TGF-β Suppresses β-Catenin-Dependent Tolerogenic Activation Program in Dendritic Cells

The mechanisms that underlie the critical dendritic cell (DC) function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC) clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance

Central Blood Pressure and Peripheral Reactive Vasodilation in Plant-Based and Typical Dieting African Americans

African American individuals (AA) face higher mortality rates from cardiovascular disease than Americans from other racial/ethnic backgrounds. The cause of this health disparity is multifactorial and is in part related to impaired vascular function as well as other variables including diet and numerous socioeconomic factors. Diets rich in whole plant foods and low in animal products may protect blood vessels through their high antioxidant capacity and low inflammatory load. PURPOSE: The purpose of this study was to test the hypothesis that AA adhering to a 100% plant-based (vegan) diet (PBD) would have a more favorable dietary intake of several key nutrients and more optimal blood cholesterol, which would contribute to better blood pressure and peripheral reactive vasodilation relative to AA following a typical American diet (TAD). METHODS: Seventeen AA participated in the study. Of them, 8 (5 female; age: 25±2 years; BMI: 23.4±1.4 kg/m2) were following a PBD for 2.5±0.3 years and 9 (5 female; age: 21±1 years; BMI: 25.3±2.1 kg/m2) were following a TAD. A fasting venous blood draw was performed to assess blood lipids. Participants completed a comprehensive diet questionnaire (DHQIII, NIH). Peripheral and central blood pressures were measured via the SphygmoCor system (AtCor Medical). Brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH) were assessed via well-established procedures. Briefly, 2 min baseline measurements of brachial artery diameter and blood velocity were taken via Doppler ultrasound before a forearm cuff was inflated to 220 mmHg for 5 min. Post-occlusion data were recorded for 3 min. Measurement of baseline to peak post-occlusion brachial artery diameter and blood velocity were performed by pairing a video capture system (Elgato) with edge-detection and blood velocity-tracking software (Quipu). RESULTS: PBD AA consumed more dark green vegetables and whole grains and less cholesterol than TAD AA (p\u3c.05 for all). Consumption of sodium, potassium, and vitamins C & E was not different between groups (p\u3e.05 for all). Total (TC) and low-density lipoprotein (LDL-C) blood cholesterol concentrations were lower in PBD AA relative to TAD AA (TC: 136±9 vs. 174±12 mg/dl; LDL-C: 77±6 vs. 106±11 mg/dl; respectively; p\u3c.05 for both). Resting brachial (b) and central (c) mean arterial blood pressures (MAP) were lower in PBD AA relative to TAD AA (bMAP: 85±2 vs. 91±2 mmHg; cMAP: 80±2 vs. 87±2 mmHg; respectively; p\u3c.05 for both). There were no differences between groups in FMD nor RH (p\u3e.05 for all). FMD and FMD/shear rate were 7.7±0.8% and 0.33±0.05 au in PBD AA and 6.2±0.9% and 0.27±0.03 au in TAD AA, respectively. For RH, the percentage change in blood velocity and flow were 1441±479% and 1425±466% in PBD AA and 707±495% and 671±76% in TAD AA, respectively. CONCLUSION: These preliminary data suggest that a diet rich in whole plant foods but devoid of animal products may be associated with healthier blood cholesterol and peripheral and central blood pressures in AA but that these differences may not yet be translating to differences in peripheral reactive vasodilation

Sympathetically-Mediated Cutaneous Vasoconstriction Is Similar Between Non-Hispanic Black and White Individuals

Cardiovascular disease (CVD) prevalence is highest in non-Hispanic Black (BL) individuals compared to any other race. The mechanisms responsible remain incompletely understood and can be impacted by several environmental, psychosocial, and socioeconomic factors. A major contributing factor to elevated CVD risk/prevalence in the BL population is altered vascular function, which could be attributed to an exaggerated vasoconstrictor response to efferent sympathetic activity (i.e., sympathetic vascular transduction). Previous data from our group demonstrates heightened sympathetic vascular transduction in the peripheral vasculature of BL males. However, whether sympathetically-mediated vasoconstriction is exaggerated in the cutaneous circulation of BL individuals remains unknown. PURPOSE: This study tested the hypothesis that BL individuals exhibit exaggerated vasoconstriction to intra-dermal infusions of the α-adrenoreceptor agonist norepinephrine (NE) relative to White (WH) individuals. METHODS: In this study, young, healthy college-aged BL (n=13; 6 females) and WH (n=10; 4 females) individuals participated. Participants were instrumented with an intradermal microdialysis membrane in the dorsal forearm. Red blood cell flux was continuously assessed via laser Doppler flowmetry before (baseline) and during incrementally stronger infusions of NE (10-8 M – 10-2 M; 6 min/dose). Data were analyzed as a relative (i.e., percent) reduction in cutaneous vascular conductance (CVC: flux/MAP) compared to the pre-infusion baseline. RESULTS: NE caused a dose-dependent reduction in CVC in both groups (P\u3c0.001). There was no difference between the BL and WH individuals (P=0.37) nor was there a race x dose interaction (P=0.84). Similarly, when the data were separated by sex there was no difference between BL and WH males (P=0.56) or females (P=0.26). CONCLUSION: Vasoconstrictor responsiveness to α-adrenoreceptor activation was similar between BL and WH individuals. These data suggest that the cutaneous circulation may exhibit divergent sympathically-mediated vasoconstrictor responsiveness relative to other peripheral vascular beds in BL individuals

Errors in stimulated-Raman-induced logic gates in 133^{133}Ba+^+

${}^{133}\mathrm{Ba}^+$ is illuminated by a laser that is far-detuned from optical transitions, and the resulting spontaneous Raman scattering rate is measured. The observed scattering rate is lower than previous theoretical estimates. The majority of the discrepancy is explained by a more accurate treatment of the scattered photon density of states. This work establishes that, contrary to previous models, there is no fundamental limit to laser-driven quantum gates from laser-induced spontaneous Raman scattering.Comment: 4 + 2 pages, 4 + 1 figure

Large Anomalous Hall effect in a silicon-based magnetic semiconductor

Magnetic semiconductors are attracting high interest because of their potential use for spintronics, a new technology which merges electronics and manipulation of conduction electron spins. (GaMn)As and (GaMn)N have recently emerged as the most popular materials for this new technology. While Curie temperatures are rising towards room temperature, these materials can only be fabricated in thin film form, are heavily defective, and are not obviously compatible with Si. We show here that it is productive to consider transition metal monosilicides as potential alternatives. In particular, we report the discovery that the bulk metallic magnets derived from doping the narrow gap insulator FeSi with Co share the very high anomalous Hall conductance of (GaMn)As, while displaying Curie temperatures as high as 53 K. Our work opens up a new arena for spintronics, involving a bulk material based only on transition metals and Si, and which we have proven to display a variety of large magnetic field effects on easily measured electrical properties.Comment: 19 pages with 5 figure

Potential of dynamic ocean management strategies for western Pacific leatherback sea turtle bycatch mitigation in New Zealand

Western Pacific leatherback sea turtles (Dermochelys coriacea) are a priority bycatch mitigation concern due to the projected extinction of the population before the end of the 21st century. The species regularly occurs as bycatch in gillnet and surface longline fisheries. Here, we explore the potential for dynamic ocean management in an emerging hotspot of leatherback sea turtle bycatch in the New Zealand pelagic longline fishery. We compared spatial areas of different sizes built from single oceanographic covariates as well as built from a composite risk surface developed through ensemble random forests. We found that, individually, the Okubo–Weiss parameter, sea surface temperature (SST) anomaly, SST, moon phase, and distance to the SST front were important oceanographic covariates for leatherback sea turtle bycatch. However, the spatial areas built from the composite risk surface were the most effective at discriminating sets with and without bycatch across a range of risk cutoffs. When we also considered implementation metrics of spatial area and coherence as part of performance, the area derived from the composite risk surface with a risk of interaction per set greater than 52% performed best. This spatial area was ephemeral, occurring 1 or 2 weeks each year, and localized, occurring along the north coast of East Cape in the North Island of New Zealand. The apparent presence of discrete spatial areas with elevated risk may be useful to inform future management in the area. Considering implementation metrics in defining utility was useful for identifying tradeoffs between the total size and the underlying covariates delineating a spatial area. As such, we recommend these types of metrics to be included when designing spatial bycatch mitigation strategies elsewhere

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment