIONS: SG in 1 week did not impact postprandial VLDL but decreased chylomicron TGs. Patients with DM keep higher postprandial chylomicron TG concentrations than patients without it after SG, potentially through some unique metabolites that increase intestinal fatty acid synthesis. These results implicate the timing for SG to reach lower intestinal fatty acid synthesis and postprandial chylomicron TG production is prior to the diagnosis of DM to potentially reduce cardiovascular risks.

Site-specific N-glycan changes during semen liquefaction.

Normal liquefaction of semen is one of the key steps to ensure the smooth progress of fertilization, and glycosylation has been reported to be involved in the whole process of fertilization. Till now, it is still unclear whether and how glycosylation changes during the liquefaction process of semen. In this study, by performing a glycoproteomic analysis of human semen with the liquefaction process (liquefaction time of semen: 0 min vs 30 min) using our recently developed StrucGP software combined with the Tandem Mass Tags (TMT) based quantification, we identified 25 intact glycopeptides (IGPs) from 10 glycoproteins in semen that were significantly changed during liquefaction, including 23 up-regulated and two down-regulated. Among the 23 up-regulated glycopeptides, half were modified with sialylated glycans, suggesting that sialylated glycans may play a key role in the semen liquefaction process. The data provide an invaluable resource for further studies on the role of glycosylation during semen liquefaction.

Acyclic cucurbit[n]uril-based nanosponges significantly enhance the photodynamic therapeutic efficacy of temoporfin in vitro and in vivo.

Acyclic cucurbit[n]uril-based nanosponges are prepared based on supramolecular vesicle-templated cross-linking. The nanosponges are capable of encapsulating the clinically approved photodynamic therapeutic (PDT) drug temoporfin. When loaded with nanosponges, the PDT bioactivity of temoporfin is enhanced 7.5-fold for HeLa cancer cells and 20.8 fold for B16-F10 cancer cells, respectively. The reason for the significant improvement in PDT efficacy is confirmed to be an enhanced cell uptake by confocal laser scanning microscopy and flow cytometry. Animal studies show that nanosponges could dramatically increase the tumor suppression effect of temoporfin. In vitro and in vivo experiments demonstrate that nanosponges are nontoxic and biocompatible.

Glycoproteomic analysis of regulatory effects of bisecting N-glycans on N-glycan biosynthesis and protein expressions in human HK-2 cells.

Bisecting N-glycan is known to be a metastasis suppressor and plays a regulatory role in the biosynthesis of N-glycans. Previous studies have shown that bisecting N-glycans are capable of modulating both the branching and terminal modifications of glycans. However, these effects have been investigated mainly by glycomic approaches and it remains unclear how they alter when glycans are attached to different glycosites of proteins. Here, we systematically investigated the regulatory roles of bisecting N-glycans in human HK-2 cells using StrucGP, a strategy we developed for structural interpretation of site-specific N-glycans on glycoproteins. The glycoproteomics analysis showed that most of bisecting N-glycans are complex type and often occur in company with core fucosylation. With the overexpression and knockdown of MGAT3, the only enzyme responsible for bisecting N-glycan synthesis, we found that bisecting N-glycans can impact the biosynthesis of N-glycans from multiple aspects, including glycan types, branching, sialylation, fucosylation (different effects for core and terminal fucosylation) as well as the presence of terminal N-acetylglucosamine. Furthermore, gene ontology analysis suggested that most proteins with bisecting N-glycans located in the extracellular region or membrane, where they function mostly in cell adhesion, extracellular matrix regulation and cell signaling. Finally, we showed that overexpression of bisecting N-glycans had a broad impact on the protein expressions of HK-2 cells, involving multiple biological processes. Taken together, our work systematically demonstrated the expression profiles of bisecting N-glycans, and their regulatory effects on the biosynthesis of N-glycans and protein expressions, which provide valuable information for the functional elucidation of bisecting N-glycans.

Pseudo[n]-pillar[5]arenes: Synthesis, Structures, and Host-Guest Binding Properties.

[1n]Paracyclophane has been known for nearly 40 years, but its derivatives and properties are understudied in comparison to those of other macrocyclic compounds. By the modification of pillar[5]arene, we successfully obtained five electron-rich pentagonal macrocycles (pseudo[n]-pillar[5]arenes, n = 1-4) with the decrease of substituted phenylenes one after another, achieving the partial derivatization of [15]paracyclophane skeleton at its phenylene sites. Pseudo[n]-pillar[5]arenes (P[n]P[5]s) served as a kind of macrocyclic host to form complexes with various guests, such as dinitriles, dihaloalkanes, and imidazolium salt, in a 1:1 host-guest stoichiometric ratio. The binding constants with the guest gradually reduce along the decrease of substituted phenylene segments from host P[1]P[5] to P[4]P[5]. It is worthy to note that P[n]P[5]s can adjust their conformations to the "pillar-like" shape effectively when binding with succinonitrile in the solid state.

Metallaphotocatalytic Amination of Aryl Chlorides Enabled by Highly Crystalline Acetylene-Based Hydrazone-Linked Covalent Organic Frameworks.

Amination of aryl chlorides by metallaphotocatalysis is highly desired but remains practically challenging. Meanwhile, relying on soluble noble-metal photocatalysts suffers from resource scarcity and structural instability which limit their practical application. Here in, a highly crystalline acetylene-based hydrazone-linked covalent organic framewok-1 (AC-COF-1) is reported that enables metallaphotocatalytic amination of aryl chlorides. The non-planar effect of hydrazone linkage and weak interlayer attraction of acetylene bond are minimized by intralayer hydrogen-bonding. As a result, the COF shows not only improved crystallinity and porosity, but also enhanced optical and electronic properties compared to a COF analog without hydrogen-bonding. Notably, dual AC-COF-1/Ni system affords CN coupling products from broad aryl chloride substrates in excellent yields (up to 99%) and good functional tolerance. Furthermore, AC-COF-1 is recoverable and reusable for seven times photocatalysis cycles. This report demonstrates simple approach to tune the structure-activity relationship in COFs at molecular level.

Decasubstituted Pillar[5]arene Derivatives Containing L-Tryptophan and L-Phenylalanine Residues: Non-Covalent Binding and Release of Fluorescein from Nanoparticles.

Sensitive systems with controlled release of drugs or diagnostic markers are attractive for solving the problems of biomedicine and antitumor therapy. In this study, new decasubstituted pillar[5]arene derivatives containing L-Tryptophan and L-Phenylalanine residues have been synthesized as pH-responsive drug nanocarriers. Fluorescein dye (Fluo) was loaded into the pillar[5]arene associates and used as a spectroscopic probe to evaluate the release in buffered solutions with pH 4.5, 7.4, and 9.2. The nature of the substituents in the pillar[5]arene structure has a huge influence on the rate of delivering. When the dye was loaded into the associates based on pillar[5]arene derivatives containing L-Tryptophan, the Fluo release occurs in the neutral (pH = 7.4) and alkaline (pH = 9.2) buffered solutions. When the dye was loaded into the associates based on pillar[5]arene with L-Phenylalanine fragments, the absence of release was observed in every pH evaluated. This happens as the result of different packing of the dye in the structure of the associate. This fact was confirmed by different fluorescence mechanisms (aggregation-caused quenching and aggregation-induced emission) and association constants. It was shown that the macrocycle with L-Phenylalanine fragments binds the dye more efficiently (lgKa = 3.92). The experimental results indicate that the pillar[5]arene derivatives with amino acids fragments have a high potential to be used as a pH-responsive drug delivery devices, especially for promoting the intracellular delivering, due to its nanometric size.

Effects of Propofol on Cortical Electroencephalograms in the Operation of Glioma-Related Epilepsy.

BACKGROUND: A cortical electroencephalogram (ECoG) is often used for the intraoperative monitoring of epilepsy surgery, and propofol is an important intravenous anesthetic, but its effect on EEGs is unclear. OBJECTIVES: To further clarify the effect of propofol on cortical ECoGs during glioma-related epilepsy surgery and to clarify the possible clinical value. METHODS: A total of 306 patients with glioma were included in the study. Two hundred thirty-nine with glioma-related epilepsy were included in the epilepsy group, and 67 without glioma-related epilepsy were included in the control group. All patients experienced continuous, real-time ECoG monitoring and long-term follow-up after surgery. RESULTS: After injection of low-dose propofol, the rate of activated ECoGs in the epilepsy group (74%) was significantly higher than in the control group (9%). Furthermore, compared with patients in the untreated group, patients in the treated group had lower rates of early and long-term postoperative seizure frequencies and fewer interictal epileptiform discharges (IEDs). CONCLUSIONS: Low-dose infusion of propofol can specifically activate ECoGs in epilepsy patients. Therefore, activated ECoGs might provide an accurate and reliable method for identifying potential epileptic zones during glioma-related epilepsy surgery, resulting in better early and long-term prognoses after epilepsy surgery.

Effects of apolipoprotein E polymorphism on cerebral oxygen saturation, cerebral perfusion, and early prognosis after traumatic brain injury.

OBJECTIVE: To investigate the effects of the apolipoprotein E (APOE) gene on oxygen saturation and cerebral perfusion in the early stages of traumatic brain injury (TBI). METHODS: This study included 136 consecutive TBI patients and 51 healthy individuals. The APOE genotypes of all subjects were determined using quantitative fluorescence polymerase chain reaction (QF-PCR). Regional cerebral oxygen saturation (rScO2) of patients with TBI and normal subjects was monitored using near-infrared spectroscopy (NIRS). Computed tomography (CT) perfusion was used to obtain cerebral perfusion in patients with TBI and normal subjects. RESULTS: In the TBI group, the rScO2 of APOEε4 carriers (53.06 ± 6.87%) was significantly lower than that of non-carriers (58.19 ± 5.83%, p < 0.05). Meanwhile, the MTT of APOEε4 carriers (6.75 ± 1.30 s) was significantly longer than that of non-carriers (5.87 ± 1.00 s, p < 0.05). Furthermore, correlation analysis showed a negative correlation between rSCO2 and MTT in patients with TBI. Both the univariate and multifactorial logistic regression analyses revealed that APOE ε4, hypoxia, MTT >5.75 s, Marshall CT Class, and GCS were independent risk factors for early poor prognosis in patients with TBI. CONCLUSION: Both cerebral perfusion and cerebral oxygen were significantly impaired after TBI, and low cerebral perfusion and hypoxia were related to poor prognosis of patients with TBI. Compared with APOE ε4 non-carriers, APOE ε4 carriers not only had poorer cerebral perfusion and cerebral oxygen metabolism but also worse prognosis in the early stages of TBI. Furthermore, a negative correlation was observed between the rSCO2 and MTT levels. In addition, both CT perfusion scanning (CTP) and NIRS are reliable for monitoring the condition of patients with TBI in the neurological intensive care unit (NICU).

Host-guest binding of tetracationic cyclophanes to photodynamic agents inhibits posttreatment phototoxicity and maintains antitumour efficacy.

In the past two decades, photodynamic therapy (PDT) has become an effective method for the treatment of cancer. However, the posttreatment residue of photodynamic agents (PDAs) causes long-term skin phototoxicity. Here, we apply naphthalene-derived, box-like tetracationic cyclophanes, named NpBoxes, to bind to clinically used porphyrin-based PDAs to alleviate their posttreatment phototoxicity by reducing their free content in skin tissues and 1O2 quantum yield. We show that one of the cyclophanes, 2,6-NpBox, could include the PDAs to efficiently suppress their photosensitivity for the generation of reactive oxygen species. A tumour-bearing mouse model study revealed that, when Photofrin, the most widely used PDA in clinic, was administrated at a dose corresponding to the clinical one, 2,6-NpBox of the same dose could significantly suppress its posttreatment phototoxicity on the skin induced by simulated sunlight irradiation, without imposing a negative influence on its PDT efficacy.