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HIV-1 spreads efficiently through direct cell-to-cell transmission at virological synapses (VSs) formed by interactions between HIV-1 envelope proteins (Env) on the surface of infected cells and CD4 receptors on uninfected target cells. Env-CD4 interactions bring the infected and uninfected cellular membranes into close proximity and induce transport of viral and cellular factors to the VS for efficient virion assembly and HIV-1 transmission. Using novel, cell-specific stable isotope labeling and quantitative mass spectrometric proteomics, we identified extensive changes in the levels and phosphorylation states of proteins in HIV-1 infected producer cells upon mixing with CD4+ target cells under conditions inducing VS formation. These coculture-induced alterations involved multiple cellular pathways including transcription, TCR signaling and, unexpectedly, cell cycle regulation, and were dominated by Env-dependent responses. We confirmed the proteomic results using inhibitors targeting regulatory kinases and phosphatases in selected pathways identified by our proteomic analysis. Strikingly, inhibiting the key mitotic regulator Aurora kinase B (AURKB) in HIV-1 infected cells significantly increased HIV activity in cell-to-cell fusion and transmission but had little effect on cell-free infection. Consistent with this, we found that AURKB regulates the fusogenic activity of HIV-1 Env. In the Jurkat T cell line and primary T cells, HIV-1 Env:CD4 interaction also dramatically induced cell cycle-independent AURKB relocalization to the centromere, and this signaling required the long (150 aa) cytoplasmic C-terminal domain (CTD) of Env. These results imply that cytoplasmic/plasma membrane AURKB restricts HIV-1 envelope fusion, and that this restriction is overcome by Env CTD-induced AURKB relocalization. Taken together, our data reveal a new signaling pathway regulating HIV-1 cell-to-cell transmission and potential new avenues for therapeutic intervention through targeting the Env CTD and AURKB activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bruce et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: Arterial and neck vessel system characteristics of patients with multiple sclerosis have not been previously investigated. Therefore, the aim of this study was to examine the frequency of neck vessels and their cross-sectional areas (in square millimeters) between patients with MS and healthy controls., Materials and Methods: In this study, 193 patients with MS and 193 age- and sex-matched healthy controls underwent 2D TOF venography at 3T. The main arterial (carotid and vertebral), venous (internal jugular), and secondary neck vessels were examined at 4 separate cervical levels (C2/3, C4, C5/6, and C7/T1). The ANCOVA adjusted for age, body mass index, smoking status, hypertension, and heart disease was used to compare the differences between patients with MS and healthy controls., Results: After controlling for all confounding factors, patients with MS had significantly lower cross-sectional areas of the carotid arteries at the C2/3 ( P = .03), C5/6 ( P = .026), and C7/T1 ( P = .005) levels as well as of the vertebral arteries at the C2/3 ( P = .02), C4 ( P = .012), and C7/T1 ( P = .006) levels, compared with healthy controls. A higher frequency of secondary neck vessels was found at all 4 levels in patients with MS: C2/3 (12.9 versus 10, P < .001), C4 (9.1 versus 7.5, P < .001), C5/6 (7.8 versus 6.8, P = .012), and C7/T1 (8.8 versus 6, P < .001). The total cross-sectional areas of secondary neck vessels were also significantly higher at all 4 levels ( P < .03). No significant differences in the cross-sectional areas of jugular veins were found between patients with MS and healthy controls., Conclusions: Patients with MS showed lower cross-sectional areas of the carotid and vertebral arteries and a higher frequency of secondary neck vessels and their cross-sectional areas compared with healthy controls., (© 2018 by American Journal of Neuroradiology.)

Objectives To assess the relationship between cross-sectional area of internal jugular veins and brain volumes in healthy individuals without neurologic disease. Methods A total of 193 healthy individuals without neurologic disease (63 male and 130 female; age > 20 to < 70 years) received magnetic resonance venography and structural brain magnetic resonance imaging at 3T. The internal jugular vein cross-sectional area was assessed at C2-C3, C4, C5-C6, and C7-T1. Normalized whole brain volume was assessed. Partial correlation analyses were used to determine associations. Results There was an inverse relationship between normalized whole brain volume and total internal jugular vein cross-sectional area (C7-T1: males r = -0.346, p = 0.029; females r = -0.301, p = 0.002). After age adjustment, association of normalized whole brain volume and normalized gray matter volume with internal jugular vein cross-sectional area became positive in males (normalized whole brain volume and right internal jugular vein cross-sectional area (C2-C3) changed from r = -0.163 to r = 0.384, p = 0.002), but not in the females. Conclusion Sex differences exist in the relationship between brain volume and internal jugular vein cross-sectional area in healthy individuals without neurologic disease.

Purpose To assess cerebral microbleed (CMB) prevalence in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and associations with clinical outcomes. Materials and Methods CMBs are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established. In this study, 445 patients with MS (266 with relapsing-remitting MS, 138 with secondary progressive MS, and 41 with primary progressive MS), 45 patients with CIS, 51 patients with other neurological diseases, and 177 healthy control subjects (HCs) underwent 3-T magnetic resonance (MR) imaging and clinical examinations. A subset of 168 patients with MS and 50 HCs underwent neuropsychological testing. Number of CMBs was assessed on susceptibility-weighted minimum intensity projections by using the Microbleed Anatomic Rating Scale; volume was calculated by using quantitative susceptibility maps. Differences between groups were analyzed with the χ 2 test, Fisher exact test, Student t test, and analysis of variance; associations of CMBs with clinical and other MR imaging outcomes were explored with correlation and regression analyses. Because CMB frequency increases with age, prevalence was investigated in participants at least 50 years of age and younger than 50 years. Results Significantly more patients with MS than HCs had CMBs (19.8% vs 7.4%, respectively; P = .01) in the group at least 50 years old. A trend toward greater presence of CMBs was found in patients with MS (P = .016) and patients with CIS who were younger than 50 years (P = .039) compared with HCs. In regression analysis adjusted for age, hypertension, and normalized brain volume, increased number of CMBs was significantly associated with increased physical disability in the MS population (R 2 = 0.23, P < .0001). In correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory and verbal learning and memory (P = .006) and visual information processing speed trends (P = .049) in patients with MS. Conclusion Monitoring CMBs may be relevant in patients with MS and CIS at higher risk for developing cognitive and physical disability. © RSNA, 2016 Online supplemental material is available for this article.

Objectives: Constricted cerebral venous outflow has been linked with increased cerebrospinal fluid (CSF) pulsatility in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy individuals. This study investigates the relationship between CSF pulsatility and internal jugular vein (IJV) cross-sectional area (CSA) in these two groups, something previously unknown., Methods: 65 relapsing-remitting MS patients (50.8% female; mean age = 43.8 years) and 74 healthy controls (HCs) (54.1% female; mean age = 43.9 years) were investigated. CSF flow quantification was performed on cine phase-contrast MRI, while IJV-CSA was calculated using magnetic resonance venography. Statistical analysis involved correlation, and partial least squares correlation analysis (PLSCA)., Results: PLSCA revealed a significant difference (p<0.001; effect size = 1.072) between MS patients and HCs in the positive relationship between CSF pulsatility and IJV-CSA at C5-T1, something not detected at C2-C4. Controlling for age and cardiovascular risk factors, statistical trends were identified in HCs between: increased net positive CSF flow (NPF) and increased IJV-CSA at C5-C6 (left: r = 0.374, p = 0.016; right: r = 0.364, p = 0.019) and C4 (left: r = 0.361, p = 0.020); and increased net negative CSF flow and increased left IJV-CSA at C5-C6 (r = -0.348, p = 0.026) and C4 (r = -0.324, p = 0.039), whereas in MS patients a trend was only identified between increased NPF and increased left IJV-CSA at C5-C6 (r = 0.351, p = 0.021). Overall, correlations were weaker in MS patients (p = 0.015)., Conclusions: In healthy adults, increased CSF pulsatility is associated with increased IJV-CSA in the lower cervix (independent of age and cardiovascular risk factors), suggesting a biomechanical link between the two. This relationship is altered in MS patients.

Background: Internal jugular vein (IJV) narrowing has been implicated in central nervous system pathologies, however normal physiological age- and gender-related IJV variance in healthy individuals (HIs) has not been adequately assessed., Objectives: We assessed the relationship between IJV cross-sectional area (CSA) and aging., Materials and Methods: This study involved 193 HIs (63 males and 130 females) who received 2-dimensional magnetic resonance venography at 3T. The minimum CSA of the IJVs at cervical levels C2/C3, C4, C5/C6, and C7/T1 was obtained using a semi-automated contouring-thresholding technique. Subjects were grouped by decade. Pearson and partial correlation (controlled for cardiovascular risk factors, including hypertension, heart disease, smoking and body mass index) and analysis of variance analyses were used, with paired t-tests comparing side differences., Results: Mean right IJV CSA ranges were: in males, 41.6 mm2 (C2/C3) to 82.0 mm2 (C7/T1); in females, 38.0 mm2 (C2/C3) to 62.3 mm2 (C7/T1), while the equivalent left side ranges were: in males, 28.0 mm2 (C2/C3) to 52.2 mm2 (C7/T1); in females, 27.2 mm2 (C2/C3) to 47.8 mm2 (C7/T1). The CSA of the right IJVs was significantly larger (p<0.001) than the left at all cervical levels. Controlling for cardiovascular risk factors, the correlation between age and IJV CSA was more robust in males than in the females for all cervical levels., Conclusions: In HIs age, gender, hand side and cervical location all affect IJV CSA. These findings suggest that any definition of IJV stenosis needs to account for these factors.

Background and Purpose: Aging of the healthy brain is characterized by focal or nonfocal white matter (WM) signal abnormality (SA) changes, which are typically detected as leukoaraiosis (LA). Hypertension is a risk factor for WM lesion formation. This study investigated whether LA might be associated with increased cerebrospinal fluid (CSF) pulsatility linked to arterial hypertension., Methods: A total of 101 individuals without neurologic diseases (53 females and 48 males) aged between 18 and 75 years underwent 3T brain MRI with cine phase contrast imaging for CSF flow estimation, after providing their informed consent. LA was defined as the presence of focal T2 WM SA changes and/or nonfocal uniform areas of signal increase termed dirty appearing white matter (DAWM). Relevant information relating to cardiovascular risk factors was also collected., Results: When controlled for age and hypertension, significant partial correlations were observed between: DAWM volume and: net negative flow (r = -.294, P = .014); net positive flow (NPF) (r = .406, P = .001); and peak positive velocity (r = .342, P = .004). Multiple linear regression analysis revealed DAWM volume to be significantly correlated with CSF NPF (P = .019) and hypertension (P = .007), whereas T2 WM SA volume was only significantly correlated with age (P = .002). Combined DAWM and T2 WM SA volumes were significantly related with age (P = .001) and CSF peak negative velocity (P = .041)., Conclusions: Rarefaction of WM leading to LA is a multifactorial process, in which formation of DAWM induced by hypertension and increased aqueductal CSF pulsatility, may play a contributory role. These two factors appear to act independently of each other in a process that is independent of age., (Copyright © 2015 by the American Society of Neuroimaging.)

Quantifying flow from phase-contrast MRI (PC-MRI) data requires that the vessels of interest be segmented. The estimate of the vessel area will dictate the type and magnitude of the error sources that affect the flow measurement. These sources of errors are well understood, and mathematical expressions have been derived for them in previous work. However, these expressions contain many parameters that render them difficult to use for making practical error estimates. In this work, some realistic assumptions were made that allow for the simplification of such expressions in order to make them more useful. These simplified expressions were then used to numerically simulate the effect of segmentation accuracy and provide some criteria that if met, would keep errors in flow quantification below 10% or 5%. Four different segmentation methods were used on simulated and phantom MRA data to verify the theoretical results. Numerical simulations showed that including partial volumed edge pixels in vessel segmentation provides less error than missing them. This was verified with MRA simulations, as the best performing segmentation method generally included such pixels. Further, it was found that to obtain a flow error of less than 10% (5%), the vessel should be at least 4 (5) pixels in diameter, have an SNR of at least 10:1 and have a peak velocity to saturation cut-off velocity ratio of at least 5:3., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging., Materials and Methods: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled ≥2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes., Results: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021)., Conclusion: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals., (© 2013 Wiley Periodicals, Inc.)

Background and Purpose: It has been demonstrated that increased levels of iron in the brain occur with aging. In this study we investigated the nature of the association between age and SWI-filtered phase values, indicative of iron content, in the subcortical deep gray matter of healthy individuals., Materials and Methods: A total of 210 healthy individuals (men: n = 89, women: n = 121), mean age, 39.8 years (standard deviation = 15.5; range = 6-76 years), were imaged on a 3T scanner. Mean MRI phase, mean phase of low-phase voxels, and normalized volumes were determined for total subcortical deep gray matter, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus, hippocampus, amygdala, nucleus accumbens, red nucleus, and substantia nigra. Linear and nonlinear regression models were used to explore the relationship between phase and volume measures, and aging., Results: Mean phase values of subcortical deep gray matter structures showed a quadratic relationship, with individuals in late middle age (40-59 years) having the lowest mean phase values, followed by a reversal of this trend in the elderly. In contrast, mean phase of low-phase voxel measurements showed strong negative linear relationships with aging. Significantly lower phase values were detected in women compared with men (P < .001), whereas no sex differences were observed for mean phase of low-phase voxels. Normalized volume measurements were also linearly related to aging, and women showed smaller normalized volumes of subcortical deep gray matter structures than men (P < .001). Lower mean phase of low-phase voxels was related to decreased volume measures., Conclusions: A strong association between phase (quadratic effect; phase decreases are followed by increases), mean phase of low-phase voxels (linear effect), volume (linear effect), and age was observed. Low phase was related to brain atrophy.

Background: Activity of disease in patients with multiple sclerosis (MS) is monitored by detecting and delineating hyper-intense lesions on MRI scans. The Minimum Area Contour Change (MACC) algorithm has been created with two main goals: a) to improve inter-operator agreement on outlining regions of interest (ROIs) and b) to automatically propagate longitudinal ROIs from the baseline scan to a follow-up scan., Methods: The MACC algorithm first identifies an outer bound for the solution path, forms a high number of iso-contour curves based on equally spaced contour values, and then selects the best contour value to outline the lesion. The MACC software was tested on a set of 17 FLAIR MRI images evaluated by a pair of human experts and a longitudinal dataset of 12 pairs of T2-weighted Fluid Attenuated Inversion Recovery (FLAIR) images that had lesion analysis ROIs drawn by a single expert operator., Results: In the tests where two human experts evaluated the same MRI images, the MACC program demonstrated that it could markedly reduce inter-operator outline error. In the longitudinal part of the study, the MACC program created ROIs on follow-up scans that were in close agreement to the original expert's ROIs. Finally, in a post-hoc analysis of 424 follow-up scans 91% of propagated MACC were accepted by an expert and only 9% of the final accepted ROIS had to be created or edited by the expert., Conclusion: When used with an expert operator's verification of automatically created ROIs, MACC can be used to improve inter- operator agreement and decrease analysis time, which should improve data collected and analyzed in multicenter clinical trials.

Purpose: To investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA)., Materials and Methods: This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (≥50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis., Results: At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group., Conclusions: PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)