Metal-free synthesis of difluoro/trifluoromethyl carbinol-containing chromones via tandem cyclization of o-hydroxyaryl enaminones.

We herein propose a HFIP-promoted tandem cyclization reaction for the synthesis of difluoro/trifluoromethyl carbinol-containing chromones from o-hydroxyphenyl enaminones at room temperature. This protocol provides a facile and efficient approach to access diverse difluoro/trifluoromethylated carbinols in good to excellent yields. In addition, gram-scale and synthetic derivatization experiments have also been performed.

Photoacoustic elasto-viscography and optical coherence microscopy for multi-parametric ex vivo brain imaging.

Optical coherence microscopy (OCM) has shown the importance of imaging ex vivo brain slices at the microscopic level for a better understanding of the disease pathology and mechanism. However, the current OCM-based techniques are mainly limited to providing the tissue's optical properties, such as the attenuation coefficient, scattering coefficient, and cell architecture. Imaging the tissue's mechanical properties, including the elasticity and viscosity, in addition to the optical properties, to provide a comprehensive multi-parametric assessment of the sample has remained a challenge. Here, we present an integrated photoacoustic elasto-viscography (PAEV) and OCM imaging system to measure the sample's optical absorption coefficient, attenuation coefficient, and mechanical properties, including elasticity and viscosity. The obtained mechanical and optical properties were consistent with anatomical features observed in the PAEV and OCM images. The elasticity and viscosity maps showed rich variations of microstructural mechanical properties of mice brain. In the reconstructed elasto-viscogram of brain slices, greater elasticity, and lower viscosity were observed in white matter than in gray matter. With the ability to provide multi-parametric properties of the sample, the PAEV-OCM system holds the potential for a more comprehensive study of brain disease pathology.

Multi-Scale Label-Free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy.

The study of aging and neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction. Here, the authors describe an integrated serial sectioning polarization-sensitive optical coherence tomography (PSOCT) and two photon microscopy (2PM) system to provide label-free multi-contrast imaging of intact brain structures, including scattering, birefringence, and autofluorescence of human brain tissue. The authors demonstrate high-throughput reconstruction of 4 × 4 × 2cm3 sample blocks and simple registration between PSOCT and 2PM images that enable comprehensive analysis of myelin content, vascular structure, and cellular information. The high-resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical properties on the same sample, revealing the densely packed fibers, capillaries, and lipofuscin-filled cell bodies in the cortex and white matter. It is  shown that the imaging system enables quantitative characterization of various pathological features in aging process, including myelin degradation, lipofuscin accumulation, and microvascular changes, which opens up numerous opportunities in the study of neurodegenerative diseases in the future.

Multi-Scale Label-free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy.

The study of neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction of the human brain. The development of a multi-scale and volumetric human brain imaging technique that can measure intact brain structure would be a major technical advance. Here, we describe the development of integrated serial sectioning Polarization Sensitive Optical Coherence Tomography (PSOCT) and Two Photon Microscopy (2PM) to provide label-free multi-contrast imaging, including scattering, birefringence and autofluorescence of human brain tissue. We demonstrate that high-throughput reconstruction of 4×4×2cm3 sample blocks and simple registration of PSOCT and 2PM images enable comprehensive analysis of myelin content, vascular structure, and cellular information. We show that 2µm in-plane resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical property maps on the same sample, revealing the sophisticated capillary networks and lipofuscin filled cell bodies across the cortical layers. Our method is applicable to the study of a variety of pathological processes, including demyelination, cell loss, and microvascular changes in neurodegenerative diseases such as Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE).

Technical Note: Performance evaluation of a small-animal PET/CT system based on NEMA NU 4-2008 standards.

PURPOSE: The MetisTM PET/CT is a self-developed, silicon photomultiplier (SiPM) detector-based, rodent PET/CT system. The objective of this study was to evaluate the performance of the system using the National Electrical Manufacturers Association (NEMA) NU 4-2008 standard protocol. METHODS: Energy resolution, spatial resolution, sensitivity, scatter fraction (SF), noise-equivalent count rate (NECR), and image quality (IQ) characteristics were measured. A micro Derenzo phantom experiment was performed to evaluate the spatial resolution using three-dimensional ordered-subsets expectation maximization (3D-OSEM) and maximum likelihood expectation maximization (MLEM) reconstructed images. In addition, the CT imaging agent Ioverol 350 was mixed with fluorine-18 (18 F)-fluorodeoxyglucose (FDG) and then injected into the micro Derenzo phantom to evaluate the PET/CT imaging. In vivo PET/CT imaging studies were also conducted in a healthy mouse and rat using 18 F-FDG. RESULTS: The mean energy resolution of the system was 15.3%. The tangential resolution was 0.82 mm full-width half-maximum (FWHM) at the center of the field of the view (FOV), and the radial and axial resolution were generally lower than 2.0 mm FWHM. The spatial resolution was significantly improved when using 3D-OSEM, especially the axial FWHM could be improved by up to about 57%. The system absolute sensitivity was 7.7% and 6.8% for an energy window of 200-750 and 350-750 keV respectively. The scatter fraction was 8.2% and 12.1% for the mouse- and rat-like phantom respectively. The peak NECR was 1343.72 kcps at 69 MBq and 640.32 kcps at 53 MBq for the mouse- and rat-like phantom respectively. The 1-mm fillable rod in the IQ phantom can be clearly observed. We can identify the 0.6-mm aperture of the micro Derenzo phantom image clearly using 3D-OSEM (10 subsets, 5 iterations). We also performed the fusion of the PET and CT images of the mouse and the brain imaging of the rat. CONCLUSIONS: The results show that the system has the characteristics of high-resolution, high-sensitivity, and excellent IQ and is suitable for rodent imaging-based research.

Silencing of miR-486 alleviates LPS-stimulated inflammatory response of macrophages through targeting SIRT1.

Previous studies identified that microRNAs (miRNAs) have promising diagnostic and prognostic value against sepsis. MiR-486 was demonstrated to be upregulated in sepsis. However, the detailed role and underlying mechanism of miR-486 in the inflammatory response of sepsis are still unclear. In this research, macrophages were stimulated with lipopolysaccharide (LPS) to establish a sepsis model in vitro. qRT-PCR was used to detect miR-486 expression and the mRNA levels of sirtuin (SIRT1), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß. ELISA assay was performed to measure the levels of TNF-α, IL-6 and IL-1ß. SIRT1 protein expression was determined by Western blot analysis. The targeted relationship of miR-486 and SIRT1 was confirmed by dual-luciferase reporter assay. Our data supported that miR-486 was upregulated in the serum of sepsis patients. MiR-486 expression and inflammatory response were elevated by LPS stimulation in macrophages. MiR-486 silencing or SIRT1 overexpression alleviated inflammatory response in LPS-stimulated macrophages. Moreover, SIRT1 was a direct target of miR-486. Anti-miR-486-mediated anti-inflammatory response in LPS-stimulated macrophages was antagonized by SIRT1 inhibition. Our data suggested that miR-486 silencing alleviated inflammatory response in macrophages under LPS stimulation at least partly through targeting SIRT1. Targeting miR-486 may provide a novel way to protect against dysregulated inflammatory response in sepsis patients.