Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity.

Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, PTG deletion also blocked hepatic steatosis in HFD-fed mice and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis

The global integrated world ocean assessment: linking observations to science and policy across multiple scales

In 2004, the United Nations (UN) General Assembly approved a Regular Process to report on the environmental, economic and social aspects of the world's ocean. The Regular Process for Global Reporting and Assessment of the State of the Marine Environment, including Socioeconomic Aspects produced the first global integrated assessment of the marine environment in December 2016 (known as the first World Ocean Assessment). The second assessment, to be delivered in December 2020, will build on the baselines included in the first assessment, with a focus on establishing trends in the marine environment with relevance to global reporting needs such as those associated with the UN Sustainable Development Goals. Central to the assessment process and its outputs are two components. First, is the utilization of ocean observation and monitoring outputs and research to temporally assess physical, chemical, biological, social, economic and cultural components of coastal and marine environments to establish their current state, impacts currently affecting coastal and marine environments, responses to those impacts and associated ongoing trends. Second, is the knowledge brokering of ocean observations and associated research to provide key information that can be utilized and applied to address management and policy needs at local, regional and global scales. Through identifying both knowledge gaps and capacity needs, the assessment process also provides direction to policy makers for the future development and deployment of sustained observation systems that are required for enhancing knowledge and supporting national aspirations associated with the sustainable development of coastal and marine ecosystems. Input from the ocean observation community, managers and policy makers is critical for ensuring that the vital information required for supporting the science policy interface objectives of the Regular Process is included in the assessment. This community white paper discusses developments in linking ocean observations and science with policy achieved as part of the assessment process, and those required for providing strategic linkages into the future.Agência financiadora - United Nations Division for Ocean Affairs and the Law of the Seainfo:eu-repo/semantics/publishedVersio

Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma

Background: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas. Methods: Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m2 with intra-patient escalation to 10 mg/m2 from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study. Results: In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 − 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m2 at cycle 2, 2 decreased to 6 mg/m2, and 3 continued on 8 mg/m2. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 − 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 − 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 − 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders. Conclusions: This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response

Lithospheric structure of an Archean craton and adjacent mobile belt revealed from 2-D and 3-D inversion of magnetotelluric data : example from southern Congo craton in northern Namibia

Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Solid Earth 118 (2013): 4378–4397, doi:10.1002/jgrb.50258.Archean cratons, and the stitching Proterozoic orogenic belts on their flanks, form an integral part of the Southern Africa tectonic landscape. Of these, virtually nothing is known of the position and thickness of the southern boundary of the composite Congo craton and the Neoproterozoic Pan-African orogenic belt due to thick sedimentary cover. We present the first lithospheric-scale geophysical study of that cryptic boundary and define its geometry at depth. Our results are derived from two-dimensional (2-D) and three-dimensional (3-D) inversion of magnetotelluric data acquired along four semiparallel profiles crossing the Kalahari craton across the Damara-Ghanzi-Chobe belts (DGC) and extending into the Congo craton. Two-dimensional and three-dimensional electrical resistivity models show significant lateral variation in the crust and upper mantle across strike from the younger DGC orogen to the older adjacent cratons. We find Damara belt lithosphere to be more conductive and significantly thinner than that of the adjacent Congo craton. The Congo craton is characterized by very thick (to depths of  250 km) and resistive (i.e., cold) lithosphere. Resistive upper crustal features are interpreted as caused by igneous intrusions emplaced during Pan-African magmatism. Graphite-bearing calcite marbles and sulfides are widespread in the Damara belt and account for the high crustal conductivity in the Central Zone. The resistivity models provide new constraints on the southern extent of the greater Congo craton and suggest that the current boundary drawn on geological maps needs revision and that the craton should be extended further south.The SAMTEX consortiummembers (Dublin Institute for Advanced Studies, Woods Hole Oceanographic Institution, Council for Geoscience (South Africa), De Beers Group Services, The University of the Witwatersrand, Geological Survey of Namibia, Geological Survey of Botswana, Rio Tinto Mining and Exploration, BHP Billiton, Council for Scientific and Industrial Research (South Africa), and ABB Sweden) are thanked for their funding and logistical support during the four phases of data acquisition. This work is also supported by research grants from the National Science Foundation (EAR-0309584 and EAR-0455242 through the Continental Dynamics Program to R. L. Evans), the Department of Science and Technology, South Africa, and Science Foundation of Ireland (grant 05/RFP/ GEO001to A. G. Jones).2014-02-0

A Two-Dimensional Model with Chiral Condensates and Cooper Pairs Having QCD-like Phase Structure

We describe how a generalization of the original Gross-Neveu model from U(N) to O(N) flavor symmetry leads to the appearance of a pairing condensate at high density, in agreement with the conjectured phenomenon of color superconductivity in $(3+1)$-dimensional QCD. Moreover, the model displays a rich phase structure which closely resembles the one expected in two-flavor QCD.Comment: 11 pages, 1 fugure, Presented at TMU-Yale Symposium on Dynamics of Gauge Fields: An External Activity of APCTP, Tokyo, Japan, 13-15 Dec 199

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes

Hubble Space Telescope Imaging of the Circumstellar Nebulosity of T Tauri

Short-exposure Planetary Camera images of T Tauri have been obtained using broadband filters spanning the wavelength range 0.55-0.80 μm. The optically visible star lies very close to an arc of reflection nebulosity. The arc's northern arm extends approximately 5" from the star, while its southwestern arm appears brighter and extends only 2". The arc shows an approximate symmetry along an axis toward the west-northwest, the direction of Hind's Nebula and the blueshifted molecular outflow. The morphology of the reflected light is similar to models of scattered light within an illuminated, axisymmetric outflow cavity in a circumbinary envelope, viewed ≈ 45° from the outflow axis. However, our model images do not successfully account for the amount of limb brightening that is seen. No optical counterpart to the infrared companion is seen to a limiting magnitude of V = 19.6, which suggests A_V > 7 mag toward this source. There is no evidence for an optical tertiary, to a limiting ΔV = 5.1 mag fainter than the primary, at the position where such an object has been previously reported