SUMMARY The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), a regulator of local protein synthesis, is the mouse homologue of ApCPEB, a functional prion protein in Aplysia. Here, we provide evidence that CPEB3 is activated by Neuralized1, an E3 ubiquitin ligase. In hippocampal cultures, CPEB3 activated by Neuralized1-mediated ubiquitination leads both to the growth of new dendritic spines and to an increase of the GluA1 and GluA2 subunits of AMPA receptors, two CPEB3 targets essential for synaptic plasticity. Conditional overexpression of Neuralized1 similarly increases GluA1 and GluA2 and the number of spines and functional synapses in the hippocampus, and is reflected in enhanced hippocampal-dependent memory and synaptic plasticity. By contrast, inhibition of Neuralized1 reduces GluA1 and GluA2 levels and impairs hippocampal-dependent memory and synaptic plasticity. These results suggest a model whereby Neuralized1-dependent ubiquitination facilitates hippocampal plasticity and hippocampal-dependent memory storage by modulating the activity of CPEB3 and CPEB3-dependent protein synthesis and synapse formation.

Objective-To test the eYcacy of high frequency intravascular ultrasound (IVUS) transducers in identifying lipid/necrotic pools in atherosclerotic plaques. Methods-40 MHz transducers were used for in vitro IVUS assessment of 12 arterial segments (10 coronary and two carotid arteries, dissected from five diVerent necropsy cases). IVUS acquisition was performed at 0.5 mm/s after ligature of the branching points to generate a closed system. Lipid/necrotic areas were defined by IVUS as large echolucent intraplaque areas surrounded by tissue with higher echodensity. To obtain histopathological sections corresponding to IVUS cross sections, vessels were divided into consecutive 3 mm long segments using the most distal recorded IVUS image as the starting reference. Samples were then fixed with 10% buVered formalin, processed for histopathological study, serially cut, and stained using the Movat pentacrome method. Results-122 sections were analysed. Lipid pools were observed by histology in 30 sections (25%). IVUS revealed the presence of lipid pools in 19 of these sections (16%; sensitivity 65%, specificity 95%). Conclusions-In vitro assessment of lipid/necrotic pools with high frequency transducers was achieved with good accuracy. This opens new perspectives for future IVUS characterisation of atherosclerotic plaques. (Heart 2001;85:567-570) Keywords: intracoronary ultrasound; atherosclerosis; plaque morphology Coronary intravascular ultrasound (IVUS) provides quantitative information on lumen and vessel dimensions and plaque severity, as well as qualitative information on plaque composition in terms of hard and soft components and calcification. Previous IVUS studies on plaque composition, mainly performed in the early 1990s with 20-30 MHz transducers, showed that the technique defines calcification with high sensitivity and specificity, but is less accurate in assessing soft tissue components. [1][2][3][4][5][6][7][8][9] Thus, although 20 and 30 MHz transducers achieved appropriate definition of plaque morphology, the imaging of details such as the lipid pool and the fibrous cap remained poorly defined. No data are available on the characterisation of plaque morphology with high frequency transducers, which should allow more accurate definition of the soft components of the plaques.In this study we correlated corresponding IVUS and histopathological findings in human arterial specimens obtained at necropsy from patients with atherosclerosis, to determine how accurately 40 MHz IVUS can identify lipid/ necrotic pools. MethodsWe performed in vitro IVUS assessments, using continuous pull back, in arterial segments dissected from necropsy hearts. Arterial samples were serially sectioned in relation to IVUS markers. We then correlated the quantitative and qualitative evaluations of lipid/ necrotic pools obtained from histopathological slides with those obtained from IVUS cross sections. SAMPLE SERIESThe pathological series comprised 12 full length arteries, 10 coronary arteries (one left main, four left anterior...

Immunotherapy is used to treat almost all patients with advanced non-small cell lung cancer (NSCLC); however, identifying robust predictive biomarkers remains challenging. Here we show the predictive capacity of integrating medical imaging, histopathologic and genomic features to predict immunotherapy response using a cohort of 247 patients with advanced NSCLC with multimodal baseline data obtained during diagnostic clinical workup, including computed tomography scan images, digitized programmed death ligand-1 immunohistochemistry slides and known outcomes to immunotherapy. Using domain expert annotations, we developed a computational workflow to extract patient-level features and used a machine-learning approach to integrate multimodal features into a risk prediction model. Our multimodal model (area under the curve (AUC) = 0.80, 95% confidence interval (CI) 0.74–0.86) outperformed unimodal measures, including tumor mutational burden (AUC = 0.61, 95% CI 0.52–0.70) and programmed death ligand-1 immunohistochemistry score (AUC = 0.73, 95% CI 0.65–0.81). Our study therefore provides a quantitative rationale for using multimodal features to improve prediction of immunotherapy response in patients with NSCLC using expert-guided machine learning.

Background and purpose Data differentiating flow diversion properties of commercially available low- and high-porosity stents are limited. This in vitro study applies angiographic analysis of intra-aneurysmal flow to compare the flow-diversion performance of five neurovascular devices in idealized sidewall and bifurcation aneurysm models. Methods Five commercial devices (Enterprise, Neuroform, LVIS, FRED, and Pipeline) were implanted in silicone sidewall and bifurcation aneurysm models under physiological average flow of blood analog fluid. High-speed angiographic images were acquired pre- and post-device implantation and contrast concentration-time curves within the aneurysm were recorded. The curves were quantified with five parameters to assess changes in contrast transport, and thus aneurysm hemodynamics, due to each device. Results Inter-device flow-diversion performance was more easily distinguished in the sidewall model than the bifurcation model. There were no obvious overall statistical trends in the bifurcation parameters but the Pipeline performed marginally better than the other devices. In the sidewall geometry, overall evidence suggests that the LVIS performed better than the Neuroform and Enterprise. The Pipeline and FRED devices were statistically superior to the three stents and Pipeline was superior to FRED in all sidewall parameters evaluated. Conclusions Based on this specific set of experiments, lower-porosity flow diverters perform significantly better in reducing intra-aneurysmal flow activity than higher-porosity stents in sidewall-type geometries. The LVIS device is potentially a better flow diverter than the Neuroform and Enterprise devices, while the Pipeline is potentially better than the FRED.