Transferrin-targeted iridium nanoagglomerates with multi-enzyme activities for cerebral ischemia-reperfusion injury therapy.

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological condition with high mortality. In particular, reperfusion can stimulate overproduction of reactive oxygen species (ROS) and activation of inflammation, causing severe secondary injuries to the brain. Despite tremendous efforts, it remains urgent to rationally design antioxidative agents with straightforward and efficient ROS scavenging capability. Herein, a potent antioxidative agent was explored based on iridium oxide nano-agglomerates (Tf-IrO2 NAs) via the facile transferrin (Tf)-templated biomineralization approach, and innovatively applied to treat CIRI. Containing some small-size IrO2 aggregates, these NAs possess intrinsic hydroxyl radicals (•OH)-scavenging ability and multifarious enzyme activities, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Moreover, they also showed improved blood-brain barrier (BBB) penetration and enhanced accumulation in the ischemic brain via Tf receptor-mediated transcytosis. Therefore, Tf-IrO2 NAs achieved robust in vitro anti-inflammatory and cytoprotection effects against oxidative stress. Importantly, mice were effectively protected against CIRI by enhanced ROS scavenging activity in vivo, and the therapeutic mechanism was systematically verified. These findings broaden the idea of expanding Ir-based NAs as potent antioxidative agents to treat CIRI and other ROS-mediated diseases. STATEMENT OF SIGNIFICANCE: (1) The ROS-scavenging activities of IrO2 are demonstrated comprehensively, which enriched the family of nano-antioxidants. (2) The engineering Tf-IrO2 nano-agglomerates present unique multifarious enzyme activities and simultaneous transferrin targeting and BBB crossing ability for cerebral ischemia-reperfusion injury therapy. (3) This work may open an avenue to enable the use of IrO2 to alleviate ROS-mediated inflammatory and brain injury diseases.

In situ melt pool measurements for laser powder bed fusion using multi sensing and correlation analysis.

Laser powder bed fusion is a promising technology for local deposition and microstructure control, but it suffers from defects such as delamination and porosity due to the lack of understanding of melt pool dynamics. To study the fundamental behavior of the melt pool, both geometric and thermal sensing with high spatial and temporal resolutions are necessary. This work applies and integrates three advanced sensing technologies: synchrotron X-ray imaging, high-speed IR camera, and high-spatial-resolution IR camera to characterize the evolution of the melt pool shape, keyhole, vapor plume, and thermal evolution in Ti-6Al-4V and 410 stainless steel spot melt cases. Aside from presenting the sensing capability, this paper develops an effective algorithm for high-speed X-ray imaging data to identify melt pool geometries accurately. Preprocessing methods are also implemented for the IR data to estimate the emissivity value and extrapolate the saturated pixels. Quantifications on boundary velocities, melt pool dimensions, thermal gradients, and cooling rates are performed, enabling future comprehensive melt pool dynamics and microstructure analysis. The study discovers a strong correlation between the thermal and X-ray data, demonstrating the feasibility of using relatively cheap IR cameras to predict features that currently can only be captured using costly synchrotron X-ray imaging. Such correlation can be used for future thermal-based melt pool control and model validation.

Neutrophil-like Cell-Membrane-Coated Nanozyme Therapy for Ischemic Brain Damage and Long-Term Neurological Functional Recovery.

Oxidative stress and a series of excessive inflammatory responses are major obstacles for neurological functional recovery after ischemic stroke. Effective noninvasive anti-inflammatory therapies are urgently needed. However, unsatisfactory therapeutic efficacy of current drugs and inadequate drug delivery to the damaged brain are major problems. Nanozymes with robust anti-inflammatory and antioxidative stress properties possess therapeutic possibility for ischemic stroke. However, insufficiency of nanozyme accumulation in the ischemic brain by noninvasive administration hindered their application. Herein, we report a neutrophil-like cell-membrane-coated mesoporous Prussian blue nanozyme (MPBzyme@NCM) to realize noninvasive active-targeting therapy for ischemic stroke by improving the delivery of a nanozyme to the damaged brain based on the innate connection between inflamed brain microvascular endothelial cells and neutrophils after stroke. The long-term in vivo therapeutic efficacy of MPBzyme@NCM for ischemic stroke was illustrated in detail after being delivered into the damaged brain and uptake by microglia. Moreover, the detailed mechanism of ischemic stroke therapy via MPBzyme@NCM uptake by microglia was further studied, including microglia polarization toward M2, reduced recruitment of neutrophils, decreased apoptosis of neurons, and proliferation of neural stem cells, neuronal precursors, and neurons. This strategy may provide an applicative perspective for nanozyme therapy in brain diseases.

A Tumor-Microenvironment-Responsive Lanthanide-Cyanine FRET Sensor for NIR-II Luminescence-Lifetime In Situ Imaging of Hepatocellular Carcinoma.

Deep tissue imaging in the second near-infrared (NIR-II) window holds great promise for widespread fundamental research. However, inhomogeneous signal attenuation due to tissue absorption and scattering hampers its application for accurate in vivo biosensing. Here, lifetime-based in situ hepatocellular carcinoma (HCC) detection in NIR-II region is presented using a tumor-microenvironment (peroxynitrite, ONOO- )-responsive lanthanide-cyanine Förster resonance energy transfer (FRET) nanosensor. A specially designed ONOO- -responsive NIR-II dye, MY-1057, is synthesized as the FRET acceptor. Robust lifetime sensing is demonstrated to be independent of tissue penetration depth. Tumor lesions are accurately distinguished from normal tissue due to the recovery lifetime. Magnetic resonance imaging and liver dissection results illustrate the reliability of lifetime-based detection in single and multiple HCC models. Moreover, the ONOO- amount can be calculated according to the standard curve.

Organic NIR-II molecule with long blood half-life for in vivo dynamic vascular imaging.

Real-time monitoring of vessel dysfunction is of great significance in preclinical research. Optical bioimaging in the second near-infrared (NIR-II) window provides advantages including high resolution and fast feedback. However, the reported molecular dyes are hampered by limited blood circulation time (~ 5-60 min) and short absorption and emission wavelength, which impede the accurate long-term monitoring. Here, we report a NIR-II molecule (LZ-1105) with absorption and emission beyond 1000 nm. Thanks to the long blood circulation time (half-life of 3.2 h), the fluorophore is used for continuous real-time monitoring of dynamic vascular processes, including ischemic reperfusion in hindlimbs, thrombolysis in carotid artery and opening and recovery of the blood brain barrier (BBB). LZ-1105 provides an approach for researchers to assess vessel dysfunction due to the long excitation and emission wavelength and long-term blood circulation properties.

Value of high-frequency two-dimensional ultrasound on evaluating puborectalis muscle.

PURPOSE: To explore the value of high-frequency two-dimensional (2D) ultrasound on demonstrating the morphology of puborectalis muscle and detect muscle avulsion. METHODS: High-frequency 2D ultrasound and tomographic ultrasound image (TUI) were peformed to demonstrate puborectalis muscle and detect muscle avulsion respectively among 158 women with or without significant pelvic organ prolapse (POP) (POP quantification grade 2 or higher). Mean values were compared using student's t test between women with or without avulsion defects. We performed Cohen's Kappa analysis to examine the test agreement between high-frequency 2D ultrasound and TUI mode. Pearson correlation analysis was performed to explore the relationship between the thickness of puborectalis muscle and the measurements of levator-urethra gap (LUG). RESULTS: The result of high-frequency 2D ultrasound in detecting muscle avulsion agreed well with TUI mode (Kappa 0.88, P < 0.05). Women with muscle avulsion had thinner muscles and larger LUG measurements than those with normal muscle insertion (P < 0.05). Pearson correlation analysis revealed the negative relationship between the thickness of puborectalis muscle and LUG measurements (r = - 0.73). CONCLUSION: The study confirmed that it was feasible to observe the morphology of puborectalis muscle and detect muscle avulsion by high-frequency 2D ultrasound.

Translabial Ultrasound Combined With Magnetic Resonance Imaging Assessing the Distensibility of Levator Ani Muscle With Unilateral High-Grade Tears.

OBJECTIVES: It is hypothesized that unilateral high-grade tears damage levator ani muscle (LAM) integrity and increase LAM distensibility. This study aimed to investigate how a unilateral high-grade tear caused overdistension of LAM and whether tear positions affect the degree of distension. METHODS: A total of 209 women were screened by translabial ultrasonography. Then, 18 nulliparous women with an intact LAM and 26 postpartum women with unilateral levator ani defects were recruited. The anteroposterior diameter (AP), coronal diameter (LR), and hiatal area (HA) of the minimum levator hiatus were recorded and compared for assessing the distensibility. All 44 subjects underwent magnetic resonance imaging for the diagnosis of levator ani defect and detection of tear positions. Within the software, 3-dimensional pelvic models were developed from magnetic resonance imaging scans for the direct visualization and measurements. RESULTS: Of the 26 postpartum women, 15 were diagnosed with unilateral high-grade tear (caudad in 9, cephalad in 6). The △AP, △LR, and △HA (Valsalva-rest) values of women with a unilateral high-grade tear were significantly larger than those of women with an intact LAM (P < 0.05). The △AP, △LR, and △HA (Valsalva-rest) values of cephalad tears were larger than those of women with caudad tears (P < 0.05). CONCLUSIONS: A unilateral high-grade tear caused the overdistension of LAM. It was validated that cephalad tears caused higher degree of LAM distension than caudad tears.

Assessment of female pelvic floor support to the urethra using 3D transperineal ultrasound.

INTRODUCTION AND HYPOTHESIS: To explore the feasibility of three-dimensional (3D) transperineal tomographic ultrasound in evaluating pelvic floor support of the urethra in women. METHODS: Three-dimensional transperineal ultrasound volume data sets of 50 women with stress urinary incontinence (SUI) and 25 women without SUI were obtained for analysis. Pelvic floor support of the urethra was evaluated by studying the relationship between the urethra and vagina in vaginal cross section and quantified by estimating the urethral depression (UD) rate. The extent of paravaginal support at level II was also evaluated in tomographic ultrasound imaging (TUI) mode in all participants. Two-sample t-test and Mann-Whitney U test were used for statistical analysis. RESULTS: The extent of paravaginal support at level II showed no difference between the two groups. Posterior depression of the urethra into the anterior vaginal wall was increased in SUI (P < 0.05). When the UD rate value was 0.53 (CI 85%) combined with three continuous "abnormal slices," the maximum Youden Index value (sensitivity 0.82, specificity 0.88) was obtained to screen dysfunctional support of the urethra. CONCLUSIONS: The pelvic floor support of the urethra can be evaluated indirectly by studying the relationship between the urethra and anterior vaginal wall in the vaginal cross section by TUI. The obvious posterior depression of the urethra into the anterior vaginal wall could be indirect evidence of a defect in the support of the urethra.

J-Aggregates of Cyanine Dye for NIR-II in Vivo Dynamic Vascular Imaging beyond 1500 nm.

Light in the second near-infrared window, especially beyond 1500 nm, shows enhanced tissue transparency for high-resolution in vivo optical bioimaging due to decreased tissue scattering, absorption, and autofluorescence. Despite some inorganic luminescent nanoparticles have been developed to improve the bioimaging around 1500 nm, it is still a great challenge to synthesize organic molecules with the absorption and emission toward this region. Here, we present J-aggregates with 1360 nm absorption and 1370 nm emission formed by self-assembly of amphiphilic cyanine dye FD-1080 and 1,2-dimyristoyl-sn-glycero-3-phosphocholine. Molecular dynamics simulations were further employed to illustrate the self-assembly process. Superior spatial resolution and high signal-to-background ratio of J-aggregates were demonstrated for noninvasive brain and hindlimb vasculature bioimaging beyond 1500 nm. The efficacy evaluation of the clinically used hypotensor is successfully achieved by high-resolution in vivo dynamic vascular imaging with J-aggregates.

Upregulated 14­3­3ß aggravates restenosis by promoting cell migration following vascular injury in diabetic rats with elevated levels of free fatty acids.

Mono­unsaturated free fatty acids (FFAs) can serve as a predictive indicator of vascular restenosis following interventional therapy, particularly in individuals with high­fat diet­induced type 2 diabetes. However, the pathogenic mechanism remains to be fully elucidated. In the present study, the levels of tyrosine 3­monooxygenase/tryptophan 5­monooxygenase activation protein ß (YWHAB; also known as 14­3­3ß), in vascular smooth muscle cells (VSMCs) treated with different concentrations of oleic acid (OA) were examined by reverse transcription­quantitative polymerase chain reaction and western blot analyses. The migration of VSMCs was examined using wound­healing and Transwell migration assays. The protein distribution of B­cell lymphoma 2 (BCL­2)­associated death promoter (BAD) in VSMCs treated with OA was examined by immunofluorescence and western blot analyses. In in vivo experiments, the carotid artery morphology of rats in different groups was assessed at 14 days post­injury by non-invasive ultrasonographic imaging and confirmed by histological staining. The expression of YWHAB was upregulated by OA in a concentration­dependent manner in VSMCs. In the in vivo experiments, carotid stenosis was more serious among high­FFA diabetic rats. However, silencing of YWHAB significantly alleviated carotid neointimal hyperplasia among the diabetic rats with elevated FFA levels. In addition, YWHAB silencing alleviated the migration of OA­treated VSMCs and increased translocation of the BAD protein from the cytoplasm to the mitochondria. In conclusion, the results showed that FFA­induced upregulation of YWHAB was involved in neointimal hyperplasia by enhancing the migration of VSMCs following carotid artery injury. The inhibition of YWHAB may serve as a novel potential pharmacological target for preventing vascular restenosis following interventional therapy in diabetic individuals with high FFA levels.

Preoperative Transurethral Contrast-Enhanced Ultrasonography in the Diagnosis of Female Urethral Diverticula.

OBJECTIVES: To explore the value of transurethral contrast-enhanced ultrasonography (CEUS) in the diagnosis and evaluation of female urethral diverticula. METHODS: This study prospectively enrolled 35 women with periurethral cystic lesions, who underwent preoperative transurethral CEUS at our single center between April 2015 and May 2017. The diagnosis of a urethral diverticulum was made by the detection of microbubbles inside the lesion. Data regarding the structure and ostia of the diverticula were collected and then compared with intraoperative findings. RESULTS: The median (interquartile range) age of the 35 patients was 43 (34-48) years. The most common manifestations were dysuria (43%) and palpable masses (40%). On transurethral CEUS, 20 patients were found to have urethral diverticula. The diverticula involved the proximal, mid, and distal urethra with different sizes. The shapes of the diverticula were simple in 4 patients (20%), U shaped in 8 patients (40%), and circumferential in 8 patients (40%). A total of 23 ostia were identified. Seventeen women (85%) had 1 ostium, and 3 women (15%) had 2 ostia. Twenty-one diverticular ostia (91%) were located from the 3- to 9-o'clock positions. The median (interquartile range) distance from the diverticular ostia to the bladder neck was 20 (9-31) mm. During surgery, all US presentations correlated well with surgical findings, and 21 patients were confirmed to have urethral diverticula. The transurethral CEUS had sensitivity of 95% and specificity of 100%. CONCLUSIONS: Transurethral CEUS is an effective method for identifying the structure and ostium of female urethral diverticula. It may have a potential role in preoperative planning and surgical management.

Value of transperineal ultrasound on the observation of paravaginal support.

OBJECTIVE: To explore the feasibility of three-dimensional (3D) transperineal ultrasound on the observation of paravaginal support in nulliparous and postpartum women. METHODS: Volume datasets were acquired in 50 nulliparous and 100 postpartum women using 3D transperineal ultrasound. Paravaginal supports were observed by studying the vaginal cross-sectional morphology. The extent of paravaginal support in specific level were evaluated by counting out at a 2 mm interval in tomographic ultrasound imaging mode in all subjects. The Mann-Whitney U test were applied to establish comparisons between the two groups. RESULTS: Three representative manifestations of vaginal cross-sectional morphology corresponding to different paravaginal support were presented from the dorsal side to the caudal side, both in nulliparous women and postpartum women. The extent of paravaginal support in middle vagina was 11 slices (range 9-12) in nulliparous women and 7 slices (range 4-10) in postpartum women (P < 0.05). CONCLUSION: This pilot study confirmed that it was feasible to indirectly study paravaginal support by observing the vaginal cross-sectional morphology using 3D transperineal ultrasound.

Determining "abnormal" levator hiatus distensibility using three-dimensional transperineal ultrasound in Chinese women.

The dimension of the levator hiatus is a possible predictor of pelvic organ prolapse (POP). This retrospective study investigated 360 women who went to urogynecological clinic for pelvic floor discomfort. Levator hiatus dimensions were obtained by three-dimensional transperineal ultrasound and results were compared between women with and without significantly objective prolapse (International Continence Society POP quantification, grade 2 or higher). Receiver operating characteristic (ROC) curve analyses were performed to determine valid screening index for detecting abnormal levator hiatus distensibility. Women with significantly objective prolapse had significantly higher levator hiatus dimensions than those without (all P < 0.001). ROC curve analyses confirmed that hiatal area (HA) of 19.5 cm2 during Valsalva maneuver can be used as single-screening index for abnormal levator hiatus distensibility with sensitivity of 0.80 and specificity of 0.70. In this study, we used a two-step method and achieved higher sensibility (0.80 vs. 0.87) without reducing specificity (0.70 vs. 0.71) compared with a single-screening index method. As a result, we suggest that HA ⩾ 19.5 cm2 during Valsalva maneuver is an indicator of abnormal levator hiatus distensibility in Chinese women and that the two-step method has higher sensitivity in detecting abnormal distensibility.

Combination of tomographic ultrasound imaging and three-dimensional magnetic resonance imaging-based model to diagnose postpartum levator avulsion.

Vaginal delivery may cause levator avulsion, which may increase the risk of pelvic floor dysfunction (PFD). To explore the morphological changes of the levator ani muscle (including the puborectalis and iliococcygeus) and levator avulsion after vaginal delivery, translabial tomographic ultrasound imaging (TUI) was used to examine 80 women 45-60 days after their vaginal delivery. Subsequently, magnetic resonance imaging (MRI) was performed if at least one-sided puborectalis avulsion was found on TUI. The incidence of puborectalis avulsion in these postpartum women was 13.75% in this study. Both MRI and TUI can detect puborectalis avulsion well, and their results have good consistency. Iliococcygeus muscle injury is difficult to detect using TUI. However, MRI is a good way to observe the morphological changes of the iliococcygeus, which may also be damaged during vaginal delivery. Interestingly, our study reveals that iliococcygeus muscle injury is often associated with severe puborectalis muscle tear.

Ultrasonographic Features of Female Urethral Diverticula: A Retrospective Study of 25 Patients.

OBJECTIVES: This article summarizes the ultrasonographic features of female urethral diverticula on biplane transrectal ultrasound (B-TRUS). METHODS: A retrospective study was performed with 25 consecutive women who were diagnosed and treated as having urethral diverticulum (UD) between January 2012 and March 2016. All the patients were preoperatively evaluated using B-TRUS. The number, location, configuration, size, and type of the UD on B-TRUS were assessed. RESULTS: Twenty-eight diverticula were found on B-TRUS. Twenty-two patients had single diverticulum, whereas the other 3 had double diverticula. The locations included proximal (14%), mid (46%), and distal (40%) urethra. In transverse section, the configuration presented as round or oval (46%), and horseshoe-like or circumferential (54%). The maximal diameter of the 28 diverticula ranged from 3 to 48 mm. The types contained simple UD (36%) and complex UD (64%). Color blood flow signal could be detected in the septa, cystic wall, and solid mass, whereas negative in other areas inside the UD. CONCLUSIONS: Various sonographic characters of female UD could be observed during the evaluation, including single or multiple diverticula, different sites, diverse shapes, and septa, calculi, or neoplasm inside diverticulum, all of which could be clearly displayed on B-TRUS.