Expression profiling of skeletal muscle following acute and chronic β2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm

Background Systemic administration of β-adrenoceptor (β-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of β-AR signaling has been highlighted by the inability of β1-3-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic) administration of the β2-AR agonist formoterol. Results Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the β2-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype) were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h) and chronic administration (1-28 days) of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc) was observed following acute and chronic administration of formoterol. Acute (but not chronic) administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol administration also appeared to influence some genes associated with the peripheral regulation of circadian rhythm (including nuclear factor interleukin 3 regulated, D site albumin promoter binding protein, and cryptochrome 2). Conclusion This is the first study to utilize gene expression profiling to examine global gene expression in response to acute β2-AR agonist treatment of skeletal muscle. In summary, systemic administration of a β2-AR agonist had a profound effect on global gene expression in skeletal muscle. In terms of hypertrophy, β2-AR agonist treatment altered the expression of several genes associated with myostatin signaling, a previously unreported effect of β-AR signaling in skeletal muscle. This study also demonstrates a β2-AR agonist regulation of circadian rhythm genes, indicating crosstalk between β-AR signaling and circadian cycling in skeletal muscle. Gene expression alterations discovered in this study provides insight into many of the underlying changes in gene expression that mediate β-AR induced skeletal muscle hypertrophy and altered metabolism

The role of science in physical natural hazard assessment : report to the UK Government by the Natural Hazard Working Group

Following the tragic Asian tsunami on 26 December 2004, the Prime Minister asked the Government’s Chief Scientific Adviser, Sir David King, to convene a group of experts (the Natural Hazard Working Group) to advise on the mechanisms that could and should be established for the detection and early warning of global physical natural hazards. 2. The Group was asked to examine physical hazards which have high global or regional impact and for which an appropriate early warning system could be put in place. It was also asked to consider the global natural hazard frameworks currently in place and under development and their effectiveness in using scientific evidence; to consider whether there is an existing appropriate international body to pull together the international science community to advise governments on the systems that need to be put in place, and to advise on research needed to fill current gaps in knowledge. The Group was asked to make recommendations on whether a new body was needed, or whether other arrangements would be more effective

Systematic analysis of tumour cell-extracellular matrix adhesion identifies independent prognostic factors in breast cancer.

Tumour cell-extracellular matrix (ECM) interactions are fundamental for discrete steps in breast cancer progression. In particular, cancer cell adhesion to ECM proteins present in the microenvironment is critical for accelerating tumour growth and facilitating metastatic spread. To assess the utility of tumour cell-ECM adhesion as a means for discovering prognostic factors in breast cancer survival, here we perform a systematic phenotypic screen and characterise the adhesion properties of a panel of human HER2 amplified breast cancer cell lines across six ECM proteins commonly deregulated in breast cancer. We determine a gene expression signature that defines a subset of cell lines displaying impaired adhesion to laminin. Cells with impaired laminin adhesion showed an enrichment in genes associated with cell motility and molecular pathways linked to cytokine signalling and inflammation. Evaluation of this gene set in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort of 1,964 patients identifies the F12 and STC2 genes as independent prognostic factors for overall survival in breast cancer. Our study demonstrates the potential of in vitro cell adhesion screens as a novel approach for identifying prognostic factors for disease outcome

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

© 2016 The Author(s) Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies

Antibacterial Solution Using Cinnamomum verum (Cinammon) and Cympobogon citratus (Lemongrass) Essential Oils with Hydrogen Peroxide Against Staphylococcus aureus and Escherichia coli

Amidst the pandemic, millions of impoverished Filipinos lack sufficient access to sanitation services that protect them from bacterial infections. As such, this study endeavored to formulate a disinfectant spray of hydrogen peroxide and varying concentrations of lemongrass (Cymbopogon citratus) and cinnamon (Cinnamomum verum) essential oils to produce a maximally effective solution. Due to their natural origin, these essential oils were chosen for their extensive antibacterial properties, affordable price, and low toxicity levels. Six disinfectant spray solutions containing different concentrations of either essential oil were tested against Staphylococcus aureus and Escherichia coli bacteria through the agar disk diffusion method. After analyzing the data using mean, standard deviation, and MANOVA, it was found that including cinnamon and lemongrass essential oil had no statistically significant effect on the antibacterial activity of the hydrogen peroxide solution, regardless of the concentration of essential oil used, p \u3e 0.05. However, the lemongrass samples were slightly more effective than the cinnamon solutions. Thus, future researchers are encouraged to investigate other components that can potentially increase the antibacterial activity of a disinfectant spray

Israel and a sports boycott: Antisemitic? Anti-Zionist?

The paper identifies and summarises the debates that surround the place of Israel in international sport and assesses how that place is increasingly being contested. The long-standing conflict between Israel and Palestine has begun to manifest in the world of sport with the paper sketching the debates of those calling for, and those opposed to, sport sanctions/boycott of Israel until the ‘Palestinian Question’ is resolved. Five related tasks are addressed: first, to summarise the call for sanctions/boycott emanating from the Boycott, Disinvestment and Sanctions movement. Second, to explore how this call is establishing itself in the world of sport. The responses of those opposed to any form of sanction/boycott are then considered. The confusion that surrounds the term antisemitism is addressed and the relationship between (anti-) Zionism and antisemitism unpacked. The discussion concludes with an assessment of the claim made by the Israeli state, and its supporters, that any action against the country’s participation in international sport would be an act of antisemitism. Offering a timely, integrated summary of the heated debates that surround the Israel/Palestine conflict, the paper contributes to a wider discussion on the relationship between sport and politics

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies

Showing Israel the red card. Activists engaged in pro-Palestinian sport-related campaigns

© 2017 Informa UK Limited, trading as Taylor & Francis Group. This article explores the motivations of activists involved in pro-Palestinian sports-based campaigns. The activists’ intention is to bring pressure to bear upon Israel until it complies with international law and supports the rights of Palestinian people under the universal principles of human rights. In response to expressions of pro-Palestinian solidarity, the Israeli state and its supporters are interpreting such activity as a ‘new’ manifestation of ‘old’ antisemitism. In seeking to assess whether such activity is informed by antisemitism, 10 semi-structured interviews were conducted with activists to examine their motives. Their political biographies were explored as were their views on the use of sport as platform to express support for the Palestinian people and/or their displeasure at Israeli participation in international sport. One central theme was the activists’ responses to the suggestion that they were motivated by antisemitism. A qualitative content analysis of the interview transcripts revealed a shared observation that the accusation of antisemitism was a ‘shameless tactic’ employed by those seeking to cover up the ongoing injustices experienced by the Palestinian people. Sport was seen as a legitimate platform for political activity, to raise public awareness and to put pressure on the Israeli state. The findings contribute to a better understanding of activist motivations, the use of sport as a political platform and the challenges facing sport and its governing bodies

Seismicity along the Pacific-North American plate boundary in California and western Nevada, 1980-81

Beginning in 1980, the number and distribution of telemetered, high-gain seismic stations operated in California and western Nevada provided the capability for locating earthquakes of M ≥ 2.0 occurring throughout the broadly-deforming Pacific-North American plate boundary from the Salton Trough to the Mendocino triple junction and as far inland as the western Great Basin. Four networks combine to provide this capability: (1) the 300-station Central California Network operated by the U.S. Geological Survey from Menlo Park, CA; (2) the 200-station Southern California Network operated jointly by the California Institute of Technology (CIT) and the U. S. Geological Survey from Pasadena, CA; (3) the 40-station Western Nevada-Eastern California Network operated by the University of Nevada from Reno, NV; and (4) the 55-station Southern Nevada Network operated by the U.S. Geological Survey from Golden, CO. The distribution of earthquake hypocenters located by this combination of networks for 1980 and 1981 brings into focus detailed seismicity patterns within the broad bands of earthquake activity that have persisted for SO years or more based on locations of M ≥ 3 earthquakes from the regional networks operated by CIT and the University of California, Berkeley, since the early 1930's. The precise focal parameters of M ≥ 2.0 earthquakes afforded by these four telemetered networks provide critical constraints on the kinematics of seismogenic deformation of the western margin of the North American plate adjacent to the San Andreas transform-fault system