Fast Metabolic Glycan Labeling for Click-Labeling and Imaging of Sialoglycans in Living Acute Brain Slices from Mice and Human Patients.

Living acute brain slices provide a practical platform for imaging sialylation in human brain pathology. However, the limited lifespan of acute brain slices has impeded the use of metabolic glycan labeling (MGL), which requires long-term incubation of clickable unnatural sugars such as N-azidoacetylmannosamine (ManNAz) to metabolically incorporate azides into sialoglycans. Here, we report a fast variant of MGL (fMGL), in which ManNAz-6-phosphate enables efficient azidosugar incorporation within 12 h by bypassing the bottleneck step in the sialic acid biosynthesis pathway, followed by click-labeling with fluorophores and imaging of sialoglycans in acute brain slices from mice and human patients. In the clinical samples of ganglioglioma, fMGL-based imaging reveals specific upregulation of sialylation in astrocyte-like but not neuron-like tumor cells. In addition, fMGL is integrated with click-expansion microscopy for high-resolution imaging of sialoglycans in brain slices. The fMGL strategy should find broad applications in the tissue imaging of glycans and surgical pathology.

Facile Synthesis of Clickable Unnatural Sugars in the Unprotected and 1,6-Di-O-Acylated Forms for Metabolic Glycan Labeling.

Clickable unnatural sugars have been widely used in studying glycosylation in living systems via the metabolic glycan labelling (MGL) strategy. Partial protection of unnatural sugars by 1,6-di-O-acylation increases the labelling efficiency while avoiding the non-specific S-glyco-modification. Herein, we report the facile synthesis of a series of clickable unnatural sugars in both the unprotected and 1,6-di-O-acylated forms at the ten-gram scale. By evaluation of the labelling specificity, efficiency, and biocompatibility of various 1,6-di-O-acylated sugars for MGL in cell lines and living mice, we demonstrate that 1,6-di-O-propionylated unnatural sugars are optimal chemical reporters for glycan labelling. The synthetic routes developed in this work should facilitate the widespread use of MGL with no artificial S-glyco-modification for investigating the functional roles of glycans.

Diagnostic utility of different dysphagia screening tools to detect dysphagia in individuals with amyotrophic lateral sclerosis.

OBJECTIVE: Dysphagia is a common and serious clinical symptom of amyotrophic lateral sclerosis (ALS). The study aimed to evaluate the diagnostic utility of four dysphagia screening tools in ALS, including the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscale, water-swallowing test (WST), Eating Assessment Tool-10 (EAT-10) and Sydney Swallow Questionnaire (SSQ). METHODS: A total of 68 individuals from First Hospital, Shanxi medical university, were recruited in the study. The ALSFRS-R, WST, EAT-10, SSQ and the gold standard video fluoroscopic swallowing study (VFSS) were performed. The Penetration Aspiration Scale (PAS) during VFSS was assessed to identify unsafe swallowing (PAS ≥ 3) and aspiration (PAS ≥ 6). Receiver operator characteristic curve (ROC) analyses were performed to evaluate the accuracy of the 4 tools. Youden index was used to determine the ideal cut-off value for each tool. RESULTS: Of the patients, 20.59% (14/68) presented unsafety swallowing and 16.18% (11/68) had aspiration. The four tools could effectively identify patients with unsafe swallowing and aspiration. The EAT-10 had the maximum AUC (0.873 and 0.963, respectively) among the tools in the diagnosis of unsafe swallowing and aspiration. To detect unsafe swallowing and aspiration, an EAT-10 score of 6 (sensitivity: 78.6%, specificity: 87.0%) and an EAT-10 score of 8 (sensitivity: 90.9%, specificity: 91.2%), were the most appropriate cut-off points, respectively. CONCLUSIONS: The ALSFRS-R bulbar subscale, WST, EAT-10, and SSQ could effectively identify unsafe swallowing and aspiration in patients with ALS. Of the four tools, the EAT-10 was relatively accurate, safe, and convenient. Further studies including more patients should be conducted to verify the conclusions.

Bioorthogonal Lanthanide Molecular Probes for Near-Infrared Fluorescence and Mass Spectrometry Imaging.

We report here the development of clickable and highly near-infrared (NIR) fluorescent lanthanide (Ln) complexes for bioorthogonal labeling of biomolecules. These azide- or alkyne-functionalized Ln complexes are hydrophilic and fluorogenic, exhibiting a strong increase of NIR fluorescence upon conjugation with biomolecules. Metabolic labeling of biomolecules with azide or alkyne, followed by click labeling with the Ln complexes, enables NIR fluorescence (NIRF) imaging of DNA, RNA, proteins, and glycans in cells. Furthermore, multicolor imaging is performed by combining click-labeling with the Ln complexes and immunostaining. In addition, the Ln complexes is compatible with click-expansion microscopy (click-ExM), which enables high-resolution NIRF imaging of cellular glycoproteins. Finally, the Ln complexes can be used for time-of-flight secondary-ion mass spectrometry (ToF-SIMS) imaging, thus achieving the first example of dual-modal imaging combining NIRF and SIMS microscopies.

Constructing and Validating a Nomogram Model for Short-Term Prognosis of Patients with AChR-Ab+ GMG.

OBJECTIVE: This study aimed to establish and validate a nomogram prognostic model for predicting short-term efficacy of acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (GMG). METHODS: A retrospective observational study was conducted at the First Hospital of Shanxi Medical University, enrolling patients diagnosed with AChR-Ab+ GMG from May 2020 to September 2022. The primary outcome was the change in the Myasthenia Gravis Foundation of America (MGFA) post-intervention status after 6 months of standard treatment. Predictive factors were identified through univariate and multivariate logistic regression analyses, with significant factors incorporated into the nomogram. The bootstrap test was used for internal validation of the nomogram model. Model performance was assessed using calibration curves, receiver-operating characteristic curve analysis, and decision curve analysis (DCA). RESULTS: A total of 90 patients were enrolled, of whom 30 achieved unchanged or worse status after 6 months of standard therapy. Univariate logistic regression analysis showed that quantitative myasthenia gravis score, gender, body mass index, course of disease, hemoglobin levels, and white blood cell counts were six potential predictors. These factors were used for multivariate logistic regression analysis, and a nomogram was constructed. The calibration curve showed that the predicted value was in good agreement with the actual value (p = 0.707), and the area under the curve value (0.792, 95% CI 0.686-0.899) indicated good discrimination ability. DCA suggests that this model has potential clinical application value. CONCLUSION: The constructed nomogram, based on key patient indicators, shows promise as a clinically useful tool for predicting the short-term efficacy of treatment of AChR-Ab+ GMG. Validation in larger, multicenter cohorts is needed to further substantiate its applicability.

Sex, Racial, and Ethnic Representation in COVID-19 Clinical Trials: A Systematic Review and Meta-analysis.

Importance: Since the onset of the COVID-19 pandemic, there have been calls for COVID-19 clinical trials to be fully representative of all demographic groups. However, limited evidence is available about the sex, racial, and ethnic representation among COVID-19 prevention and treatment trials. Objective: To investigate whether female participants and racial and ethnic minority individuals are adequately represented in COVID-19 prevention and treatment trials in the US. Data Sources: Identified studies were registered on ClinicalTrials.gov or published in the PubMed database from October 2019 to February 2022. Study Selection: Included studies must have provided the number of enrolled participants by sex, race, or ethnicity. Only interventional studies conducted in the US for the primary purpose of the diagnosis, prevention, or treatment of (or supportive care for) COVID-19 conditions were included. Data Extraction and Synthesis: Data on counts of enrollments by demographic variables (sex, race, and ethnicity) and location (country and state) were abstracted. Studies were broadly categorized by primary purpose as prevention (including vaccine and diagnosis studies) vs treatment (including supportive care studies). A random effects model for single proportions was used. Trial estimates were compared with corresponding estimates of representation in the US population with COVID-19. Main Outcomes and Measures: Sex, racial, and ethnic representation in COVID-19 clinical trials compared with their representation in the US population with COVID-19. Results: Overall, 122 US-based COVID-19 clinical trials comprising 176 654 participants were analyzed. Studies were predominantly randomized trials (n = 95) for treatment of COVID-19 (n = 103). Sex, race, and ethnicity were reported in 109 (89.3%), 95 (77.9%), and 87 (71.3%) trials, respectively. Estimated representation in prevention and treatment trials vs the US population with COVID-19 was 48.9% and 44.6% vs 52.4% for female participants; 23.0% and 36.6% vs 17.7% for Hispanic or Latino participants; 7.2% and 16.5% vs 14.1% for Black participants; 3.8% and 4.6% vs 3.7% for Asian participants; 0.2% and 0.9% vs 0.2% for Native Hawaiian or Other Pacific Islander participants; and 1.3% and 1.4% vs 1.1% for American Indian or Alaska Native participants. Compared with expected rates in the COVID-19 reference population, female participants were underrepresented in treatment trials (85.1% of expected; P < .001), Black participants (53.7% of expected; P = .003) and Asian participants (64.4% of expected; P = .003) were underrepresented in prevention trials, and Hispanic or Latino participants were overrepresented in treatment trials (206.8% of expected; P < .001). Conclusions and Relevance: In this systematic review and meta-analysis, aggregate differences in representation for several demographic groups in COVID-19 prevention and treatment trials in the US were found. Strategies to better ensure diverse representation in COVID-19 studies are needed, especially for prevention trials.

A systematic review and meta-analysis of the effectiveness of hypertension interventions in faith-based organisation settings.

Background: Hypertension is the global, leading cause of mortality and is the main risk factor for cardiovascular disease. Community-based partnerships can provide cost-saving ways of delivering effective blood pressure (BP) interventions to people in resource-poor settings. Faith-based organisations (FBOs) prove important potential health partners, given their reach and community standing. This potential is especially strong in hard-to-reach, socio-economically marginalised communities. This systematic review explores the state of the evidence of FBO-based interventions on BP management, with a focus on randomised controlled trials (RCTs) and cluster RCTs (C-RCTs). Methods: Seven academic databases (English = 5, Chinese = 2) and grey literature were searched for C-/RCTs of community-based interventions in FBO settings. Only studies with pre- and post-intervention BP measures were kept for analysis. Random effects models were developed using restricted maximum likelihood estimation (REML) to estimate the population average mean change and 95% confidence interval (CI) of both systolic and diastolic blood pressure (SBP and DBP). The overall heterogeneity was assessed by successively adding studies and recording changes in heterogeneity. Prediction intervals were generated to capture the spread of the pooled effect across study settings. Results: Of the 19 055 titles identified, only 11 studies of fair to good quality were kept for meta-analysis. Non-significant, average mean differences between baseline and follow-up for the intervention and control groups were found for both SBP (0.78 mm of mercury (mmHg) (95% CI = 2.11-0.55)) and DBP (-0.20 mm Hg (95% CI = -1.16 to 0.75)). Subgroup analysis revealed a significant reduction in SBP of -6.23 mm Hg (95% CI = -11.21 to -1.25) for populations with mean baseline SBP of ≥140 mm Hg. Conclusions: The results support the potential of FBO-based interventions in lowering SBP in clinically hypertensive populations. However, the limited evidence was concentrated primarily in Christian communities in the US More research is needed to understand the implications of such interventions in producing clinically meaningful long-term effects in a variety of settings. Further research can illuminate factors that affect success and potential expansion to sites outside the US as well as non-Christian FBOs. Current evidence is inadequate to evaluate the potential of FBO-based interventions in preventing hypertension in non-hypertensive populations. Intervention effects in non-hypertensive population might be better reflected through intermediate outcomes.

Exploring the bioavailability of nickel in a soil system: Physiological and histopathological toxicity study to the earthworms (Eisenia fetida).

Nickel (Ni) contamination in soils, at high concentrations, is considered to be very common. Knowledge of the total content of Ni is frequently insufficient to estimate environmental risk. Our explored findings showed that the earthworms adding reduced the available Ni, along with the superior performance of HCl than CaCl2. The bioaccumulation of Ni in earthworms was aggravated with increasing Ni dosage and exposure time. Bioaccumulation factor was significantly correlated with the extractable Ni, which was the most suitable predicting the variations of Ni bioavailability. LC50 of earthworms on 7 and 14 days were 1202.444 mg kg-1 and 1069.324 mg kg-1, respectively along with the recovery rate in 500 mg kg-1 Ni polluted soil reached up to 92.5%. Earthworms' respiration was sensitive presenting a significant dose-effect relationship with the Ni concentration. Five biochemical indices in earthworms were induced along with the relevance of a dose- and time-response pattern. Additionally, histological damage in earthworm's body wall, intestine and seminal vesicles were observed under high level of Ni exposure. Overall, we believe that our current study will open a new window for deeper insights into the potential availability of Ni along with other associated metals on the function of soil ecosystem.

Boosting photocatalytic hydrogen generation of cadmium telluride colloidal quantum dots by nickel ion doping.

Splitting water into hydrogen (H2) with sunlight is an appealing approach towards alleviating the fossil fuel crisis. However, as one of the most promising light harvesters, colloidal quantum dots (QDs) generally exhibit low photocatalytic activity towards H2 evolution because of the lack of catalytic sites on their surface. Many researchers have focused on activating QDs by anchoring metal complexes on their surface, in which the photoexcited electrons may transfer from the QDs to the metal centres via the organic ligands. These bulky organic ligands usually have poor electrical conductivity and chemical instability, thereby causing high charge recombination and low durability in these QDs/metal complex catalysts. To address these issues, we herein report the doping of cadmium telluride (CdTe) QDs with nickel ions (Ni2+), achieving a remarkable H2 generation rate without the use of co-catalysts. The formation rate of H2 exceeded 27.3 mmol/g/h under visible light irradiation, which is approximately 110-fold higher than that of pristine CdTe QDs. This doping strategy provides a versatile route to reduce protons to H2 with a turnover number of 13,650 in terms of Ni and confer superior durability on the CdTe QDs.

Toxicity responses of bacterial community as a biological indicator after repeated exposure to lead (Pb) in the presence of decabromodiphenyl ether (BDE209).

Continuous exposure of chemicals could cause various environmental impacts. Decabromodiphenyl ether (BDE209) and lead (Pb) can co-exist and are discharged simultaneously at e-waste recycling sites (EWRSs). Extensive concerns have been attracted by their toxic effects on soil microorganisms. Thus, by using high-throughput sequencing, this study explored bacterial community responses in a soil system after repeated Pb exposure in the presence of BDE209 in the laboratory during 90-day indoor incubation period. Gene sequencing of 16S rDNA performed on an Illumina MiSeq platform proved that one-off Pb exposure caused higher microbial abundance and community diversity. Additionally, both repetitive Pb treatment and exogenous BDE209 input could change bacterial community composition. Twenty-three different bacterial phyla were detected in the soil samples, while more than 90% of the sequences in each treatment belonged to a narrow variety. The sequence analyses elucidated that Proteobacteria, Acidobacteria, and Bacteroidetes were the top three dominant phyla. Our observations could provide a few insights into the ecological risks of Pb and BDE209 co-existed contamination in soils at EWRSs.

The reproductive responses of earthworms (Eisenia fetida) exposed to nanoscale zero-valent iron (nZVI) in the presence of decabromodiphenyl ether (BDE209).

Reproductive toxicity of nanoscale zero-valent iron (nZVI) along with coexisting decabromodiphenyl ether (BDE209) to earthworm Eisenia fetida (E. fetida) remains unknown. In the present study, the reproductive responses of E. fetida exposed to 100, 500 and 1000 mg kg-1 of nZVI showed a significant (P < 0.05) decline up to 35.6%, 60.0% and 93.3%, respectively, compared to the controls. Expression levels of annetocin (ANN) gene indicated a remarkable (P < 0.05) down-regulation (59.2%, 58.2% and 95.0%, correspondingly), and it was positively correlated with reproductive rates (R = 0.94). Iron contents in E. fetida were also relevant to reproductive behavior (R = 0.84) and ANN expression (R = 0.75). Additionally, seminal vesicles displayed a progressive degeneration with increasing nZVI levels. The addition of BDE209 to low level of nZVI-polluted group (100 mg kg-1 dw) barely caused clear changes on reproduction, histopathology and ANN, while the coexistence resulted in significant impacts in comparison with high level of single nZVI exposure (1000 mg kg-1 dw). These observations would provide some significant information concerning joint toxicity of the two chemicals in a soil system.

Toxic responses of microorganisms to nickel exposure in farmland soil in the presence of earthworm (Eisenia fetida).

Nickel (Ni)-contamination impairs soil ecosystem, threatening human health. A laboratory simulation of Ni-polluted farmland soil study, in the presence or absence of earthworm, was carried out to investigate the toxic responses of soil microorganisms, including microbial biomass C (MBC), soil basal respiration (SBR), metabolic quotient (qCO2), urease (UA) and dehydrogenase activities (DHA). Additionally, the variations of Ni bioavailability were also explored. Results manifested that MBC and SBR were stimulated at 50 and 100 mg·kg-1 of Ni but inhibited by further increasing Ni level, showing a Hormesis effect. Earthworm input delayed the occurrence of a maximum SBR inhibition rate under the combined double-factors of time and dose. No specific effect of Ni concentration on the qCO2 was observed. UA was significantly suppressed at 800 mg·kg-1 Ni (P < 0.05 or 0.01), whereas DHA was more sensitive and significantly inhibited throughout all the treatments (P < 0.01), indicating a pronounced dose-response relationship. The addition of earthworm facilitated all the biomarkers above. The time-dependent of dose-effect relationship (TDR) on MBC and SBR inhibition rates suggested that the peak responsiveness of microorganisms to Ni stress were approximate on the 21st day. The bioavailable form of per unit Ni concentration declined with time expanded and concentration increased, and the changeable process of the relative amount of bioavailability was mainly controlled by a physicochemical reactions.

Bioaccumulation and toxic effects of decabromodiphenyl ether in the presence of nanoscale zero-valent iron in an earthworm-soil system.

In this study, the bioaccumulation and toxic effects of decabromodiphenyl ether (BDE209) (1 and 10 mg kg-1) were investigated in the earthworm Eisenia fetida in the presence of different levels of nanoscale zero-valent iron (nZVI) (100, 500, and 1000 mg kg-1) in an earthworm-soil system. The results demonstrated that compared to single BDE209 exposure, the addition of high levels of nZVI significantly (P < 0.05) inhibited growth and respiration, while increased the avoidance response of earthworms. The perturbations of antioxidant enzyme activities (superoxide dismutase (SOD) and catalase (CAT)) and the malondialdehyde (MDA) content clearly revealed that oxidative stress was induced by the two chemicals. The histopathological observations of the body wall of earthworms under a combined exposure of 10 mg kg-1 BDE209 with 500 or 1000 mg kg-1 nZVI illustrated the presence of a serious injury in the intestinal tissues after a 28-day exposure. Additionally, a gas chromatography-mass spectrometry analysis revealed that the coexistence of high level of nZVI significantly (P < 0.05) decreased the bioaccumulation of BDE209 in earthworms; BDE208 and BDE206 were the predominant congeners of debrominated metabolites, and 4,6-dibromobenzene-1,2,3,5-tetraol along with benzene-1,2,4,5-tetraol were determined as the two main intermediates. The possible degradation pathways were proposed on the basis of the identified products. This work provides useful information on the biological effects of BDE209 and nZVI.

The biochemical and toxicological responses of earthworm (Eisenia fetida) following exposure to nanoscale zerovalent iron in a soil system.

Nanomaterials have increasingly gained a great amount of interest due to their widespread applications, while their potential impacts on invertebrates in soil lack thorough investigation. This study is mainly aimed at determining the acute and subacute toxicity to the earthworm Eisenia fetida, induced by different levels of nanoscale zerovalent iron (nZVI) (100, 500, 1000 mg kg-1) in natural soils. The results showed that compared to the controls, exposure to 500 and 1000 mg kg-1 of nZVI significantly (P < 0.05) inhibited growth and respiration and increased avoidance response in earthworms. The perturbations of antioxidant enzyme activities (superoxide dismutase-SOD and catalase-CAT), malondialdehyde (MDA) content, and reactive oxygen species (ROS) clearly revealed that oxidative stress was induced in E. fetida exposed to nZVI. Good correlations were observed in current results among the growth, respiration, MDA, and ROS (R > 0.8; P < 0.05), and that ROS was the most sensitive parameter in response to the stress caused by nZVI. Additionally, the histopathological examination of transverse sections of the exposed earthworms passing through the body wall illustrated that there was a serious injury in epidermal tissue after an exposure of 28 days. These findings will provide a comprehensive understanding of toxicological effects of nZVI in a soil-earthworm system.