Stevensmunck8078

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.OBJECTIVE To investigate the association of carotid atherosclerosis, dilation, and stiffness with imaging markers of cerebral small vessel disease (CSVD) in a community-based sample. METHODS The study comprised 1,051 participants (age 57.5 ± 9.2 years). Carotid plaques, intima-media thickness (IMT), diastolic diameter, pulse wave velocity, and stiffness index (β) were measured by ultrasound. Imaging markers of CSVD, including lacunes, cerebral microbleeds, dilated PVS, and white matter hyperintensities (WMH) volume, were assessed. RESULTS Carotid plaque was associated with the presence of lacunes (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.78-4.33; p less then 0.001) and larger WMH volume (natural log transformed, β ± SE, 0.32 ± 0.10; p = 0.002). The increased carotid diameter was associated with the presence of lacunes (OR 1.82, 95% CI 1.22-2.72; p = 0.003), larger WMH volume (β ± SE, 0.37 ± 0.10; p less then 0.001), and PVS in the basal ganglia (OR 1.59, 95% CI 1.20-2.11; p = 0.001). Associations of carotid dilation and CSVD were independent of carotid IMT and plaque. Most parenchymal lesions were located in the basal ganglia and deep white matter. Carotid IMT and stiffness were not associated with CSVD. CONCLUSIONS Carotid atherosclerosis and dilation are associated with imaging markers of CSVD. The noninvasive carotid assessment would seem to be a rational approach to risk stratification of CSVD. © 2020 American Academy of Neurology.The emergence of novel Coronavirus 2019 (COVID-19)1 and the subsequent pandemic present a unique challenge to Neurologists managing patients with multiple sclerosis (MS) and related neuroinflammatory disorders, such as neuromyelitis spectrum disorder (NMOSD). © 2020 American Academy of Neurology.Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer (N = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm2/year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%-67%) for MD, 23% (2%-45%) for microcalcifications, and 13% (1%-25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, -8% to 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. Zosuquidar concentration In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer. SIGNIFICANCE These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk. ©2020 American Association for Cancer Research.Understanding the neurobiological underpinnings of emotion relies on objective readouts of the emotional state of an individual, which remains a major challenge especially in animal models. We found that mice exhibit stereotyped facial expressions in response to emotionally salient events, as well as upon targeted manipulations in emotion-relevant neuronal circuits. Facial expressions were classified into distinct categories using machine learning and reflected the changing intrinsic value of the same sensory stimulus encountered under different homeostatic or affective conditions. Facial expressions revealed emotion features such as intensity, valence, and persistence. Two-photon imaging uncovered insular cortical neuron activity that correlated with specific facial expressions and may encode distinct emotions. Facial expressions thus provide a means to infer emotion states and their neuronal correlates in mice. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC - is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC - subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo-designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions.