Drosophila Hsc70-4 Is Critical for Neurotransmitter Exocytosis In Vivo

AbstractPrevious in vitro studies of cysteine-string protein (CSP) imply a potential role for the clathrin-uncoating ATPase Hsc70 in exocytosis. We show that hypomorphic mutations in Drosophila Hsc70-4 (Hsc4) impair nerve-evoked neurotransmitter release, but not synaptic vesicle recycling in vivo. The loss of release can be restored by increasing external or internal Ca2+ and is caused by a reduced Ca2+ sensitivity of exocytosis downstream of Ca2+ entry. Hsc4 and CSP are likely to act in common pathways, as indicated by their in vitro protein interaction, the similar loss of evoked release in individual and double mutants, and genetic interactions causing a loss of release in trans-heterozygous hsc4-csp double mutants. We suggest that Hsc4 and CSP cooperatively augment the probability of release by increasing the Ca2+ sensitivity of vesicle fusion

Improved data acquisition efficiency for respiratory motion correction in coronary MRI

To investigate the performance of a novel algorithm for correcting respiratory-induced heart motion for whole-heart coronary MRI

Free-breathing late gadolinium enhancement CMR with a fixed short scan time using CosMo

To evaluate the performance of compressed sensing for motion correction (CosMo) [1] in compensating the respiratory motion of the heart in 3D late gadolinium enhancement (LGE) CMR

Left Atrial scar assessment using imaging with isotropic spatial resolution and compressed sensing

Summary. We assess left atrial scar using late gadolinium enhancement (LGE) with isotropic spatial resolution of $1.4^3 mm^3$ by using highly accelerated LOST [1] reconstruction. Background. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia [2]. Pulmonary vein isolation (PVI) using radiofrequency (RF)-ablation is the leading treatment for AF. Recently, LGE imaging of the LA has been used to identify atrial wall scar due to RF-ablation [3]. However, current LGE methods have limited spatial resolution that substantially impact assessment of scar in the complex geometry of PVs and LA. In this study, we sought to utilize prospective random k-space sampling and LOST [1] for accelerated LGE imaging, where reduction in imaging time was traded-off for improved isotropic spatial-resolution. Methods. 23 patients with history of AF (6 females, $58.1 \pm 9.6$ years, 9 pre-PVI, 2 with history of PVI; 8 post-PVI; 3 with both pre and post-PVI) were recruited for this study. LGE images were acquired 10-to-20 minutes after bolus infusion of 0.2 mmol/kg Gd-DTPA. Free-breathing ECG-triggered navigator-gated inversion-recovery GRE sequences were used for all acquisitions ($TR/TE/ \alpha = 5.2/2.6ms/25°, FOV=320×320×100mm$). The PV inflow artifact reduction technique in [4] was also utilized. For each patient, a standard non-isotropic 3D LGE scan ($1.4×1.4×4.0mm^3$) and a 3-fold-accelerated highresolution 3D LGE scan ($1.4^3 mm^3$) were performed, with randomized acquisition order. For random undersampling, central k-space (45×35 in ky-kz) was fullysampled, edges randomly discarded, and phase reordering performed as in [5]. Acquisition times were ~4 mins assuming 100% scan-efficiency at 70bpm for both scans. All undersampled data were reconstructed offline using LOST [1]. LOST-reconstructed high-resolution, and standard LGE images were scored by two blinded readers for diagnostic value, presence of LGE(yes/no); and image quality in axial(Ax), coronal(Co) and sagittal (Sa) views (1=poor,4=excellent). Results. Three cases were declared non-diagnostic due to contrast-washout and imperfect inversion-time. LGE was visually present in 14 of the remaining 20 patients based on standard-LGE images, and 12 based on LOST-reconstructed ones (disagreement on one pre- and one postPVI patient). Figure 1 and 2 show comparisons of isotropic vs. non-isotropic LGE images in two patients. Image scores for LOST-LGE: $Ax=2.90 \pm 0.70, Sa=3.33 \pm 0.66, Co=3.00 \pm 0.63$; and standard LGE: $Ax=3.76 \pm 0.54, Sa=2.48 \pm 0.60, Co=2.24 \pm 0.44$, where differences were significant in all views. Conclusions. LOST allows isotropic spatial-resolution in LGE for assessment of LA and PV scar. Isotropic resolution allows reformatting LGE images in any orientation and facilitates assessment of scar. Further clinical study is needed to assess if the improved spatial resolution will impact the diagnostic interpretation of data

Scar heterogeneity on cardiovascular magnetic resonance as a predictor of appropriate implantable cardioverter defibrillator therapy

Background: Despite the survival benefit of implantable-cardioverter-defibrillators (ICDs), the vast majority of patients receiving an ICD for primary prevention do not receive ICD therapy. We sought to assess the role of heterogeneous scar area (HSA) identified by late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) in predicting appropriate ICD therapy for primary prevention of sudden cardiac death (SCD). Methods: From September 2003 to March 2011, all patients who underwent primary prevention ICD implantation and had a pre-implantation LGE-CMR were identified. Scar size was determined using thresholds of 4 and 6 standard deviations (SD) above remote normal myocardium; HSA was defined using 3 different criteria; as the region between 2 SD and 4 SD (HSA2-4SD), between 2SD and 6SD (HSA2-6SD), and between 4SD and 6SD (HSA4-6SD). The end-point was appropriate ICD therapy. Results: Out of 40 total patients followed for 25 ± 24 months, 7 had appropriate ICD therapy. Scar size measured by different thresholds was similar in ICD therapy and non-ICD therapy groups (P = NS for all). However, HSA2-4SD and HSA4-6SD were significantly larger in the ICD therapy group (P = 0.001 and P = 0.03, respectively). In multivariable model HSA2-4SD was the only significant independent predictor of ICD therapy (HR = 1.08, 95%CI: 1.00-1.16, P = 0.04). Kaplan-Meier analysis showed that patients with greater HSA2-4SD had a lower survival free of appropriate ICD therapy (P = 0.026). Conclusions: In primary prevention ICD implantation, LGE-CMR HSA identifies patients with appropriate ICD therapy. If confirmed in larger series, HSA can be used for risk stratification in primary prevention of SCD

Atherosclerotic Biomarkers and Aortic Atherosclerosis by Cardiovascular Magnetic Resonance Imaging in the Framingham Heart Study

Background: The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community‐based cohort. Methods and Results: We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high‐sensitivity C‐reactive protein, fibrinogen, intercellular adhesion molecule‐1, interleukin‐6, interleukin‐18, lipoprotein‐associated phospholipase‐A2 activity and mass, monocyte chemoattractant protein‐1, P‐selectin, and tumor necrosis factor receptor‐2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age‐ and sex‐adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09). Conclusions: In our community‐based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Importance Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. Objective To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). Design, Setting, and Participants A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. Exposures Selective serotonin reuptake inhibitors and untreated maternal depression. Main Outcomes and Measures Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. Results The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction). Conclusions and Relevance Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes