Systematic health risks assessment of chiral fungicide famoxadone: Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior.

Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.

An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus.

The hippocampus contains many unique cell types, which serve the structure's specialized functions, including learning, memory and cognition. These cells have distinct spatial topography, morphology, physiology, and connectivity, highlighting the need for transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus across ten adult neurotypical donors. We defined molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization and transfer learning, we integrated these data to define gene expression patterns within the snRNA-seq data and infer the expression of these patterns in the SRT data. With this approach, we leveraged existing rodent datasets that feature information on circuit connectivity and neural activity induction to make predictions about axonal projection targets and likelihood of ensemble recruitment in spatially-defined cellular populations of the human hippocampus. Finally, we integrated genome-wide association studies with transcriptomic data to identify enrichment of genetic components for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders across cell types, spatial domains, and gene expression patterns of the human hippocampus. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.

Enantioselective bioaccumulation and toxicological effects of chiral neonicotinoid sulfoxaflor in rats.

Sulfoxaflor is a widely used fourth-generation neonicotinoid pesticide, which has been detected in biological and environmental samples. Sulfoxaflor can potentially be exposed to humans via the food chain, thus understanding its toxic effects and enantioselective bioaccumulation is crucial. In this study, toxicokinetics, bioaccumulation, tissue distribution and enantiomeric profiles of sulfoxaflor in rats were investigated through single oral exposure and 28-days continuous exposure experiment. Sulfoxaflor mainly accumulated in liver and kidney, and the (-)-2R,3R-sulfoxaflor and (-)-2S,3R-sulfoxaflor had higher enrichment than their enantiomers in rats. The toxicological effects were evaluated after 28-days exposure. Slight inflammation in liver and kidney were observed by histopathology. Sphingolipid, amino acid, and vitamin B6 metabolism pathways were significantly disturbed in metabonomics analysis. These toxicities were in compliance with dose-dependent effects. These results improve understanding of enantioselective bioaccumulation and the potential health risk of sulfoxaflor.

Spatial domain detection using contrastive self-supervised learning for spatial multi-omics technologies.

Recent advances in spatially-resolved single-omics and multi-omics technologies have led to the emergence of computational tools to detect or predict spatial domains. Additionally, histological images and immunofluorescence (IF) staining of proteins and cell types provide multiple perspectives and a more complete understanding of tissue architecture. Here, we introduce Proust, a scalable tool to predict discrete domains using spatial multi-omics data by combining the low-dimensional representation of biological profiles based on graph-based contrastive self-supervised learning. Our scalable method integrates multiple data modalities, such as RNA, protein, and H&E images, and predicts spatial domains within tissue samples. Through the integration of multiple modalities, Proust consistently demonstrates enhanced accuracy in detecting spatial domains, as evidenced across various benchmark datasets and technological platforms.

Thyroid Dysfunction Induced by Fungicide Famoxadone Exposure Contributes to Nonalcoholic Fatty Liver Disease in Male Mice: In Vivo, In Vitro, and In Silico Studies.

Thyroid dysfunction has become a serious public health problem, which is considered a trigger of nonalcoholic fatty liver disease (NAFLD). Pesticide exposure could contribute to thyroid dysfunction and NAFLD, but the relationship between these factors remains unclear. In this study, the effects of subchronic famoxadone exposure on thyroid and liver at no observed adverse effect level (NOEL) related concentrations were investigated using in vivo, in vitro, and in silico models. Famoxadone caused hepatic steatosis, lipid metabolism disorder, and liver oxidative stress and induced NAFLD in male mice. The suppression of hepatic fatty acid ß-oxidation was the key factor of NAFLD, which was highly associated with hypothalamic-pituitary-thyroid (HPT) axis hormones disorder. Famoxadone disrupted thyroid hormone biosynthesis by causing thyroid follicle aberrations and abnormal HPT axis-related gene expression. In vitro studies confirmed that famoxadone inhibited the transport of thyroxine (T4) into hepatocytes and the conversion of T4 to triiodothyronine (T3). In silico studies verified that famoxadone interfered with the binding of thyroid hormones to proteins mediating thyroid hormone transport, conversion, and activation. This study comprehensively reported the association between NAFLD and thyroid dysfunction caused by famoxadone, providing new perspectives for the health risk evaluation of pesticides with a similar structure in mammals.

Degradation and chiral properties of metamifop during rice processing.

Metamifop has been used to control gramineous weeds in paddy fields and may form residues in rice. In this study, the residue analysis method for metamifop and the metabolites was set up based on high-performance liquid chromatography-mass spectrometry and the chiral analysis method was also developed. The enantioselective degradation and residue of metamifop in rice processing were studied, and the major metabolites were monitored. The removal rate of metamifop by washing could reach 60.03%, while the loss in rice and porridge cooking was less than 16%. No decrease was found in fermentation into fermented grains, but metamifop was degraded in the process of rice wine fermentation with half-lives of around 9.5 days. N-(2-fluorophenyl)-2-(4-hydroxyphenoxy)-N-methylpropionamide and 6-chlorobenzo [d] oxazole-2 (3H)-one were found to be the major metabolites. This study reveals the enantioselective residue of metamifop in rice processing, which helps understand the potential risk in food consumption.

A microbiome abundant environment remodels the intestinal microbiota and improves resistance to obesity induced by chlorpyrifos in mice.

There is a growing consensus that the appropriate microbiome abundant environment actuates microbiota changes to influence human health. Whether living environment reacts on the threat of contaminants and the underlying mechanism remain largely unknown. Therefore, we constructed microbiome abundant environment models, focusing on their regulatory effects on the obesity induced by the exogenous chemical chlorpyrifos (CPF) and the related mechanisms. The results uncovered that the constructed farm and woodland microbiome abundant environment could protect mice against CPF-induced obesity effectively. The microbiome abundant environment regulated CPF-induced microbiota imbalance, characterized by an increase in Lactobacillus abundance. These altered microbiotas modified the intestinal immune system by increasing the expression of Foxp3 and IL-10, and mitigated intestinal barrier injury by upregulating the expression of IL-22 and intestinal tight junction proteins. Fecal microbiota transplantation could receive similar phenotypes on alleviating CPF-induced obesity development. Our results demonstrate that the microbiome abundant environment attenuates exogenous chemical-induced health risks by remodeling the intestinal microbiota, improving the intestinal ecosystem, and preventing intestinal epithelial leakage.

Cryogen-free one hundred microkelvin refrigerator.

A temperature below 100 µK is achieved in a customized cryogen-free dilution refrigerator with a copper-nuclear demagnetization stage. The lowest temperature of conduction electrons of the demagnetization stage is below 100 µK as measured by using a pulsed platinum nuclear magnetic resonance thermometer, and the temperature can remain below 100 µK for over 10 h. A demagnetization magnetic field of up to 9 T and a research magnetic field of up to 12 T can be controlled independently, provided by a coaxial room-temperature-bore cryogen-free magnet.

Point-cloud noncontact metrology of freeform optical surfaces.

In this paper, we demonstrate the development of a point-cloud metrology method for the noncontact, high resolution, high precision testing of freeform surfaces. The method leverages swept source optical coherence tomography together with a common-path setup in the sample arm configured to mitigate the axial jitter caused by scanning and environmental perturbations. The lateral x-y scanning field was also rigorously evaluated for the sampling step, linearity, straightness, and orthogonality. Based on the finely engineered system hardware, a comprehensive system model was developed capable of characterizing the vertical displacement sensitivity and lateral scanning noise. The model enables predicting the point-cloud surface-metrology uncertainty map of any freeform surface and guiding the selection of optimum experimental conditions. A system was then assembled and experimentally evaluated first with flat and spherical standards to demonstrate the measurement uncertainty. Results of measuring an Alvarez freeform surface with 400-µm peak-to-valley sag show 93 nm (< λ/14) precision and 128 nm (< λ/10) root-mean-square residual from the nominal shape. The high resolution measurements also reveal mid spatial frequency structures on the test part.

Comparative study of shear wave-based elastography techniques in optical coherence tomography.

We compare five optical coherence elastography techniques able to estimate the shear speed of waves generated by one and two sources of excitation. The first two techniques make use of one piezoelectric actuator in order to produce a continuous shear wave propagation or a tone-burst propagation (TBP) of 400 Hz over a gelatin tissue-mimicking phantom. The remaining techniques utilize a second actuator located on the opposite side of the region of interest in order to create three types of interference patterns: crawling waves, swept crawling waves, and standing waves, depending on the selection of the frequency difference between the two actuators. We evaluated accuracy, contrast to noise ratio, resolution, and acquisition time for each technique during experiments. Numerical simulations were also performed in order to support the experimental findings. Results suggest that in the presence of strong internal reflections, single source methods are more accurate and less variable when compared to the two-actuator methods. In particular, TBP reports the best performance with an accuracy error < 4.1 % . Finally, the TBP was tested in a fresh chicken tibialis anterior muscle with a localized thermally ablated lesion in order to evaluate its performance in biological tissue.

Volumetric rendering and metrology of spherical gradient refractive index lens imaged by angular scan optical coherence tomography system.

In this paper, we develop the methodology, including the refraction correction, geometrical thickness correction, coordinate transformation, and layer segmentation algorithms, for 3D rendering and metrology of a layered spherical gradient refractive index (S-GRIN) lens based on the imaging data collected by an angular scan optical coherence tomography (OCT) system. The 3D mapping and rendering enables direct 3D visualization and internal defect inspection of the lens. The metrology provides assessment of the surface geometry, the lens thickness, the radii of curvature of the internal layer interfaces, and the misalignment of the internal S-GRIN distribution with respect to the lens surface. The OCT metrology results identify the manufacturing defects, and enable targeted process development for optimizing the manufacturing parameters. The newly fabricated S-GRIN lenses show up to a 7x spherical aberration reduction that allows a significantly increased utilizable effective aperture.

Crawling wave optical coherence elastography.

Elastography is a technique that measures and maps the local elastic property of biological tissues. Aiming for detection of micron-scale inclusions, various optical elastography, especially optical coherence elastography (OCE), techniques have been investigated over the past decade. The challenges of current optical elastography methods include the decrease in elastographic resolution as compared with its parent imaging resolution, the detection sensitivity and accuracy, and the cost of the overall system. Here we report for the first time, we believe, on an elastography technique-crawling wave optical coherence elastography (CRW-OCE)-which significantly lowers the requirements on the imaging speed and opens the path to high-resolution and high-sensitivity OCE at relatively low cost. Methods of crawling wave excitation, data acquisition, and crawling wave tracking are presented.

Simultaneous estimation of thickness and refractive index of layered gradient refractive index optics using a hybrid confocal-scan swept-source optical coherence tomography system.

A hybrid confocal-scan swept-source optical coherence tomography metrology system was conceived for simultaneous measurements of the refractive index and thickness profiles of polymeric layered gradient refractive index (GRIN) optics. An uncertainty analysis predicts the metrology capability of the system and guides the selection of an optimum working numerical aperture. Experimental results on both a monolithic and a GRIN layered sheet are demonstrated to be in close agreement with theoretical predictions. Index measurement precision reached 0.0001 and 0.0008 for measuring 2.8 mm and ~300 µm thick layers, respectively. The thicknesses of these layers were simultaneously measured with a precision of 0.28 and 0.17 µm, respectively.

Performance analysis of optical coherence tomography in the context of a thickness estimation task.

Thickness estimation is a common task in optical coherence tomography (OCT). This study discusses and quantifies the intensity noise of three commonly used broadband sources, such as a supercontinuum source, a superluminescent diode (SLD), and a swept source. The performance of the three optical sources was evaluated for a thickness estimation task using both the fast Fourier transform (FFT) and maximum-likelihood (ML) estimators. We find that the source intensity noise has less impact on a thickness estimation task compared to the width of the axial point-spread function (PSF) and the trigger jittering noise of a swept source. Findings further show that the FFT estimator yields biased estimates, which can be as large as 10% of the thickness under test in the worst case. The ML estimator is by construction asymptotically unbiased and displays a 10× improvement in precision for both the supercontinuum and SLD sources. The ML estimator also shows the ability to estimate thickness that is at least 10× thinner compared to the FFT estimator. Finally, findings show that a supercontinuum source combined with the ML estimator enables unbiased nanometer-class thickness estimation with nanometer-scale precision.

Angular scan optical coherence tomography imaging and metrology of spherical gradient refractive index preforms.

The fabrication of high-performance spherical gradient refractive index (S-GRIN) optics requires nondestructive metrology techniques to inspect the samples. We have developed an angular-scan, swept-source-based, Fourier-domain optical coherence tomography (OCT) system centered at 1318 nm with 5 mm imaging depth capable of 180° polar scan and 360° azimuthal scan to investigate polymeric S-GRIN preforms. We demonstrate a method that enables simultaneous mapping of the group optical thickness, physical thickness, the radially-averaged group refractive index, and the transmitted wavefront of the S-GRIN preforms. The angular scan OCT imaging and metrology enables direct visualization, molding uniformity characterization, and optical property evaluations of the preforms. The results on two generations of S-GRIN preforms are discussed that showcase the evolution of the manufacturing process in response to the OCT metrology feedback.

Virtual skin biopsy with Gabor Domain optical coherence microscopy.

We report in-vivo volumetric optical coherence microscopy images of the skin, with resolution at the cellular level. With resolution of 2 µm both laterally and axially, structures below the skin as deep as 1 mm may be imaged at various anatomic locations. Custom optical instrumentation was designed, built, and integrated to achieve this unprecedented optical imaging resolution, in three dimensions, at clinically feasible configuration and speed.