The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective

The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. 1H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. 1H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of 1H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment. This review describes the theoretical basis of 1H NMR; compares MS and 1H NMR and provides a tabular overview of recent 1H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. 1H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention

Prolonged FGF signaling is necessary for lung and liver induction in Xenopus

BACKGROUND: FGF signaling plays numerous roles during organogenesis of the embryonic gut tube. Mouse explant studies suggest that different thresholds of FGF signaling from the cardiogenic mesoderm induce lung, liver, and pancreas lineages from the ventral foregut progenitor cells. The mechanisms that regulate FGF dose in vivo are unknown. Here we use Xenopus embryos to examine the hypothesis that a prolonged duration of FGF signaling from the mesoderm is required to induce foregut organs. RESULTS: We show that both mesoderm and FGF signaling are required for liver and lung development in Xenopus; formally demonstrating that this important step in organ induction is conserved with other vertebrate species. Prolonged contact with the mesoderm and persistent FGF signaling through both MEK and PI3K over an extended period of time are required for liver and lung specification. Inhibition of FGF signaling results in reduced liver and lung development, with a modest expansion of the pancreas/duodenum progenitor domain. Hyper-activation of FGF signaling has the opposite effect expanding liver and lung gene expression and repressing pancreatic markers. We show that FGF signaling is cell autonomously required in the endoderm and that a dominant negative FGF receptor decreases the ability of ventral foregut progenitor cells to contribute to the lung and liver buds. CONCLUSIONS: These results suggest that the liver and lungs are specified at progressively later times in development requiring mesoderm contact for different lengths of time. Our data suggest that this is achieved at least in part through prolonged FGF signaling. In addition to providing a foundation for further mechanistic studies on foregut organogenesis using the experimental advantages of the Xenopus system, these data have implications for the directed differentiation of stem cells into foregut lineages

Twenty-five-year outcomes after multiple internal thoracic artery bypass

ObjectiveCoronary artery bypass grafting with multiple internal thoracic artery grafts is currently controversial. This study assessed single institutional outcomes with multiple internal thoracic artery grafting for guidance with future clinical decisions.MethodsIn 19,482 patients undergoing multivessel coronary artery bypass grafting (1984-2009), baseline characteristics were recorded in a prospective databank, and follow-up was obtained by questionnaires, phone contact, or National Death Index. Outcomes examined were subsequent myocardial infarction, percutaneous coronary intervention, reoperative coronary artery bypass grafting, all-cause death, and a composite of the 4. Three groups were defined: (1) no internal thoracic artery graft (1874/19,482 or 9%); (2) single internal thoracic artery grafts and adjunctive venous conduits (single internal thoracic artery; 16,881/19,482 or 87%); and (3) multiple internal thoracic artery grafts (728/19,482 or 4%). Multivariable Cox modeling adjusted for differences in baseline characteristics, and comparisons were performed using area under the curve analysis.ResultsDifferences in baseline characteristics for the no internal thoracic artery graft, single internal thoracic artery, and multiple internal thoracic artery groups were as follows: median age 66, 64, and 59 years, respectively; congestive heart failure 22%, 18%, and 13%, respectively; ejection fraction 0.50, 0.52, and 0.51, respectively; reoperation 10%, 3%, and 7%, respectively; diabetes 27%, 30%, and 15%, respectively; and female gender 33%, 28%, and 20%, respectively. No differences existed in the median number of diseased vessels (3, 3, and 3, respectively) or number of grafts per patient (3, 3, and 3, respectively). Composite outcome improved with increasing internal thoracic artery grafts, whether assessing unadjusted or risk-adjusted data. Compared with no internal thoracic artery graft, the adjusted hazard ratio was 0.79 (confidence interval, 0.74-0.83) for single internal thoracic artery grafting and 0.70 (confidence interval, 0.62-0.80) for multiple internal thoracic artery grafting (both P < .001), reducing risk by 21% and 30%, respectively.ConclusionsThis study confirms improved patient outcomes with multiple internal thoracic artery grafting, achieving half again as much benefit as single internal thoracic artery grafting alone. The data suggest that increasing application of multiple internal thoracic artery grafting should be encouraged to mitigate the inherent risks and costs of long-term cardiac events

A Tale of Two Current Sheets

I outline a new model of particle acceleration in the current sheet separating the closed from the open field lines in the force-free model of pulsar magnetospheres, based on reconnection at the light cylinder and "auroral" acceleration occurring in the return current channel that connects the light cylinder to the neutron star surface. I discuss recent studies of Pulsar Wind Nebulae, which find that pair outflow rates in excess of those predicted by existing theories of pair creation occur, and use those results to point out that dissipation of the magnetic field in a pulsar's wind upstream of the termination shock is restored to life as a viable model for the solution of the "$\sigma$" problem as a consequence of the lower wind 4-velocity implied by the larger mass loading.Comment: 17 pages, 6 figures, Invited Review, Proceedings of the "ICREA Workshop on The High-Energy Emission from Pulsars and their Systems", Sant Cugat, Spain, April 12-16, 201

Sox17 and ß-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mukherjee, S., Chaturvedi, P., Rankin, S. A., Fish, M. B., Wlizla, M., Paraiso, K. D., MacDonald, M., Chen, X., Weirauch, M. T., Blitz, I. L., Cho, K. W. Y., & Zorn, A. M. Sox17 and ß-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network. Elife, 9, (2020): e58029, doi:10.7554/eLife.58029.Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD073179) Ken WY Cho Aaron M Zorn National Institute of Diabetes and Digestive and Kidney Diseases (P30DK078392) Aaron M Zorn Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD093363) Aaron M Zor

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from the rupture of a blood vessel in the brain, leading to a mass of blood within the brain parenchyma. The injury causes a rapid inflammatory reaction that includes activation of the tissue-resident microglia and recruitment of blood-derived macrophages and other leukocytes. In this work, we investigated the specific responses of microglia following ICH with the aim of identifying pathways that may aid in recovery after brain injury. We used longitudinal transcriptional profiling of microglia in a murine model to determine the phenotype of microglia during the acute and resolution phases of ICH in vivo and found increases in TGF-β1 pathway activation during the resolution phase. We then confirmed that TGF-β1 treatment modulated inflammatory profiles of microglia in vitro. Moreover, TGF-β1 treatment following ICH decreased microglial Il6 gene expression in vivo and improved functional outcomes in the murine model. Finally, we observed that patients with early increases in plasma TGF-β1 concentrations had better outcomes 90 days after ICH, confirming the role of TGF-β1 in functional recovery from ICH. Taken together, our data show that TGF-β1 modulates microglia-mediated neuroinflammation after ICH and promotes functional recovery, suggesting that TGF-β1 may be a therapeutic target for acute brain injury

A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)

We present a measurement of time-dependent CP-violating asymmetries in neutral B meson decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data sample consists of 29.7 ${\rm fb}^{-1}$ recorded at the $\Upsilon(4S)$ resonance and 3.9 ${\rm fb}^{-1}$ off-resonance. One of the neutral B mesons, which are produced in pairs at the $\Upsilon(4S)$, is fully reconstructed in the CP decay modes $J/\psi K^0_S$, $\psi(2S) K^0_S$, $\chi_{c1} K^0_S$, $J/\psi K^{*0}$ ($K^{*0}\to K^0_S\pi^0$) and $J/\psi K^0_L$, or in flavor-eigenstate modes involving $D^{(*)}\pi/\rho/a_1$ and $J/\psi K^{*0}$ ($K^{*0}\to K^+\pi^-$). The flavor of the other neutral B meson is tagged at the time of its decay, mainly with the charge of identified leptons and kaons. The proper time elapsed between the decays is determined by measuring the distance between the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample finds $\Delta m_d = 0.516\pm 0.016 {\rm (stat)} \pm 0.010 {\rm (syst)} {\rm ps}^{-1}$. The value of the asymmetry amplitude $\sin2\beta$ is determined from a simultaneous maximum-likelihood fit to the time-difference distribution of the flavor-eigenstate sample and about 642 tagged $B^0$ decays in the CP-eigenstate modes. We find $\sin2\beta=0.59\pm 0.14 {\rm (stat)} \pm 0.05 {\rm (syst)}$, demonstrating that CP violation exists in the neutral B meson system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review