Early-stage star forming cloud cores in GLIMPSE Extended Green Objects (EGOs) as traced by organic species

In order to investigate the physical and chemical properties of massive star forming cores in early stages, we analyse the excitation and abundance of four organic species, CH3OH, CH3OCH3, HCOOCH3 and CH3CH2CN, toward 29 Extended Green Object (EGO) cloud cores that were observed by our previous single dish spectral line survey. The EGO cloud cores are found to have similar methanol J_3-J_2 rotation temperatures of ~44 K, a typical linear size of ~0.036 pc, and a typical beam averaged methanol abundance of several 10^(-9) (the beam corrected value could reach several 10^(-7)). The abundances of the latter three species, normalized by that of methanol, are found to be correlated also across a large variety of clouds such as EGO cloud cores, hot corinos, massive hot cores and Galactic Center clouds. The chemical properties of the EGO cloud cores lie between that of hot cores and hot corinos. However, the abundances and abundance ratios of the four species can not be satisfactorily explained by recent chemical models either among the EGO cloud cores or among the various types of cloud cores from literature

Analyzing Passenger Incidence Behavior in Heterogeneous Transit Services Using Smartcard Data and Schedule-Based Assignment

Passenger incidence (station arrival) behavior has been studied primarily to understand how changes to a transit service will affect passenger waiting times. The impact of one intervention (e.g., increasing frequency) could be overestimated when compared with another (e.g., improving reliability), depending on the assumption of incidence behavior. Understanding passenger incidence allows management decisions to be based on realistic behavioral assumptions. Earlier studies on passenger incidence chose their data samples from stations with a single service pattern such that the linking of passengers to services was straightforward. This choice of data samples simplifies the analysis but heavily limits the stations that can be studied. In any moderately complex network, many stations may have more than one service pattern. This limitation prevents the method from being systematically applied to the whole network and constrains its use in practice. This paper considers incidence behavior in stations with heterogeneous services and proposes a method for estimating incidence headway and waiting time by integrating disaggregate smartcard data with published timetables using schedule-based assignment. This method is applied to stations in the entire London Overground to demonstrate its practicality; incidence behavior varies across the network and across times of day and reflects headways and reliability. Incidence is much less timetable-dependent on the North London Line than on the other lines because of shorter headways and poorer reliability. Where incidence is timetable-dependent, passengers reduce their mean scheduled waiting time by more than 3 min compared with random incidence

The uncertain benefits of environmental reform in open economies

We compare the instantaneous and the long run effects of environmental reform in closed and open economies. Harmonization upward (decreasing distortions where they are most severe) or harmonization downward (increasing distortions where they are less severe), both tend to increase instantaneous world welfare. Environmental reform in a country with less severe distortions works against harmonization and may decrease welfare. Harmonization upward has more beneficial long-run effects than harmonization downward, and also provides higher expected instantaneous benefits if the current stock is uncertain. In the short run there is a conflict between environmental protection and reduction of unemployment, but in the long run the two goals are consistent

Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation.

Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2). We inhibited the kinase activities and reduced the abundances of ERK5 and MEK5, a MAPK kinase directly upstream of ERK5, in primary human vascular endothelial cells and monocytes, and found that ERK5 promoted inflammation induced by a broad range of microbial TLR agonists and by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, we found that inhibitors of MEK5 or ERK5 reduced the plasma concentrations of proinflammatory cytokines in mice challenged with TLR ligands or heat-killed Staphylococcus aureus, as well as in mice that underwent sterile lung ischemia-reperfusion injury. Finally, we found that inhibition of ERK5 protected endotoxemic mice from death. Together, our studies support a proinflammatory role for ERK5 in primary human endothelial cells and monocytes, and suggest that ERK5 is a potential therapeutic target in diverse disorders that cause inflammatory critical illness

Weak Sharp Minima on Riemannian Manifolds

This is the first paper dealing with the study of weak sharp minima for constrained optimization problems on Riemannian manifolds, which are important in many applications. We consider the notions of local weak sharp minima, boundedly weak sharp minima, and global weak sharp minima for such problems and obtain their complete characterizations in the case of convex problems on finite-dimensional Riemannian manifolds and their Hadamard counterparts. A number of the results obtained in this paper are also new for the case of conventional problems in linear spaces. Our methods involve appropriate tools of variational analysis and generalized differentiation on Riemannian and Hadamard manifolds developed and efficiently implemented in this paper

Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins

Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production

Surface chemistry and structure manipulation of graphene-related materials to address the challenges of electrochemical energy storage

Energy storage devices are important components in portable electronics, electric vehicles, and the electrical distribution grid. Batteries and supercapacitors have achieved great success as the spearhead of electrochemical energy storage devices, but need to be further developed in order to meet the ever-increasing energy demands, especially attaining higher power and energy density, and longer cycling life. Rational design of electrode materials plays a critical role in developing energy storage systems with higher performance. Graphene, the well-known 2D allotrope of carbon, with a unique structure and excellent properties has been considered a “magic” material with its high energy storage capability, which can not only aid in addressing the issues of the state-of-the-art lithium-ion batteries and supercapacitors, but also be crucial in the so-called post Li-ion battery era covering different technologies, e.g., sodium ion batteries, lithium-sulfur batteries, structural batteries, and hybrid supercapacitors. In this feature article, we provide a comprehensive overview of the strategies developed in our research to create graphene-based composite electrodes with better ionic conductivity, electron mobility, specific surface area, mechanical properties, and device performance than state-of-the-art electrodes. We summarize the strategies of structure manipulation and surface modification with specific focus on tackling the existing challenges in electrodes for batteries and supercapacitors by exploiting the unique properties of graphene-related materials

PO-099 Targeting the mitogen activated protein kinase ERK5 in human melanoma

Introduction Melanoma is the most aggressive skin cancer with a poor prognosis in advanced stages. Available treatments for melanoma are unsatisfactory, because rapidly lead to an acquired resistance in the majority of cases. Therefore, there is urgent need to identify novel possible targets involved in melanoma growth. ERK5/BMK1 is a member of the Mitogen-Activated Protein Kinases (MAPK) family and regulates cell functions critical for tumour development. Indeed, several studies reported a direct involvement of ERK5 in several types of cancer including prostate and breast cancer and hepatocellular carcinoma. However, no data have been reported about a possible role of ERK5 in melanoma. Material and methods Cell lines and patient-derived primary melanoma cells (wild type B-RAF: SSM2c and M26c; BRAFV600E: A375, SK-Mel-5, SK-Mel-28, 501-Mel, expressing; NRASQ61R: SK-Mel-2; MeWo) have been used for in vitro and in vivo experiments. HEK293T cells were used for protein overexpression. ERK5 inhibition was achieved using ERK5 and MEK5 inhibitors or lentiviral vectors encoding shRNA specific for ERK5. BRAF inhibition was achieved using Vemurafenib, a BRAFV600E inhibitor. Results and discussions In silico data analysis indicated that components of the ERK5 pathway are upregulated in up to 47% melanoma patients. Accordingly, we found that ERK5 is consistently expressed and active in commercial and patients derived melanoma cell lines. On that basis, we investigated the role of ERK5 in melanoma cell growth. In vitro , pharmacological or genetic inhibition of ERK5 decreased the number of viable cells in several melanoma cell lines. Moreover, xenografts performed using LV-shERK5-transduced A375 or SSM2c cells showed a reduced tumour growth when compared to those transduced with control LV-shC. We also found that oncogenic BRAF positively regulates expression, phosphorylation and nuclear localization of exogenous and endogenous ERK5. Accordingly, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Furthermore, the combination of MEK5 or ERK5 inhibitors with vemurafenib is more effective than single treatments in reducing 2D colony formation and growth of BRAFV600E melanoma cells and xenografts. Conclusion Our results identify ERK5 as a critical regulator of melanoma growth in vitro and in vivo , and point toward the possibility of targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, for the treatment of melanoma