Emerging anticancer targets for the design and synthesis of small molecule inhibitors: ADAM 10 and MDM2.

ADAMs (a disintegrin and metalloproteinase) are a family of type I transmembrane glycoproteins emerging as the major proteinase family that mediates ectodomain shedding of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. Recently, specific ADAMs were implicated in a number of diseases and in particular ADAM-10 overexpression was found to be involved in cancer. The pharmaceutical research has dedicated many efforts to the discovery of potent and selective inhibitors of this enzyme. Incyte Corporation in 2008 disclosed INCB 3619, a potent, selective and orally bioavailable ADAM-10 small molecule inhibitor able to block the shedding of HER ligands. In the first part of my thesis project I have synthesized new sulfonamide hydroxamate compounds, analogues of INCB3619 to be studied for their inhibitory properties (selectivity profile and potency of action) on Metzincin family (MMPs and ADAMs). In the second part of my thesis, I have developed a study on ligands active as inhibitors on MDM2-p53 interaction. P53 plays a protective roles in normal somatic tissues, constantly monitors cell integrity and homeostasis. MDM2 (murine double minute 2) regulates p53 through an autoregulatory feedback loop in which both proteins control mutually their cellular level. Low molecolar weight compounds which interacts with the deep cavity on the surface of the MDM2 molecule were designed

A FUSE View of the Stellar Winds of Planetary Nebula Central Stars

Since the IUE satellite produced a vast collection of high-resolution UV spectra of central stars of planetary nebulae (CSPNe), there has not been any further systematic study of the stellar winds of these stars. The high spectral resolution, sensitivity and large number of archival observations in the FUSE archive allow the study of the stellar winds of CSPNe in the far UV domain where lines of species spanning a wide excitation range can be observed. We present here a preliminary analysis of the P Cygni profiles of a sample of 60 CSPNe observed by FUSE. P Cygni profiles evidencing fast stellar winds with velocities between 200 and 4,300 km/s have been found in 40 CSPNe. In many cases, this is the first time that fast stellar winds have been reported for these PNe. A detailed study of these far-UV spectra is on-going.Comment: 4 pages, 3 figures; accepted, to appear in Publications of the Astronomical Society of Australi

Nonthermal Radio Emission from Planetary Nebulae

In a recent analysis of the radio emission from the planetary nebula A30, Dgani, Evans & White (1998) claim that the emission, located in the inner region, is probably dominated by nonthermal emission. We propose a model to explain this. We assume that the fast wind, blown by the central star of A30 carries a very weak magnetic field. The interaction of this wind with a cluster of dense condensations traps the magnetic field lines for a long time and stretches them, leading to a strong magnetic field. If relativistic particles are formed as the fast wind is shocked, then the enhanced magnetic field will result in nonthermal radio emission. The typical nonthermal radio flux at 1 GHz can be up to several milli-Jansky. In order to detect the nonthermal emission, the emitting region should be spatially resolved from the main optical nebula. We list other planetary nebulae which may possess nonthermal radio emission.Comment: 11 page

Abundances in Evolved Intermediate Mass Stars

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Nanodelivery of a functional membrane receptor to manipulate cellular phenotype.

Modification of membrane receptor makeup is one of the most efficient ways to control input-output signals but is usually achieved by expressing DNA or RNA-encoded proteins or by using other genome-editing methods, which can be technically challenging and produce unwanted side effects. Here we develop and validate a nanodelivery approach to transfer in vitro synthesized, functional membrane receptors into the plasma membrane of living cells. Using β2-adrenergic receptor (β2AR), a prototypical G-protein coupled receptor, as an example, we demonstrated efficient incorporation of a full-length β2AR into a variety of mammalian cells, which imparts pharmacologic control over cellular signaling and affects cellular phenotype in an ex-vivo wound-healing model. Our approach for nanodelivery of functional membrane receptors expands the current toolkit for DNA and RNA-free manipulation of cellular function. We expect this approach to be readily applicable to the synthesis and nanodelivery of other types of GPCRs and membrane receptors, opening new doors for therapeutic development at the intersection between synthetic biology and nanomedicine

Indications of a Large Fraction of Spectroscopic Binaries Among Nuclei of Planetary Nebulae

Previous work indicates that about 10% of planetary-nebula nuclei (PNNi) are photometrically variable short-period binaries with periods of hours to a few days. These systems have most likely descended from common-envelope (CE) interactions in initially much wider binaries. Population-synthesis studies suggest that these very close pairs could be the short-period tail of a much larger post-CE binary population with periods of up to a few months. We have initiated a radial-velocity (RV) survey of PNNi with the WIYN 3.5-m telescope and Hydra spectrograph, which is aimed at discovering these intermediate-period binaries. We present initial results showing that 10 out of 11 well-observed PNNi have variable RVs, suggesting that a significant binary population may be present. However, further observations are required because we have as yet been unable to fit our sparse measurements with definite orbital periods, and because some of the RV variability might be due to variations in the stellar winds of some of our PNNi.Comment: 11 pages, 1 table, no figures. Accepted by the Astrophysical Journal Letter

Engineering, applications, and future perspectives of GPCR-based genetically encoded fluorescent indicators for neuromodulators

This review explores the evolving landscape of G-protein-coupled receptor (GPCR)-based genetically encoded fluorescent indicators (GEFIs), with a focus on their development, structural components, engineering strategies, and applications. We highlight the unique features of this indicator class, emphasizing the importance of both the sensing domain (GPCR structure and activation mechanism) and the reporting domain (circularly permuted fluorescent protein (cpFP) structure and fluorescence modulation). Further, we discuss indicator engineering approaches, including the selection of suitable cpFPs and expression systems. Additionally, we showcase the diversity and flexibility of their application by presenting a summary of studies where such indicators were used. Along with all the advantages, we also focus on the current limitations as well as common misconceptions that arise when using these indicators. Finally, we discuss future directions in indicator engineering, including strategies for screening with increased throughput, optimization of the ligand-binding properties, structural insights, and spectral diversity

Stimulation of VTA dopamine inputs to LH upregulates orexin neuronal activity in a DRD2-dependent manner

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the LH. We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons, and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH. Optical VTA DA neuron stimulation is sufficient to elicit a Pavlovian-like dopamine transient in the NAc Dopamine in the LH encodes both negative and positive reward prediction errors Dopamine in the LH positively modulates orexin neuronal activity locally in a D2R dependent wa

PN fast winds: Temporal structure and stellar rotation

To diagnose the time-variable structure in the fast winds of central stars of planetary nebulae (CSPN), we present an analysis of P Cygni line profiles in FUSE satellite far-UV spectroscopic data. Archival spectra are retrieved to form time-series datasets for the H-rich CSPN NGC 6826, IC 418, IC 2149, IC 4593 and NGC 6543. Despite limitations due to the fragmented sampling of the time-series, we demonstrate that in all 5 CSPN the UV resonance lines are variable primarily due to the occurrence of blueward migrating discrete absorption components (DACs). Empirical (SEI) line-synthesis modelling is used to determine the range of fluctuations in radial optical depth, which are assigned to the temporal changes in large-scale wind structures. We argue that DACs are common in CSPN winds, and their empirical properties are akin to those of similar structures seen in the absorption troughs of massive OB stars. Constraints on PN central star rotation velocities are derived from Fast-Fourier Transform analysis of photospheric lines for our target stars. Favouring the causal role of co-rotating interaction regions, we explore connections between normalised DAC accelerations and rotation rates of PN central stars and O stars. The comparative properties suggest that the same physical mechanism is acting to generate large-scale structure in the line-driven winds in the two different settings.Comment: Accepted for publication in MNRAS; 10 pages, 5 figure