MR Imaging of the Cerebral Aneurysmal Wall for Assessment of Rupture Risk.

The evaluation of unruptured intracranial aneurysms requires a comprehensive and multifaceted approach. The comprehensive analysis of aneurysm wall enhancement through high-resolution MRI, in tandem with advanced processing techniques like finite element analysis, quantitative susceptibility mapping, and computational fluid dynamics, has begun to unveil insights into the intricate biology of aneurysms. This enhanced understanding of the etiology, progression, and eventual rupture of aneurysms holds the potential to be used as a tool to triage patients to intervention versus observation. Emerging tools such as radiomics and machine learning are poised to contribute significantly to this evolving landscape of diagnostic refinement.

Bidirectional Multiphoton Communication between Remote Superconducting Nodes.

Quantum communication test beds provide a useful resource for experimentally investigating a variety of communication protocols. Here we demonstrate a superconducting circuit test bed with bidirectional multiphoton state transfer capability using time-domain shaped wave packets. The system we use to achieve this comprises two remote nodes, each including a tunable superconducting transmon qubit and a tunable microwave-frequency resonator, linked by a 2 m-long superconducting coplanar waveguide, which serves as a transmission line. We transfer both individual and superposition Fock states between the two remote nodes, and additionally show that this bidirectional state transfer can be done simultaneously, as well as being used to entangle elements in the two nodes.

Alternative end-joining results in smaller deletions in heterochromatin relative to euchromatin.

Pericentromeric heterochromatin is highly enriched for repetitive sequences prone to aberrant recombination. Previous studies showed that homologous recombination (HR) repair is uniquely regulated in this domain to enable 'safe' repair while preventing aberrant recombination. In Drosophila cells, DNA double-strand breaks (DSBs) relocalize to the nuclear periphery through nuclear actin-driven directed motions before recruiting the strand invasion protein Rad51 and completing HR repair. End-joining (EJ) repair also occurs with high frequency in heterochromatin of fly tissues, but how alternative EJ (alt-EJ) pathways operate in heterochromatin remains largely uncharacterized. Here, we induce DSBs in single euchromatic and heterochromatic sites using a new system that combines the DR- white reporter and I-SceI expression in spermatogonia of flies. Using this approach, we detect higher frequency of HR repair in heterochromatin, relative to euchromatin. Further, sequencing of mutagenic repair junctions reveals the preferential use of different EJ pathways across distinct euchromatic and heterochromatic sites. Interestingly, synthesis-dependent microhomology-mediated end joining (SD-MMEJ) appears differentially regulated in the two domains, with a preferential use of motifs close to the cut site in heterochromatin relative to euchromatin, resulting in smaller deletions. Together, these studies establish a new approach to study repair outcomes in fly tissues, and support the conclusion that heterochromatin uses more HR and less mutagenic EJ repair relative to euchromatin.

Lipid biosynthesis perturbation impairs endoplasmic reticulum-associated degradation.

The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation of Deg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, in Saccharomyces cerevisiae. This screen revealed that INO4 is required for efficient Deg1-Sec62 degradation. INO4 encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis. Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect in ino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases by INO4 deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Loss of INO4 sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.

Evaluation of ocular blood flow in the assessment of symptomatic carotid stenosis.

BACKGROUND AND PURPOSE: The degree of internal carotid artery (ICA) stenosis determined by criteria from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) is not the most accurate index to assess distal flow compromise. Distal ICA perfusion is also determined by factors such as tandem carotid stenosis and collateral circulation. Quantification of end-organ ocular perfusion using non-invasive laser speckle flowgraphy (LSFG) may provide insights into distal ICA flow. This study prospectively assessed the degree of ICA flow using LSFG. METHODS: Eighteen patients with symptomatic carotid stenosis underwent LSFG evaluation. LSFG was used to extract ocular blood flow metrics recorded simultaneously in the retina, choroid, and optic nerve head. The following ocular flow parameters were measured with LSFG: mean blur rate (MBR), flow acceleration index (FAI), and rising rate (RR). Syngo iFlow perfusion imaging was used to objectively quantify contrast flow in the ICA and brain parenchyma during digital subtraction angiography. Time to peak (TTP) and contrast delay were extracted from seven different regions of interest (ROIs). RESULTS: MBR, FAI, and RR were correlated with NASCET degree of stenosis. FAI and RR also improved after stenting. TTP improved after stenting in three ROIs. A moderate negative correlation was observed between FAI and contrast delay. CONCLUSIONS: LSFG non-invasively quantifies end-organ blood flow distal to the ICA origin. LSFG metrics have the potential to quantify end-organ perfusion and determine if a proximal carotid stenosis is symptomatic.

Macro-ER-phagy receptors Atg39p and Atg40p confer resistance to aminoglycoside hygromycin B in S. cerevisiae.

Receptor-mediated autophagic turnover of portions of the endoplasmic reticulum (ER) is mediated by macro-ER-phagy. We hypothesized macro-ER-phagy promotes proteotoxic stress resistance. We predicted Saccharomyces cerevisiae lacking macro-ER-phagy receptors would exhibit enhanced sensitivity to hygromycin B, which reduces translational fidelity and is expected to globally disrupt protein homeostasis, including at the ER. We observed that loss of either of two yeast macro-ER-phagy receptors (Atg39p or Atg40p) compromised cellular resistance to hygromycin B to a similar extent as loss of ER-associated degradation (ERAD) ubiquitin ligases Hrd1p and Doa10p. Our data are consistent with a model whereby macro-ER-phagy and ERAD collaborate to mediate ER protein quality control. Disruptions of macro-ER-phagy have been linked to neuropathy, dementia, and cancer. A dampened capacity to mediate protein quality control may contribute to these conditions.

High resolution 7T MR imaging in characterizing culprit intracranial atherosclerotic plaques.

BACKGROUND: Current imaging modalities underestimate the severity of intracranial atherosclerotic disease (ICAD). High resolution vessel wall imaging (HR-VWI) MRI is a powerful tool in characterizing plaques. We aim to show that HR-VWI MRI is more accurate at detecting and characterizing intracranial plaques compared to digital subtraction angiography (DSA), time-of-flight (TOF) MRA, and computed tomography angiogram (CTA). METHODS: Patients with symptomatic ICAD prospectively underwent 7T HR-VWI. We calculated: degree of stenosis, plaque burden (PB), and remodeling index (RI). The sensitivity of detecting a culprit plaque for each modality as well as the correlations between different variables were analyzed. Interobserver agreement on the determination of a culprit plaque on every imaging modality was evaluated. RESULTS: A total of 44 patients underwent HR-VWI. Thirty-four patients had CTA, 18 TOF-MRA, and 18 DSA. The sensitivity of plaque detection was 88% for DSA, 78% for TOF-MRA, and 76% for CTA. There's significant positive correlation between PB and degree of stenosis on HR-VWI MRI (p < 0.001), but not between PB and degree of stenosis in DSA (p = 0.168), TOF-MRA (p = 0.144), and CTA (p = 0.253). RI had a significant negative correlation with degree of stenosis on HR-VWI MRI (p = 0.003), but not on DSA (p = 0.783), TOF-MRA (p = 0.405), or CTA (p = 0.751). The best inter-rater agreement for culprit plaque detection was with HR-VWI (p = 0.001). CONCLUSIONS: The degree of stenosis measured by intra-luminal techniques does not fully reflect the true extent of ICAD. HR-VWI is a more accurate tool in characterizing atherosclerotic plaques and may be the default imaging modality in clinical practice.

The Impact of Multiple Sclerosis Disease Status and Subtype on Hematological Profile.

Multiple sclerosis (MS) is an immune-mediated, demyelinating disease of the central nervous system. In this study, an MS cohort and healthy controls were stratified into Caucasian and African American groups. Patient hematological profiles-composed of complete blood count (CBC) and complete metabolic panel (CMP) test values-were analyzed to identify differences between MS cases and controls and between patients with different MS subtypes. Additionally, random forest models were used to determine the aggregate utility of common hematological tests in determining MS disease status and subtype. The most significant and relevant results were increased bilirubin and creatinine in MS cases. The random forest models achieved some success in differentiating between MS cases and controls (AUC values: 0.725 and 0.710, respectively) but were not successful in differentiating between subtypes. However, larger samples that adjust for possible confounding variables, such as treatment status, may reveal the value of these tests in differentiating between MS subtypes.

Acoustofluidic-mediated molecular delivery to human T cells with a three-dimensional-printed flow chamber.

Cell-based therapies have garnered significant interest to treat cancer and other diseases. Acoustofluidic technologies are in development to improve cell therapy manufacturing by facilitating rapid molecular delivery across the plasma membrane via ultrasound and microbubbles (MBs). In this study, a three-dimensional (3D) printed acoustofluidic device was used to deliver a fluorescent molecule, calcein, to human T cells. Intracellular delivery of calcein was assessed after varying parameters such as MB face charge, MB concentration, flow channel geometry, ultrasound pressure, and delivery time point after ultrasound treatment. MBs with a cationic surface charge caused statistically significant increases in calcein delivery during acoustofluidic treatment compared to MBs with a neutral surface charge (p < 0.001). Calcein delivery was significantly higher with a concentric spiral channel geometry compared to a rectilinear channel geometry (p < 0.001). Additionally, calcein delivery was significantly enhanced at increased ultrasound pressures of 5.1 MPa compared to lower ultrasound pressures between 0-3.8 MPa (p < 0.001). These results demonstrate that a 3D-printed acoustofluidic device can significantly enhance intracellular delivery of biomolecules to T cells, which may be a viable approach to advance cell-based therapies.

A Systematic Review of Sexual Orientation Disparities in Disordered Eating and Weight-Related Behaviors among Adolescents and Young Adults: Toward a Developmental Model.

Adolescence is a sensitive period for the development of disordered eating and weight-related behaviors, and sexual minorities may be particularly at risk due to heightened minority stress and challenges related to sexual identity development. This review synthesized findings from 32 articles that examined sexual orientation disparities (each with a heterosexual referent group) in four disordered eating behaviors (binging, purging, restrictive dieting, diet pill use) and four weight-related behaviors (eating behaviors, physical activity, body image, and Body Mass Index [BMI]). Potential variations by outcome, sex, race/ethnicity, and developmental stage were systematically reviewed. Evidence supporting sexual orientation disparities in disordered eating and weight-related behaviors was more consistent among males than females. Among females, sexual orientation disparities in disordered eating behaviors appeared to be more pronounced during adolescence than in young adulthood. Sexual minority females generally reported more positive body image than heterosexual females but experienced disparities in BMI. Sexual orientation differences in eating behaviors and physical activity were especially understudied. Incorporating objectification and minority stress theory, a developmental model was devised where body image was conceptualized as a key mechanism leading to disordered eating behaviors. To advance understanding of sexual orientation disparities and tailor intervention efforts, research in this field should utilize longitudinal study designs to examine developmental variations and incorporate multi-dimensional measurements of sexual orientation and body image.

A longitudinal investigation of perceived weight status as a mediator of sexual orientation disparities in maladaptive eating behaviors.

Sexual minority adolescents are more likely than heterosexual peers to engage in maladaptive eating behaviors such as restrictive dieting. However, prior studies relied on cross-sectional data and did not test potential mechanisms. This study examined longitudinal associations between adolescent sexual minority status and three maladaptive eating behaviors (restrictive dieting, diet pill use, and drug-related dieting) in young adulthood and tested higher perceived weight status as a mediator of observed disparities. Data were drawn from Waves 2 (11th grade in 2010/2011) to 7 (4 years post high school in 2015/2016) of the NEXT Generation Health Study, a U.S. national longitudinal cohort of adolescents (n = 1925). Logistic regression analyses revealed that, relative to heterosexual females, sexual minority females were more likely to report any restrictive dieting (extreme food intake restriction) in the past year (62.9% vs. 37.0%; Adjusted Odds Ratio = 2.26, 95% CI = 1.07, 4.76). Associations between sexual minority status and diet pills use or drug-related dieting were not found. Results from structural equation modeling indicated that higher perceived weight status was a significant mediator of the association between sexual minority status and restrictive dieting among females. These findings highlight higher perceived weight status as an important cognitive mechanism explaining why sexual minority females are at heightened risk for restrictive dieting in young adulthood. To optimally inform prevention efforts, additional research is needed to test the extent to which minority stressors may shape weight perceptions and their contribution to maladaptive and disordered eating behaviors among sexual minority adolescents.

Sexual Minority Status and Adolescent Eating Behaviors, Physical Activity, and Weight Status.

INTRODUCTION: This study examined sexual orientation differences in eating behaviors, physical activity, and weight status among adolescents in the U.S. Moreover, this study tested whether parental and peer influences contribute to sexual orientation disparities in adolescent eating behaviors, physical activity, BMI, and examined disparities in weight misperception. METHODS: Cross-sectional data were from 1,926 adolescents who participated in the NEXT Generation Health Study in 2010-2011. Linear and multinomial logistic regressions conducted in 2017-2018 were used to test disparities and interactions with social influences. RESULTS: Relative to their heterosexual peers, sexual minority males and females consumed fruits and vegetables more frequently; sexual minority males engaged in less frequent physical activity; and sexual minority females were more likely to be overweight, perceive themselves as overweight, and to overestimate their weight. High parental expectation for physical activity was associated with more frequent vigorous physical activity among heterosexual adolescents, but less frequent vigorous physical activity among sexual minority males. Exercising with a same-sex peer buffered against the risk of higher BMI among sexual minority females. CONCLUSIONS: Parental and peer influences may serve as potential intervention targets to reduce disparities in weight-related behaviors. Longitudinal research is needed to understand the consequences of weight misperception among sexual minority females.