Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins.

JOURNAL/nrgr/04.03/01300535-202501000-00032/figure1/v/2024-05-14T021156Z/r/image-tiff Human brain development is a complex process, and animal models often have significant limitations. To address this, researchers have developed pluripotent stem cell-derived three-dimensional structures, known as brain-like organoids, to more accurately model early human brain development and disease. To enable more consistent and intuitive reproduction of early brain development, in this study, we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture. This involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation, resulting in a new type of human brain organoid system. This cerebral organoid system replicated the temporospatial characteristics of early human brain development, including neuroepithelium derivation, neural progenitor cell production and maintenance, neuron differentiation and migration, and cortical layer patterning and formation, providing more consistent and reproducible organoids for developmental modeling and toxicology testing. As a proof of concept, we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins. Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns, including bursts of cortical cell death and premature differentiation. Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity, accompanied by compensatory cell proliferation at ectopic locations. The convenience, flexibility, and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental, neurological, and neurotoxicological studies.

Machine Learning Identification of Nutrient Intake Variations across Age Groups in Metabolic Syndrome and Healthy Populations.

This study undertakes a comprehensive examination of the intricate link between diet nutrition, age, and metabolic syndrome (MetS), utilizing advanced artificial intelligence methodologies. Data from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018 were meticulously analyzed using machine learning (ML) techniques, specifically extreme gradient boosting (XGBoost) and the proportional hazards model (COX). Using these analytic methods, we elucidated a significant correlation between age and MetS incidence and revealed the impact of age-specific dietary patterns on MetS. The study delineated how the consumption of certain dietary components, namely retinol, beta-cryptoxanthin, vitamin C, theobromine, caffeine, lycopene, and alcohol, variably affects MetS across different age demographics. Furthermore, it was revealed that identical nutritional intakes pose diverse pathogenic risks for MetS across varying age brackets, with substances such as cholesterol, caffeine, and theobromine exhibiting differential risks contingent on age. Importantly, this investigation succeeded in developing a predictive model of high accuracy, distinguishing individuals with MetS from healthy controls, thereby highlighting the potential for precision in dietary interventions and MetS management strategies tailored to specific age groups. These findings underscore the importance of age-specific nutritional guidance and lay the foundation for future research in this area.

A static precise single-point positioning method based on carrier phase zero-baseline self-differencing.

Satellite navigation positioning has become an indispensable component of everyday life, where precise pinpointing and rapid convergence are crucial in delivering timely and accurate location information. However, due to the damping of integer ambiguities and system residual errors, the rapid convergence of Precise Point Positioning (PPP) implementation is a significant challenge. To address this, this paper proposes a novel Carrier Phase Zero-Baseline Self-Differencing Precise Point Positioning (CZS-PPP) technique and its ionosphere-free fusion model. By employing the proposed CZS-PPP approach in separate scenarios involving BDS-3, GPS, and dual-system settings, we systematically validate the efficacy of the method. The experimental results indicate that the convergence time of the method is less than 4 min in a single-system scenario. Furthermore, in a dual-system scenario, the method can achieve rapid convergence in less than 3 min. The CZS-PPP technique presented demonstrates the elimination of integer ambiguities and the effective suppression of system residuals, in comparison to the conventional method. The proposed approach has demonstrated remarkable performance across different systems, offering a promising new pathway for achieving PPP fast convergence in BDS/GNSS.

A cytotoxicity and mechanistic investigation of mono- and di-chloro naphthalenes.

Polychlorinated naphthalenes (PCNs) were characterized as persistent organic pollutants (POPs) that were widely distributed in the environment. Although the striking in vivo toxicity of these pollutants towards both animals and humans was well documented, their cytotoxicity and mechanism of action have not been extensively investigated. In this study, the in vitro antiproliferative activity of mono- and di-chloronaphthalenes as representative PCNs were evaluated and the results indicated strong growth inhibitory effects against mammalian cells, especially the human breast MCF-10A cell and human hepatic HL-7702 cells. 2-Chloronaphthalene with the most potent antiproliferative effects within the tested PCNs, which showed IC50 values ranging from 0.3 mM to 1.5 mM against selected human cell lines, was investigated for its working mechanisms. It promoted cellular apoptosis of MCF-10A cells upon the concentration of 200 µM. It also induced the autophagy of MCF-10A cells in a dose-dependent manner, resulting in cell death via the interaction of autophagy and apoptosis. Thus, these findings supported the theoretical foundation for interventional treatment of PCNs toxicity and also provided implications for the use of chemopreventive agents against the toxic chlorinated naphthalenes in the environments.

Modeling early human cortical development and evaluating neurotoxicity with a forebrain organoid system.

The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in pluripotent cell-derived organoid systems open up novel avenues for human development, disease and toxicity modeling. Here, we have established a forebrain organoid system and recapitulated early human cortical development spatiotemporally including neuroepithelium induction, apical-basal axis formation, neural progenitor proliferation and maintenance, neuronal differentiation and layer/region patterning. To explore whether this forebrain organoid system is suitable for neurotoxicity modeling, we subjected the organoids to bisphenol A (BPA), a common environmental toxicant of global presence and high epidemic significance. BPA exposure caused substantial abnormalities in key cortical developmental events, inhibited progenitor cell proliferation and promoted precocious neuronal differentiation, leading premature progenitor cell depletion and aberrant cortical layer patterning and structural organization. Consistent with an antagonistic mechanism between thyroid hormone and BPA, T3 supplementation attenuated BPA-mediated cortical developmental abnormalities. Altogether, our in vitro recapitulation of cortical development with forebrain organoids provides a paradigm for efficient neural development and toxicity modeling and related remedy testing/screening.

S-o-(p-Methoxyphenylethynyl)benzyl (SMPEB) Glycosides for Catalytic Glycosylation and Their Application in the Synthesis of Polyporus Umbellatus Polysaccharides.

We herein reported a new type of S-o-(p-methoxyphenylethynyl)benzyl donor for a highly efficient glycosylation method. The donor was activated by 10% Tf2O and underwent glycosylation with various acceptors to provide the corresponding glycosides in excellent yield. Furthermore, two repetitive fragments of Polyporus umbellatus polysaccharides (PUPs), isolated from traditional Chinese medicine "Polyporus umbellatus", were prepared by combining the "single-catalyst one-pot" and "latent-active" strategies for the first time for future clear studies on the structure-activity relationship of PUPs.

Target the neglected VOCs emission from iron and steel industry in China for air quality improvement.

Recent years have witnessed significant improvement in China's air quality. Strict environmental protection measures have led to significant decreases in sulfur dioxide (SO2), nitrogen oxides (NO x ), and particulate matter (PM) emissions since 2013. But there is no denying that the air quality in 135 cities is inferior to reaching the Ambient Air Quality Standards (GB 3095-2012) in 2020. In terms of temporal, geographic, and historical aspects, we have analyzed the potential connections between China's air quality and the iron and steel industry. The non-target volatile organic compounds (VOCs) emissions from iron and steel industry, especially from the iron ore sinter process, may be an underappreciated index imposing a negative effect on the surrounding areas of China. Therefore, we appeal the authorities to pay more attention on VOCs emission from the iron and steel industry and establish new environmental standards. And different iron steel flue gas pollutants will be eliminated concurrently with the promotion and application of new technology.

Anticancer activity of synthesized 5-benzyl juglone on selected human cancer cell lines.

BACKGROUND: Cancer is a malignant disease that causes millions of deaths each year worldwide. As one of the cancer therapeutic strategies, chemotherapy is a means to destroy rapidly dividing cells. The main problem with cancer chemotherapy is the lack of selectivity of conventional chemotherapeutic drugs, leading to toxicity towards normal cells. Therefore, the discovery of anticancer agents with selectivity for fast-growing cancer cells was desirable. OBJECTIVE: In this study, we report the synthesis and identification of the novel 5-benzyl juglone as a potential anticancer agent with selectivity toward certain cancer cell lines. METHODS: An efficient synthetic method for 5-benzyl juglone has been established. The proliferation of cancer cell lines and a normal cell line treated by the target compound were studied using an MTT assay. In addition, the cell cycle arrest and apoptosis were determined by flow cytometry. RESULTS: Based on the Diels-Alder (D-A) reaction between 3,6-dimethoxy benzyne intermediate with furan, further acid-catalyzed intramolecular rearrangement and CAN-mediated oxidation, a convenient synthesis of 5-benzyl juglone has been achieved with high overall yield. The results from in vitro biological evaluation indicated that the juglone derivative exhibited potent antiproliferative activity against HCT-15 human colorectal cancer cells with an IC50 value of 12.27 µM. It exerted high inhibitory activity toward MCF-7 human breast cancer cells and, to a much lesser extent, to corresponding MCF-10A human breast epithelial normal cells with the IC50 ratio (IC50 in MCF-7 divided by IC50 in MCF-10A) of 0.62. CONCLUSION: The mechanistic investigations indicated that 5-benzyl juglone could induce cell cycle arrest at the G0/G1 phase and promote apoptosis of HCT-15 cells. The apoptotic effects possibly also contributed to its higher selectivity toward cancer cells than normal cell lines.

Insights into the Activation of Alkyne-Installed Glycosyl Donors with Dual Acidic Metal Catalysts: Reaction Pathway, Influencing Factors, and Enlightenment for Glycosylation.

The activation of alkyne-installed glycosyl donors with dual acidic metal catalysts were studied. Lewis and/or π acidity-activated pathways were observed for alkynyl carbonate-, ester-, and ether-type donors, and π acidity-promoted reaction mode afforded higher efficiency and yields. The activation mode for a certain metal catalyst is determined by the nature of catalysts itself, protecting groups on sugar rings, type of sugars, and structure of aglycones. The discovery gives us valuable insights into the glycosylation of alkyne-containing donors.

[In vitro study of a new lasso device for intra-canal broken instrument removal].

PURPOSE: To collect facial stereo images of different lip protrusion by using three dimensional surface imaging device, and investigate facial aesthetic evaluation and differences between orthodontists, general dentists and laypeople. METHODS: In this study, one college student was recruited to take a three-dimensional image of the natural head and face. The software was simulated with a gradient of 2 mm to make the soft tissue lips move back and forth along the sagittal axis from the VSL line.The movement limit was 6 mm in front of and behind the VSL line. The observers included orthodontists, general dentists and laypeople. The data were analyzed with SAS 9.4 software package,visual analog scoring (VAS) was used for evaluation, and fixed-effect model was used for statistical analysis. RESULTS: The results showed that when the lip was on the VSL line, it got the highest scores amount all three groups and had no significant difference.When the lip became protrusive or retractive, it had negative impact on facial esthetics. There were significant differences in the scores of three groups in every 2mm of lip protrusion and lip retraction(P＜0.05). VAS 5 points or less were used as the unacceptable facial aesthetic score. The results showed that lip protrusion was 4 mm before the VSL line in the orthodontist group and less than 5 in the laypeople group . When the lip protruded 6mm before the VSL line and retracted 4 mm behind the VSL line, the scores of the three groups were lower than 5 points. The results also showed that male evaluation of lip protrusion 2 mm before the VSL line had a lower score than female; On the other hand, female evaluation of lip retraction behind the VSL line above 4mm had a lower score than male. CONCLUSIONS: Lip position has significant effect on facial aesthetics. Different observers had significant differences in the evaluation of lip position on facial aesthetics. It is suggested that orthodontists need more communication with patients in determining the target position of orthodontic treatment to improve treatment satisfaction.

Accuracy of in vitro mandibular volumetric measurements from CBCT of different voxel sizes with different segmentation threshold settings.

BACKGROUND: To determine the accuracy of volumetric measurements of the mandible in vitro by cone-beam computed tomography (CBCT) and to analyze the influence of voxel sizes and segmentation threshold settings on it. METHODS: The samples were obtained from pig mandibles and scanned with 4 voxel sizes: .125 mm, .20 mm, .30 mm, and .40 mm. The minimum segmentation thresholds in Hounsfield units (HU) were set as 0, 100, 200, 300, and 400, respectively, for each voxel size for 3D reconstruction. Laser scanning as the reference, the volumes of each CBCT scanning, the mean iterative distances of superimposition and total positive and negative deviations were recorded and compared. RESULTS: The volumes of CBCT-scan deviated from those of laser-scan by + 7.67% to - 3.05% with different HU and voxel sizes. The deviation increased with the voxel size. There was a more suitable minimum HU threshold of segmentation (HU100 for .125 mm, 200 for .20 mm, 300 for .30 mm, and 400 for .40 mm) for each voxel size. CONCLUSIONS: Voxel sizes and Hounsfield unit thresholds influence the accuracy of volumetric measurements in CBCT scanning. The volume increase with the voxel size, and different voxel sizes correspond to different optimal Hounsfield unit thresholds.

n-Pentenyl-Type Glycosides for Catalytic Glycosylation and Their Application in Single-Catalyst One-Pot Oligosaccharide Assemblies.

We have developed a new type of n-pentenyl-type glycosides that can be activated by catalytic amounts of promoter, Hg(NTf2)2 or PPh3AuCl/AgNTf2, at room temperature. The mild activation conditions and outstanding stability of common protection/deprotection manipulations enable the enynyl donors to have broad applications in constructing various glycosidic bonds. Furthermore, under the Hg(NTf2)2-catalyzed conditions, the sequential activation of different types of donors was achieved, based on which a gentiotetrasaccharide was synthesized via the newly developed single-catalyst one-pot strategy.

Geometric Self-Calibration of YaoGan-13 Images Using Multiple Overlapping Images.

Geometric calibration is an important means of improving the absolute positioning accuracy of space-borne synthetic aperture radar imagery. The conventional calibration method is based on a calibration field, which is simple and convenient, but requires a great deal of manpower and material resources to obtain ground control points. Although newer cross-calibration methods do not require ground control points, calibration accuracy still depends on a periodically updated reference image. Accordingly, this study proposes a geometric self-calibration method based on the positioning consistency constraint of conjugate image points to provide rapid and accurate calibration of the YaoGan-13 satellite. The proposed method can accurately calibrate geometric parameters without requiring ground control points or high-precision reference images. To verify the absolute positioning accuracy obtained using the proposed self-calibration method, YaoGan-13 Stripmap images of multiple regions were collected and evaluated. The results indicate that high-accuracy absolute positioning can be achieved with a plane accuracy of 3.83 m or better for Stripmap data, without regarding elevation error. Compared to the conventional calibration method using high-accuracy control data, the difference between the two methods is only about 2.53 m, less than the 3-m resolution of the image, verifying the effectiveness of the proposed self-calibration method.