Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

Multimodal optoacoustic imaging: methods and contrast materials.

Optoacoustic (OA) imaging offers powerful capabilities for interrogating biological tissues with rich optical absorption contrast while maintaining high spatial resolution for deep tissue observations. The spectrally distinct absorption of visible and near-infrared photons by endogenous tissue chromophores facilitates extraction of diverse anatomic, functional, molecular, and metabolic information from living tissues across various scales, from organelles and cells to whole organs and organisms. The primarily blood-related contrast and limited penetration depth of OA imaging have fostered the development of multimodal approaches to fully exploit the unique advantages and complementarity of the method. We review the recent hybridization efforts, including multimodal combinations of OA with ultrasound, fluorescence, optical coherence tomography, Raman scattering microscopy and magnetic resonance imaging as well as ionizing methods, such as X-ray computed tomography, single-photon-emission computed tomography and positron emission tomography. Considering that most molecules absorb light across a broad range of the electromagnetic spectrum, the OA interrogations can be extended to a large number of exogenously administered small molecules, particulate agents, and genetically encoded labels. This unique property further makes contrast moieties used in other imaging modalities amenable for OA sensing.

Exosome-delivered miR-410-3p reverses epithelial-mesenchymal transition, migration and invasion of trophoblasts in spontaneous abortion.

Current studies have indicated that insufficient trophoblast epithelial-mesenchymal transition (EMT), migration and invasion are crucial for spontaneous abortion (SA) occurrence and development. Exosomal miRNAs play significant roles in embryonic development and cellular communication. Hereon, we explored the roles of serum exosomes derived from SA patients on trophoblast EMT, migration and invasion. Exosomes were isolated from normal control (NC) patients with abortion for unplanned pregnancy and SA patients, then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. Exosomal miRNA profiles were identified by miRNA sequencing. The effects of serum exosomes on trophoblast migration and invasion were detected by scratch wound healing and transwell assays, and other potential mechanisms were revealed by quantitative real-time PCR (RT-PCR), western blotting and dual-luciferase reporter assay. Finally, animal experiments were used to explore the effects of exosomal miR-410-3p on embryo absorption in mice. The serum exosomes from SA patients inhibited trophoblast EMT and reduced their migration and invasion ability in vitro. The miRNA sequencing showed that miR-410-3p was upregulated in SA serum exosomes. The functional experiments showed that SA serum exosomes restrained trophoblast EMT, migration and invasion by releasing miR-410-3p. Mechanistically, SA serum exosomal miR-410-3p inhibited trophoblast cell EMT, migration and invasion by targeting TNF receptor-associated factor 6 (TRAF6) at the post-transcriptional level. Besides, SA serum exosomal miR-410-3p inhibited the p38 MAPK signalling pathway by targeting TRAF6 in trophoblasts. Moreover, milk exosomes loaded with miR-410-3p mimic reached the maternal-fetal interface and aggravated embryo absorption in female mice. Clinically, miR-410-3p and TRAF6 expression were abnormal and negatively correlated in the placental villi of SA patients. Our findings indicated that exosome-derived miR-410-3p plays an important role between SA serum and trophoblasts in intercellular communication, suggesting a novel mechanism by which serum exosomal miRNA regulates trophoblasts in SA patients.

Effects of Guizhi and Erxian Decoction on menopausal hot flashes: insights from the gut microbiome and metabolic profiles.

AIMS: To examine the influence of GED on the gut microbiota and metabolites using a bilateral ovariectomized (OVX) rat model. We tried to elucidate the underlying mechanisms of GED in the treatment of menopausal hot flashes. METHODS AND RESULTS: 16S rRNA sequencing, metabonomics, molecular biological analysis, and fecal microbiota transplantation (FMT) were conducted to elucidate the mechanisms by which GED regulates the gut microbiota. GED significantly reduced OVX-induced hot flashes and improved disturbances in the gut microbiota metabolites. Moreover, FMT validated that the gut microbiota can trigger hot flashes, while GED can alleviate hot flash symptoms by modulating the composition of the gut microbiota. Specifically, GED upregulated the abundance of Blautia, thereby increasing l(+)-ornithine levels for the treatment of menopausal hot flashes. Additionally, GED affected endothelial nitric oxide synthase and heat shock protein 70 (HSP70) levels in the hypothalamic preoptic area by changing the gut microbiota composition. CONCLUSIONS: Our study illuminated the underlying mechanisms by which GED attenuated the hot flashes through modulation of the gut microbiota and explored the regulatory role of the gut microbiota on HSP70 expression in the preoptic anterior hypothalamus, thereby establishing a foundation for further exploration of the role of the gut-brain axis in hot flashes.

Compliance Prediction for Structural Topology Optimization on the Basis of Moment Invariants and a Generalized Regression Neural Network.

Topology optimization techniques are essential for manufacturing industries, such as designing fiber-reinforced polymer composites (FRPCs) and structures with outstanding strength-to-weight ratios and light weights. In the SIMP approach, artificial intelligence algorithms are commonly utilized to enhance traditional FEM-based compliance minimization procedures. Based on an effective generalized regression neural network (GRNN), a new deep learning algorithm of compliance prediction for structural topology optimization is proposed. The algorithm learns the structural information using a fourth-order moment invariant analysis of the structural topology obtained from FEA at different iterations of classical topology optimization. A cantilever and a simply supported beam problem are used as ground-truth datasets, and the moment invariants are used as independent variables for input features. By comparing it with the well-known convolutional neural network (CNN) and deep neural network (DNN) models, the proposed GRNN model achieves a high prediction accuracy (R2 > 0.97) and drastically shortens the training and prediction cost. Furthermore, the GRNN algorithm exhibits excellent generalization ability on the prediction performance of the optimized topology with rotations and varied material volume fractions. This algorithm is promising for the replacement of the FEA calculation in the SIMP method, and can be applied to real-time optimization for advanced FRPC structure design.

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography.

PURPOSE: Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer's disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired. METHODS: We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 µm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). In vitro probe characterization, concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice, followed by ex vivo validation using AT-8 antibody for phosphorylated tau. RESULTS: PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer's disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Dose-dependent optoacoustic and fluorescence signal intensities were observed in the mouse brains following i.v. administration of different concentrations of PBB5. In vivo vMSOT brain imaging of P301L mice showed higher retention of PBB5 in the tau-laden cortex and hippocampus compared to wild-type mice, as confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, and immunofluorescence staining. CONCLUSIONS: We demonstrated non-invasive whole-brain imaging of tau in P301L mice with vMSOT system using PBB5 at a previously unachieved ~ 115 µm spatial resolution. This platform provides a new tool to study tau spreading and clearance in a tauopathy mouse model, foreseeable in monitoring tau targeting putative therapeutics.

Excellent outcomes with Oxford Uni-compartmental knee arthroplasty in anteromedial osteoarthritis patients (≤60 years) at mid-term follow-up.

BACKGROUND: The use of Oxford uni-compartmental knee arthroplasty (UKA) has rapidly increased worldwide,however,the relevance of younger patients for postoperative function after Oxford UKA remains unclear. The main purpose of our study is to clarify the effectivemess of Oxford UKA in the younger Chinese patients with anteromedial osteoarthritis (AMOA). METHODS: We retrospectively enrolled 252 consecutive patients who underwent Oxford UKA for AMOA with a minimum follow-up of 5 years between March 2013 and December 2016. The patients were divided into the younger (≤60 years) and elderly (> 60 years) age groups. The demographic data and surgery variables were recorded and compared. Patient satisfaction grade, range of motion (ROM), Oxford knee score (OKS), Hospital for Special Surgery (HSS) score, Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index score and postoperative complications were recorded. The 5-year survival of the implants were also compared with TKA revision as the endpoint. RESULTS: A total of 252 consecutive patients were recruited, including 96 aged 60 years or less and 156 aged over 60 years. The mean follow-up duration in the younger and elderly groups were 73.6 months (SD,standard deviation, 4.1) and 74.7 months (SD 6.2) respectively. Patient satisfaction rate was high in both groups (P = 0.805). Furthermore, no significant differences were observed in postoperative ROM(P = 0.299), OKS(P = 0.117), HSS(P = 0.357) and WOMAC scores(P = 0.151) between the younger and elderly groups (P>0.05). However, the incidence of joint stiffness (P = 0.033) and delayed wound dehiscence (P = 0.026) were significantly different between both groups. Five-year implant survival without revision were also similar in both groups (96.9% vs 97.4%, P = 0.871), and that for the entire cohort was 97.2% (95% CI 95.4-99.6). CONCLUSION: Oxford UKA for AMOA demonstrated favorable results in younger patients aged ≤60 years at a minimum 5-year follow-up in terms of patient satisfaction, functional outcomes, implant survival and postoperative complications. Therefore, younger patients might not be considered as an absolute contraindication to Oxford UKA.

Widefield fluorescence localization microscopy for transcranial imaging of cortical perfusion with capillary resolution.

Imaging of cerebral vasculature is impeded with the existing fluorescence microscopy methods due to intense light scattering in living tissues and the need for highly invasive craniotomy procedures to resolve structures on a capillary scale. We propose a widefield fluorescence localization microscopy technique for high-resolution transcranial imaging and quantitative assessment of cortical perfusion in mice. The method is based on tracking single fluorescent microparticles sparsely distributed in the blood stream using a simple CMOS camera and a continuous-wave laser source. We demonstrate quantitative transcranial in vivo mapping of the blood flow velocity and direction at capillary level resolution (5 µm) across the entire cortex. The new technique opens a new high-resolution transcranial window into the brain function in health and disease.

MALAT1 promoted cell proliferation and migration via MALAT1/miR-155/MEF2A pathway in hypoxia of cardiac stem cells.

Accumulating evidence revealed that hypoxia contributed to many human diseases, including ischemic myocardium and heart failure (HF). In recent years, the roles of hypoxia in stem cell survival and cardiac biology have been studied extensively. However, the underlying molecular mechanisms remain to be elucidated. As a leading cause of HF, ischemic heart disease was correlated with hypoxia. In this study, we firstly constructed the hypoxia cell model by CoCl2 in cardiac stem cells (CSCs) and found that hypoxia induced the cell proliferation and migration potential in CSCs. Then, we demonstrated that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was promoted in CoCl2 -induced CSCs hypoxia model. Furthermore, we found that knockdown of MALAT1 inhibited the cell proliferation and migration in CoCl2 -induced CSCs hypoxia model. In addition, we revealed that MALAT1 regulated the microRNA-155 (miR-155) expression in CSCs under both the normal and hypoxia conditions and further, manipulation of the miR-155 expression affected the role of MALAT1 in CoCl2 -induced CSCs hypoxia cell model. We then illustrated that miR-155 regulated the myocyte enhancer factor 2A (MEF2A) expression in CSCs under both the normal and hypoxia conditions and further, changing the expression of MEF2A affected the role of miR-155. Finally, we demonstrated that MALAT1 regulated the MEF2A expression and exerted its role via modulation of the MALAT1/miR-155/MEF2A pathway. Taken together, our study illustrated that MALAT1 promoted the cell proliferation and migration in CoCl2 -induced CSCs hypoxia model, acting mechanistically by promoting MEF2A expression via "sponging" miR-155.

Hybrid system for in vivo epifluorescence and 4D optoacoustic imaging.

Epifluorescence imaging is widely used in cell and molecular biology due to its excellent sensitivity, contrast, and ease of implementation. Optoacoustic imaging has been shown to deliver a highly complementary and unique set of capabilities for biological discovery, such as high spatial resolution in noninvasive deep tissue observations, fast volumetric imaging capacity, and spectrally enriched contrast. In this Letter, we report on a hybrid system combining planar fluorescence and real-time volumetric four-dimensional optoacoustic imaging by means of a fiberscope integrated within a handheld hemispherical ultrasound detection array. The in vivo imaging performance is demonstrated by non-invasive visualization of fast contrast agent perfusion through the mouse brain. The proposed synergistic combination of fluorescence and optoacoustic imaging can benefit numerous studies looking at multi-scale in vivo dynamics, such as functional neuroimaging, visualization of organ perfusion and contrast agent uptake, cell tracking, and pharmacokinetic and bio-distribution analysis.

Snapshot phase shift fringe projection 3D surface measurement.

We propose a novel snapshot phase shift fringe projection three-dimensional (3D) surface measurement method using polarization-coded light illumination and polarization camera. The light from the light source is split into two beams, one is left circularly polarized and the other is right circularly polarized, to illuminate the object simultaneously. A four-channel division of focal plane (DoFP) polarization camera is employed to capture the light reflected from the object surface. Four images with a phase shift of π/2 are extracted from the snapshot image and then analyzed to reconstruct a 3D object surface. The proposed method is the first snapshot phase shift fringe projection approach for 3D surface imaging. It is insensitive to motion and has the potential for ultrafast 3D surface imaging.

Evidence of an Association between Age-Related Functional Modifications and Pathophysiological Changes in Zebrafish Heart.

BACKGROUND: Zebrafish have become a valuable model for the study of developmental biology and human disease, such as cardiovascular disease. It is difficult to discriminate between disease-related and age-related alterations. OBJECTIVE: This study was aimed to investigate the effects and potential mechanisms of age-related cardiac modifications in an older zebrafish population. METHODS: In this study, we calculated the survival rate and measured the spinal curvature through the aging process. A swimming challenge test was performed and showed that swimming capacity and endurance dramatically dropped in older fish groups. RESULTS: To find out the effect of stress on zebrafish during the aging process, we recorded electrocardiograms on zebrafish and showed that during stress, aging not only led to a significant reduction in heart rate, but also caused other age-related impairments, such as arrhythmias and ST-T depression. Echocardiography showed a marked increase in end-diastolic ventricular dimensions and in isovolumic relaxation time and a notably slower mean and peak velocity of the bulboventricular valve in older zebrafish, but stroke volume and cardiac output were not different in young and old zebrafish. Both nppa and nppb (cardiac fetal genes for natriuretic factor) expression detected by real-time polymerase chain reaction analysis increased in older fish compared to the younger group. Histological staining revealed fibrosis within cardiomyocytes and an increase in ventricular myocardial density and a decrease in epicardial vessel dimensions in older fish hearts that may correlate with a deterioration of cardiac function and exercise capacity. CONCLUSION: These data suggest that cardiac functional modifications in zebrafish are comparable to those in humans and may partly be due to changes in the cardiovascular system including cardiac fetal gene reprogramming, myocardial density, and epicardial vessel dimensions.

Calibration method of microgrid polarimeters with image interpolation.

Microgrid polarimeters have large advantages over conventional polarimeters because of the snapshot nature and because they have no moving parts. However, they also suffer from several error sources, such as fixed pattern noise (FPN), photon response nonuniformity (PRNU), pixel cross talk, and instantaneous field-of-view (IFOV) error. A characterization method is proposed to improve the measurement accuracy in visible waveband. We first calibrate the camera with uniform illumination so that the response of the sensor is uniform over the entire field of view without IFOV error. Then a spline interpolation method is implemented to minimize IFOV error. Experimental results show the proposed method can effectively minimize the FPN and PRNU.

RGB-NIR multispectral camera.

A multispectral imaging technique with a new CMOS camera is proposed. With a four channel Bayer patterns, the camera can acquire four spectral images simultaneously. We have developed a color correction process to obtain accurate color information, and we have also demonstrated its applications on portrait enhancement, shadow removal, and vein enhancement.

Multi-polarization fringe projection imaging for high dynamic range objects.

Traditional fringe-projection three-dimensional (3D) imaging techniques struggle to estimate the shape of high dynamic range (HDR) objects where detected fringes are of limited visibility. Moreover, saturated regions of specular reflections can completely block any fringe patterns, leading to lost depth information. We propose a multi-polarization fringe projection (MPFP) imaging technique that eliminates saturated points and enhances the fringe contrast by selecting the proper polarized channel measurements. The developed technique can be easily extended to include measurements captured under different exposure times to obtain more accurate shape rendering for very HDR objects.

Impact of CCD camera SNR on polarimetric accuracy.

A comprehensive charge-coupled device (CCD) camera noise model is employed to study the impact of CCD camera signal-to-noise ratio (SNR) on polarimetric accuracy. The study shows that the standard deviations of the measured degree of linear polarization (DoLP) and angle of linear polarization (AoLP) are mainly dependent on the camera SNR. With increase in the camera SNR, both the measurement errors and the standard deviations caused by the CCD camera noise decrease. When the DoLP of the incident light is smaller than 0.1, the camera SNR should be at least 75 to achieve a measurement error of less than 0.01. When the input DoLP is larger than 0.5, a SNR of 15 is sufficient to achieve the same measurement accuracy. An experiment is carried out to verify the simulation results.

Shedding light on ultrasound in action: Optical and optoacoustic monitoring of ultrasound brain interventions.

Monitoring brain responses to ultrasonic interventions is becoming an important pillar of a growing number of applications employing acoustic waves to actuate and cure the brain. Optical interrogation of living tissues provides a unique means for retrieving functional and molecular information related to brain activity and disease-specific biomarkers. The hybrid optoacoustic imaging methods have further enabled deep-tissue imaging with optical contrast at high spatial and temporal resolution. The marriage between light and sound thus brings together the highly complementary advantages of both modalities toward high precision interrogation, stimulation, and therapy of the brain with strong impact in the fields of ultrasound neuromodulation, gene and drug delivery, or noninvasive treatments of neurological and neurodegenerative disorders. In this review, we elaborate on current advances in optical and optoacoustic monitoring of ultrasound interventions. We describe the main principles and mechanisms underlying each method before diving into the corresponding biomedical applications. We identify areas of improvement as well as promising approaches with clinical translation potential.

Cortex-wide transcranial localization microscopy with fluorescently labeled red blood cells.

Large-scale imaging of brain activity with high spatio-temporal resolution is crucial for advancing our understanding of brain function. The existing neuroimaging techniques are largely limited by restricted field of view, slow imaging speed, or otherwise do not have the adequate spatial resolution to capture brain activities on a capillary and cellular level. To address these limitations, we introduce fluorescence localization microscopy aided with sparsely-labeled red blood cells for cortex-wide morphological and functional cerebral angiography with 4.9 µm spatial resolution and 1 s temporal resolution. When combined with fluorescence calcium imaging, the proposed method enables extended recordings of stimulus-evoked neuro-vascular changes in the murine brain while providing simultaneous multiparametric readings of intracellular neuronal activity, blood flow velocity/direction/volume, and vessel diameter. Owing to its simplicity and versatility, the proposed approach will become an invaluable tool for deciphering the regulation of cortical microcirculation and neurovascular coupling in health and disease.

Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance.

The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China, including the lack of unified definitions and diagnostic standards, broad grasp of diagnosis, and unscientific management strategies. Based on that, this consensus carefully summarized the statin-related gene polymorphism and statin usage issue among Chinese population, and comprehensively reviewed global research data on statin intolerance, referenced guidelines, and consensus literature on statin intolerance in foreign and different regions, proposes an appropriate and easy to implement statin intolerance definition as well as corresponding diagnostic criteria and management strategies for Chinese clinicians, in order to improve the clinical application of statin drugs and enhance the prevention and treatment level of atherosclerotic cardiovascular disease in China.

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.